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Query Topic: Metabolic memory Diabetes

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diabetic retinopathy(35)

Epigenetics and Mitochondrial Stability in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.
Retinopathy continues to progress even when diabetic patients try to control their blood sugar, but the molecular mechanism of this 'metabolic memory' phenomenon remains elusive. Retinal mitochondria remain damaged and vicious cycle of free radicals continues to self-propagate. DNA methylation suppresses gene expression, and diabetes activates DNA methylation machinery. Our aim was to investigate the role of DNA methylation in continued compromised mitochondrial dynamics and genomic stability in diabetic retinopathy Using retinal endothelial cells, incubated in 20 mM glucose for four days, followed by 5 mM glucose for four days, and retinal microvessels from streptozotocin-induced diabetic rats in poor glycemia for four months, followed by normal glycemia for four additional months, DNA methylation of mitochondrial fusion and mismatch repair proteins, Mfn2 and Mlh1 respectively, was determined. Retinopathy was detected in trypsin-digested microvasculature. Re-institution of good glycemia had no beneficial effect on hypermethylation of Mfn2 and Mlh1 and retinal function (electroretinogram), and the  retinopathy continued to progress. However, intervention of good glycemia directly with DNA methylation inhibitors (Azacytidine or Dnmt1-siRNA), prevented Mfn2 and Mlh1 hypermethylation, and ameliorated retinal dysfunction and diabetic retinopathy Thus, direct regulation of DNA methylation can prevent/reverse diabetic retinopathy by maintaining mitochondrial dynamics and DNA stability, and prevent retinal functional damage.
Publication Date: 2020-04-22 00:00:00
Journal: Scientific reports

cognitive impairment(42)

The aim: Was to improve the effectiveness of the treatment of cognitive impairment in patients with hypertension and type 2 diabetes. Materials and methods: 56 patients (11 women and 45 men, average age 61.7 ± 4.3 years) with hypertension II, 2 degree and type 2 diabetes (average severity, subcompensation stage) were examined. 40 patients had moderate CI and 16 had mild CI. After the examination, the patients were divided into two groups and treated accordingly. The control group consisted of 20 healthy individuals. Results: Vascular brain lesions that cause hypertension and diabetes very often lead to impaired cognitive function whose therapeutic correction has received little attention, especially in the pre-operative stages. 56 patients have been examined to study the efficacy and safety a combination of Phenibut and Ipidacrine as an additional therapy to standard basic treatment (antihypertensive and hypoglycemic) for the correction of cognitive dysfunction in patients with comorbidity of hypertension and type 2 diabetes mellitus. Conclusions: One month after the beginning of the treatment, an improvement in psycho-emotional state and psychometric parameters was identified, which was manifested by an increase in concentration of attention, memory, psychomotor functions, speech activity together with normalization of blood pressure and metabolic parameters.
Publication Date: 2021-01-18 00:00:00
Journal: Wiadomosci lekarskie (Warsaw, Poland : 1960)

2 diabetes mellitus(22)

Type 3 Diabetes Mellitus: A Link Between Alzheimer's Disease and Type 2 Diabetes Mellitus.
Chronic diseases, as their name suggests, are progressive and can have overlapping features. Similar to this, Alzheimer's disease (AD) and diabetes mellitus (DM) fall into the category of chronic degenerative diseases. The global burden of these two ailments is manifold; hence, it seems important to view the pathophysiologic mechanisms of DM in the worsening of AD. Genetic as well as environmental factors are seen to play a role in the disease pathogenesis. Several genes, metabolic pathways, electrolytes, and dietary habits are seen to hasten brain atrophy. Lying behind this is the accumulation of amyloid precursor and tau - the misfolded proteins - within the brain substance. This mechanism is usually innate to AD itself, but the impact of insulin resistance, disturbing the homeostatic milieu, is seen as a powerful contributing factor aggravating the neuronal loss impairing an individual's memory. Since this neuronal loss is permanent, it may lead to complications as seen with AD. To reach a consensus, we conducted an electronic literature review search using different databases. This aided us in understanding the common aspects between AD and DM on genetic, molecular, cellular levels, as well as the impact of minerals and diet on the disease manifestation. We also found that despite exceptional work, additional efforts are needed to explore the relationship between the two entities. This will help physicians, researchers, and pharmaceuticals to frame remedies targeting the cause and avoid the progression of AD.
Publication Date: 2021-01-05 00:00:00
Journal: Cureus

metabolic syndrome(39)

Biochemical and Behavioral Consequences of Ethanol Intake in a Mouse Model of Metabolic Syndrome.
Ethanol abuse is a common issue in individuals with sedentary lifestyles, unbalanced diets, and metabolic syndrome Both ethanol abuse and metabolic syndrome have negative impacts on the central nervous system, with effects including cognitive impairment and brain oxidative status deterioration. The combined effects of ethanol abuse and metabolic syndrome at a central level have not yet been elucidated in detail. Thus, this work aims to determine the effects of ethanol intake on a mouse model of metabolic syndrome at the behavioral and biochemical levels. Seven-week-old male control (B6.V-Lep ob/+JRj) and leptin-deficient ( metabolic syndrome (B6.V-Lep ob/obJRj) mice were used in the study. Animals were divided into four groups: control, ethanol, obese, and obese-ethanol. Ethanol consumption was monitored for 6 weeks. Basal glycemia, insulin, and glucose overload tests were performed. To assess short- and long-term memory, an object recognition test was used. In order to assess oxidative status in mouse brain samples, antioxidant enzyme activity was analyzed with regard to glutathione peroxidase, glutathione reductase, glutathione, glutathione disulfide, lipid peroxidation products, and malondialdehyde. Ethanol intake modulated the insulin response and impaired the oxidative status in the ob mouse brain.
Publication Date: 2021-01-21 00:00:00
Journal: International journal of molecular sciences

insulin resistance(35)

Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review.
Insulin plays a major neuroprotective and trophic function for cerebral cell population, thus countering apoptosis, beta-amyloid toxicity, and oxidative stress; favoring neuronal survival; and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer's disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events, especially in the late-onset form. As a bridge between AD and type 2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the insulin response substrate (IRS)-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve insulin axis physiology, mitochondrial biogenesis-integral functionality, and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyze inflammation. Central and/or peripheral inflammation may account for a local flood of proinflammatory cytokines that along with astrogliosis amplify insulin resistance mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor, pro-senescent factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.
Publication Date: 2020-11-24 00:00:00
Journal: Frontiers in endocrinology

cognitive function(31)

Associations between cognitive function, metabolic factors and depression: A prospective study in Quebec, Canada.
Metabolic risk factors, low cognitive function and history of depression are known risk factors for future depressive episodes. This paper aims to evaluate the potential interactions between these factors on the risk of a major depressive episodes in middle-age. Baseline and follow-up data from a population-based study of Quebec, Canada were used. The sample consisted of 1788 adults between 40 and 69 years of age without diabetes. Cognitive function and metabolic risk factors were assessed at baseline. Three cognitive domains were assessed: processing speed, episodic memory and executive function. History of depression was assessed five years later by a clinical interview. Logistic regression analysis was conducted to evaluate interactions between individual metabolic factors, low cognitive function and depression history. Participants with a comorbidity of at least one metabolic factor, history of depression and low cognitive function had the highest risk of experiencing a depressive episode in middle age. The highest risk was observed in individuals with abdominal obesity, low cognitive function and a history of depression (OR= 8.66, 95% CI 3.83-19.59). The risks for those with abdominal obesity only, depression history only, and low cognitive function were 1.20 (95%CI 0.71-2.02), 3.10 (95%CI 1.81-5.24), and 1.39 (95%CI 0.72-2.67), respectively. Depression was only assessed at follow-up. Metabolic risk factors comorbid with low cognitive function in middle-aged individuals with a history of depression were associated with an increased risk of a future depressive episode. This study highlights the importance of screening for metabolic and cognitive comorbidities in patients with a history of depression.
Publication Date: 2021-02-02 00:00:00
Journal: Journal of affective disorders

diabetic rats(18)

Neuroprotective Effect of Syringic Acid by Modulation of Oxidative Stress and Mitochondrial Mass in Diabetic Rats.
Diabetes is a metabolic complaint associated with oxidative stress and dysfunction of mitochondria. One of the most common complications of diabetes mellitus is neuropathy. This study evaluated the possible neuroprotective effects of syringic acid (SYR), a natural polyphenolic derivative of benzoic acid, on oxidative damage and mitochondria in the brain, spinal cord, and sciatic nerve of streptozotocin-induced diabetic rats Different groups of rats including normal control, diabetics (induced by streptozotocin), diabetic groups treated with 25, 50, and 100 mg/kg of SYR, and non-diabetic group treated with only 100 mg/kg of SYR were treated for 6 weeks. Learning and memory function, physical coordination, and acetylcholinesterase (AChE) and antioxidant indexes, as well as mRNA expression of mitochondrial biogenesis, were measured in the brain, spinal cord, and sciatic nerves. Diabetic rats treated with 100 mg/kg SYR exhibited significantly improved learning, memory, and movement deficiency (
Publication Date: 2021-01-19 00:00:00
Journal: BioMed research international

glycation end products(11)

Advanced Glycation End Products, Oxidation Products, and the Extent of Atherosclerosis During the VA Diabetes Trial and Follow-up Study.
To determine whether plasma levels of advanced glycation end products and oxidation products play a role in the development of atherosclerosis in patients with type 2 diabetes (T2D) over nearly 10 years of the VA Diabetes Trial and Follow-up Study. Baseline plasma levels of methylglyoxal hydroimidazolone, Nε-carboxymethyl lysine, Nε-carboxyethyl lysine (CEL), 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone (G-H1), 2-aminoadipic acid (2-AAA), and methionine sulfoxide were measured in a total of 411 participants, who underwent ultrasound assessment of carotid intima-media thickness (CIMT), and computed tomography scanning of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) after an average of 10 years of follow-up. In risk factor-adjusted multivariable regression models, G-H1 was associated with the extent of CIMT and CAC. In addition, 2-AAA was strongly associated with the extent of CAC, and CEL was strongly associated with the extent of AAC. The combination of specific advanced glycation end products and oxidation products (G-H1 and 2-AAA) was strongly associated with all measures of subclinical atherosclerosis. Specific advanced glycation end products and metabolic oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the "negative metabolic memory" of macrovascular complications in people with long-standing T2D.
Publication Date: 2017-02-06 00:00:00
Journal: Diabetes care

cognitive decline(21)

Insulin sensitivity predicts cognitive decline in individuals with prediabetes.
Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment). We investigated longitudinal data from participants of the 'Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration' Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer's Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1-3: 2.2-4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%-6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects. Insulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition. Insulin resistance rather than sole elevation of blood glucose predicts cognitive decline specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.
Publication Date: 2020-11-19 00:00:00
Journal: BMJ open diabetes research & care

products ages(7)

Advanced glycation end products (AGEs), oxidative stress and diabetic retinopathy.
Diabetic retinopathy is a common and devastating microvascular complication in diabetes and is a leading cause of acquired blindness among the people of occupational age. Recent large landmark clinical studies have shown that intensive control of blood glucose or blood pressure (BP) reduces the risk for diabetic retinopathy. However, the strict control of blood glucose or BP is often difficult to maintain. Further, current therapeutic options for the treatment of sight-threatening proliferative diabetic retinopathy (PDR) such as photocoagulation and vitrectomy are limited by considerable side effects and far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target PDR is actually desired for most patients with diabetes. Although various biochemical and hemodynamic pathways are implicated in the diabetic retinopathy, recent clinical study has substantiated the concept of 'metabolic memory', and suggested the active involvement of advanced glycation end products (AGEs) and oxidative stress in this sight-threatening disorder. We, along with others, have recently found that pigment epithelium-derived factor (PEDF), a glycoprotein with complex neuroprotective, anti-angiogenic, anti-oxidative, and anti-inflammatory properties, could potentially be exploited as a therapeutic option for the treatment of diabetic retinopathy. Therefore, this article summarizes the role of AGEs and oxidative stress in diabetic retinopathy and discusses a potential utility of the blockade of this system by PEDF in this devastating disorder.
Publication Date: 2010-10-14 00:00:00
Journal: Current pharmaceutical biotechnology


The bile acid TUDCA improves glucose metabolism in streptozotocin-induced Alzheimer's disease mice model.
Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of dementia. According to predictions of the World Health Organization, more than 150 million people worldwide will suffer from dementia by 2050. An increasing number of studies have associated AD with type 2 diabetes mellitus (T2DM), since most of the features found in T2DM are also observed in AD, such as insulin resistance and glucose intolerance. In this sense, some bile acids have emerged as new therapeutic targets to treat AD and metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA), reduces amyloid oligomer accumulation and improves cognition in APP/PS1 mice model of AD, and also improves glucose-insulin homeostasis in obese and type 2 diabetic mice. Herein, we investigated the effect of TUDCA upon glucose metabolism in streptozotocin-induced AD mice model (Stz). The Stz mice that received 300 mg/kg TUDCA during 10 days (Stz + TUDCA), showed improvement in glucose tolerance and insulin sensitivity, reduced fasted and fed glycemia, increased islet mass and β-cell area, as well as increased glucose-stimulated insulin secretion, compared with Stz mice that received only PBS. Stz + TUDCA mice also displayed lower neuroinflammation, reduced protein content of amyloid oligomer in the hippocampus, improved memory test and increased protein content of insulin receptor β-subunit in the hippocampus. In conclusion, TUDCA treatment enhanced glucose homeostasis in the streptozotocin-induced Alzheimer's disease mice model pointing this bile acid as a good strategy to counteract glucose homeostasis disturbance in AD pathology.
Publication Date: 2020-12-16 00:00:00
Journal: Molecular and cellular endocrinology

diabetic mice(14)

Co-administration of berberine/gypenosides/bifendate ameliorates metabolic disturbance but not memory impairment in type 2 diabetic mice.
Cognitive impairment is a well-known complication of Type 2 diabetes mellitus (T2DM) characterized by cellular insulin resistance, chronic inflammation, and metabolic disturbances. Berberine, gypenosides and bifendate are traditional Chinese herbal medicines with multiple pharmacological activities including anti-inflammation, anti-oxidant, metabolism improvement and memory improvement. To investigate whether they have synergistic effect on T2DM metabolic syndrome and associated memory impairment, we measured in this study the effect of a low dose of berberine/gypenosides/bifendate (BGB) co-administration on metabolism and memory performance of T2DM model mice. We found that BGB co-administration ameliorated metabolic abnormalities of both high-fat diet/streptozotocin (STZ)-induced T2DM mice and
Publication Date: 2021-02-05 00:00:00
Journal: Heliyon


Legacy effect of intensive glucose control on major adverse cardiovascular outcome: Systematic review and meta-analyses of trials according to different scenarios.
Early and intensive glycaemic control provides long-term protection against the development of microvascular complications, a phenomenon defined legacy effect. Whether a legacy effect of high glucose exists also on macrovascular endpoints is uncertain. We performed a systematic review of both randomized clinical trials (RCT)s and observational studies pertinent to the research question. We searched PubMed, Embase, Scopus and the Cochrane database up to January 31th 2020. Eligibility criteria for RCTs were: 1 - efficacy assessment of intensive glucose lowering treatment vs a less-stringent/conventional treatment; 2 - the inclusion of a post-active phase, observational follow-up; 3 - enrolment of patients with T1DM, pre-diabetes, and T2DM; and 4 - data report on major adverse cardiovascular events (MACE) incidence, which was the primary endpoint of this meta-analysis. We performed multiple meta-analyses of the available RCTs according to different scenarios considering the type of diabetes, diabetes duration, the presence of previous cardiovascular events, follow-up extension, and the incidence of MACE recorded only during the observational, post-active phase of the trials. Results from observational studies reporting the association between HbA1c levels during the first year after diabetes diagnosis and subsequent MACE incidence were also collected and are reported narratively. We included data from 7 RCTs and 40,346 patients. The intensive glucose-lowering approach significantly decrease the incidence of MACE compared with conventional treatment (OR 0.86, CI 0.77-0.96; p = 0.007) when considering all the available studies, with a more consistent effect (OR 0.73, CI 0.56-0.94; p = 0.01) in the case of RCTs enrolling patients with diabetes duration <10 years, and an even more pronounced protection (OR 0.64, 48 CI 0.48, 0.86; p = 0.003) when analysing only RCTs enrolling patients without previous cardiovascular events at baseline. Considering only RCTs with a post-trial follow-up >10 years also yielded a relevant beneficial effect of the intensive approach (OR 0.71, CI 0.57, 0.88; p = 0.002). On the other hand, no effect was observed (OR 0.99, CI 0.92, 1.06; p = 0.81) when considering only the events recorded during the post-active, observational phases of the trials. Observational studies showed that HbA1c values >6.5% or 7% during the first year of diabetes diagnosis are associated with a higher incidence of late MACE with increased risk ranging from 19 up to 64%, according to the different study design and HbA1c stratification. These results support the recommendation regarding glucose-lowering treatment intensification in order to decrease the probability of having a macrovascular event in patients with short diabetes duration, no prevalent cardiovascular diseases, and long life-expectancy. On the other side, data from RCTs do not support the existence of a protective legacy effect on the macrovasculature beyond the period of intensive glycaemic treatment.
Publication Date: 2020-07-07 00:00:00
Journal: Metabolism: clinical and experimental


Epigenetic Mechanisms in Diabetic Vascular Complications and Metabolic Memory: The 2020 Edwin Bierman Award Lecture.
Macrovascular complications such as atherosclerosis, myocardial infarction and stroke, and microvascular complications such as nephropathy, retinopathy, and neuropathy are the major causes of increased morbidity and mortality in both type 1 and type 2 diabetes. Increased inflammation, oxidative stress, and fibrosis are common features in most diabetes complications. Although extensive studies have examined the biochemical pathways leading to the expression of inflammatory, profibrotic, and other pathological genes, as well as genetic factors related to diabetes and associated complications, much less is known about the contribution of epigenetic changes that occur without alterations in the DNA sequence. Environmental factors, lifestyles, and improper diet implicated in diabetes can affect epigenetic states. Epigenetic modifications, including DNA methylation and histone modifications, can alter gene transcription in response to environmental stimuli and cooperate with noncoding RNAs. These epigenetic modifications have been observed in various target cells under diabetic conditions. Moreover, epigenetic has also been implicated in the phenomenon of metabolic memory observed in clinic trials and animal studies, in which prior episodes of poor glycemic control can confer continued risk of complications despite subsequent glucose normalization. Epigenome-wide association studies in cohorts with diabetes are uncovering epigenotype variations that provide new insights into diabetic vascular complications. Here, I discuss the role of epigenetic and noncoding RNAs in diabetes complications and metabolic memory, and their translation potential to serve as biomarkers and drug targets to improve clinical management of diabetic vascular complications.
Publication Date: 2021-01-22 00:00:00
Journal: Diabetes


Cucurbitacin B Suppresses Hyperglycemia Associated with a High Sugar Diet and Promotes Sleep in
Secondary metabolites enable plants to protect themselves from herbivorous insects. Among these, cucurbitacin B (cuc-B) is a bitter-tasting compound with promising pharmacological potential. Dietary exposure to cuc-B lowered the hemolymph glucose levels of
Publication Date: 2021-02-06 00:00:00
Journal: Molecules and cells


Treatment of Diabetic Kidney Disease: Current and Future.
Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatment is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2-related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.
Publication Date: 2021-01-30 00:00:00
Journal: Diabetes & metabolism journal


Obesity Impairs Short-Term and Working Memory through Gut Microbial Metabolism of Aromatic Amino Acids.
The gut microbiome has been linked to fear extinction learning in animal models. Here, we aimed to explore the gut microbiome and memory domains according to obesity status. A specific microbiome profile associated with short-term memory, working memory, and the volume of the hippocampus and frontal regions of the brain differentially in human subjects with and without obesity. Plasma and fecal levels of aromatic amino acids, their catabolites, and vegetable-derived compounds were longitudinally associated with short-term and working memory. Functionally, microbiota transplantation from human subjects with obesity led to decreased memory scores in mice, aligning this trait from humans with that of recipient mice. RNA sequencing of the medial prefrontal cortex of mice revealed that short-term memory associated with aromatic amino acid pathways, inflammatory genes, and clusters of bacterial species. These results highlight the potential therapeutic value of targeting the gut microbiota for memory impairment, specifically in subjects with obesity.
Publication Date: 2020-10-08 00:00:00
Journal: Cell metabolism

gestational diabetes(14)

Animal models of gestational diabetes: characteristics and consequences to the brain and behavior of the offspring.
Gestational diabetes (GD) is the glucose intolerance that occurs during pregnancy. Mothers who develop diabetes during gestation are at increased risk of developing type 2 diabetes mellitus (T2DM) later in life, and the risk of adverse fetal and neonatal outcomes are also increased as a function of maternal hyperglycemia. Infants who are exposed to fetal hyperglycemia show an increased risk of becoming obese and developing T2DM later in life. Due to the need of new research on this field, and the difficulty of performing studies in human brain, studies using experimental models are necessary to suggest possible ways to avoid or inhibit offspring brain damage or harmful metabolic alterations. Here, it was made a review about the characteristics of the main animal models of GD, and what are the consequences to the brain and behavior of the offspring. In many experimental models, either by pharmacological induction, diet manipulation, or in the use of transgenic animals, glycemic conditions are severe. S961, a selective insulin receptor antagonist, revealed an increased fasting blood glucose level and glucose intolerance during mid-gestation, which returned to basal levels postpartum in mice. GD contributes to offspring neuroinflammation, influences neuronal distribution in central nervous system (CNS), and apoptosis during embryogenesis, which in turn may contribute to changes in behavior and memory in adult life and aging. The usage of animal models to study GD allows to examine extensively the characteristics of this condition, the molecular mechanisms involved and the consequences to the brain and behavior of the offspring.
Publication Date: 2021-01-06 00:00:00
Journal: Metabolic brain disease

high-fat diet(18)

Sex-specific effects of high-fat diet on cognitive impairment in a mouse model of VCID.
Mid-life metabolic disease (ie, obesity, diabetes, and prediabetes) causes vascular dysfunction and is a risk factor for vascular contributions to cognitive impairment and dementia (VCID), particularly in women. Using middle-aged mice, we modeled metabolic disease (obesity/prediabetes) via chronic high-fat (HF) diet and modeled VCID via unilateral common carotid artery occlusion. VCID impaired spatial memory in both sexes, but episodic-like memory in females only. HF diet caused greater weight gain and glucose intolerance in middle-aged females than males. HF diet alone impaired episodic-like memory in both sexes, but spatial memory in females only. Finally, the combination of HF diet and VCID elicited cognitive impairments in all tests, in both sexes. Sex-specific correlations were found between metabolic outcomes and memory. Notably, both visceral fat and the pro-inflammatory cytokine tumor necrosis factor alpha correlated with spatial memory deficits in middle-aged females, but not males. Overall, our data show that HF diet causes greater metabolic impairment and a wider array of cognitive deficits in middle-aged females than males. The combination of HF diet with VCID elicits deficits across multiple cognitive domains in both sexes. Our data are in line with clinical data, which shows that mid-life metabolic disease increases VCID risk, particularly in females.
Publication Date: 2020-09-18 00:00:00
Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology


Clusterin as a Potential Biomarker of Obesity-Related Alzheimer's Disease Risk.
Over 35% of the adult US population is obese. In turn, excess adiposity increases the risk of multiple complications including type 2 diabetes (T2D), insulin resistance, and cardiovascular disease; yet, obesity also independently heightens risk of Alzheimer's Disease (AD), even after adjusting for other important confounding risk factors including blood pressure, sociodemographics, cholesterol levels, smoking status, and Apolipoprotein E (ApoE) genotype. Among patients over the age of 65 with dementia, 37% have coexisting diabetes, and an estimated 7.3% of cases of AD are directly attributable to midlife obesity. Clusterin, also known as apolipoprotein J (ApoJ), is a multifunctional glycoprotein that acts as a molecular chaperone, assisting folding of secreted proteins. Clusterin has been implicated in several physiological and pathological states, including AD, metabolic disease, and cardiovascular disease. Despite long-standing interest in elucidating clusterin's relationship with amyloid beta (Aβ) aggregation/clearance and toxicity, significant knowledge gaps still exist. Altered clusterin expression and protein levels have been linked with cognitive and memory function, disrupted central nervous system lipid flux, as well as pathogenic brain structure; and its role in cardiometabolic disease suggests that it may be a link between insulin resistance, dyslipidemia, and AD. Here, we briefly highlight clusterin's relevance to AD by presenting existing evidence linking clusterin to AD and cardiometabolic disease, and discussing its potential utility as a biomarker for AD in the presence of obesity-related metabolic disease.
Publication Date: 2020-10-29 00:00:00
Journal: Biomarker insights

metabolic memory phenomenon(12)

Interpretation of metabolic memory phenomenon using a physiological systems model: What drives oxidative stress following glucose normalization?
Hyperglycemia is generally associated with oxidative stress, which plays a key role in diabetes-related complications. A complex, quantitative relationship has been established between glucose levels and oxidative stress, both in vitro and in vivo. For example, oxidative stress is known to persist after glucose normalization, a phenomenon described as metabolic memory. Also, uncontrolled glucose levels appear to be more detrimental to patients with diabetes (non-constant glucose levels) vs. patients with high, constant glucose levels. The objective of the current study was to delineate the mechanisms underlying such behaviors, using a mechanistic physiological systems modeling approach that captures and integrates essential underlying pathophysiological processes. The proposed model was based on a system of ordinary differential equations. It describes the interplay between reactive oxygen species production potential (ROS), ROS-induced cell alterations, and subsequent adaptation mechanisms. Model parameters were calibrated using different sources of experimental information, including ROS production in cell cultures exposed to various concentration profiles of constant and oscillating glucose levels. The model adequately reproduced the ROS excess generation after glucose normalization. Such behavior appeared to be driven by positive feedback regulations between ROS and ROS-induced cell alterations. The further oxidative stress-related detrimental effect as induced by unstable glucose levels can be explained by inability of cells to adapt to dynamic environment. Cell adaptation to instable high glucose declines during glucose normalization phases, and further glucose increase promotes similar or higher oxidative stress. In contrast, gradual ROS production potential decrease, driven by adaptation, is observed in cells exposed to constant high glucose.
Publication Date: 2017-02-09 00:00:00
Journal: PloS one


The pathogenic subpopulation of Th17 cells in obesity.
Obesity is a metabolic disease characterized by a chronic subclinical inflammatory response associated with an imbalance/dysregulation of cellular homeostasis in response to excessive nutrient intake and accumulation. CD4+ Tlymphocytes form different populations, Th1, Th2, Th9, Th17, Th22, and Treg cells which have phenotypic and functional differences. Despite the active study of Th17 cells in severe disorders, their role in metabolic disorders, particularly in obesity, is not well understood. Th17 lymphocytes, depending on the microenvironment, can form pathogenic and nonpathogenic subpopulations. Systemic inflammation induces the reprogramming of the transcriptome of normal Th17 cells formed in epithelial tissues, which acquire new properties. A zone of overlapping states exists between IL-17A-producing cells which does not allow a clear boundary between non-pathogenic Th17 and pathogenic Th17 lymphocytes. We assume that in obesity, the pool of inflammatory pathogenic Th17 cells with cytotoxic potential is a fraction of terminally differentiated memory lymphocytes and is responsible for developing autoimmune reactions.
Publication Date: 2021-01-04 00:00:00
Journal: Current pharmaceutical design

advanced glycation(21)

The Development of Maillard Reaction, and Advanced Glycation End Product (AGE)-Receptor for AGE (RAGE) Signaling Inhibitors as Novel Therapeutic Strategies for Patients with AGE-Related Diseases.
Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE-RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE-RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of "metabolic memory", the "French paradox", and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.
Publication Date: 2020-12-03 00:00:00
Journal: Molecules (Basel, Switzerland)


Memory impairment and depressive-like phenotype are accompanied by downregulation of hippocampal insulin and BDNF signaling pathways in prediabetic mice.
Prediabetes is the stage before diabetes in which not all the symptoms or signs required to diagnose diabetes are present, but blood glucose is abnormally high. This study aimed to investigate memory impairment and depressive-like phenotype in prediabetic mice, as well as the contribution of the hippocampal insulin and BDNF signaling to behavioral effects. Male adult Swiss mice received streptozotocin (STZ, 200 mg/kg, ip) to induce prediabetes. Control mice were treated with citrate buffer (5 ml/kg, ip). To characterize prediabetes status, metabolic parameters were determined in mice. The behavioral test battery to assess memory consisted of object recognition (ORT), object location (OLT), and Morris water maze (MWM) tests. The mouse depressive-like phenotype was investigated using the forced swimming (FST) and tail suspension (TST) tests. The pIRS-1/Akt/GLUT4 and BDNF/TrkB/CREB protein contents were determined in the hippocampus of mice. Prediabetic mice showed mild hyperglycemia, reduced body weight gain, and an increase in glucose and insulin tolerance tests (AUCs). Prediabetic mice had smaller recognition and location indexes, in the ORT and OLT, than the control group. Prediabetic mice showed hippocampus-dependent spatial memory impairment, in the MWM test, and an increase in immobility time, in the TST and FST, when compared to the control group. The molecular findings indicate the downregulation of hippocampal insulin and BDNF signaling in prediabetic mice. In conclusion, memory impairment and depressive-like phenotype were accompanied by the downregulation of hippocampal pIRS-1/Akt/GLUT4 and BDNF/CREB signaling in prediabetic mice.
Publication Date: 2021-02-06 00:00:00
Journal: Physiology & behavior

mild cognitive impairment(9)

Mild Cognitive Impairment Subtypes and Type 2 Diabetes in Elderly Subjects.
Type 2 diabetes (T2D) is correlated to amnestic mild cognitive impairment (aMCI) and to non-amnestic mild cognitive impairment (naMCI). This study evaluated whether the T2D variable characterizes a peculiar cognitive profile in elderly patients. Moreover, it explores the association between glycated hemoglobin levels (HbA1c), T2D duration, insulin and oral hypoglycemic agent treatment, and cognition in elderly diabetic patients. Detailed neuropsychological battery was used to diagnose MCI subtypes. A total of 39 MCI subjects with T2D (T2D-MCI) and 37 MCI subjects without T2D (ND-MCI), matched for age, educational level, and Mini-Mental State Examination score, were included. ND-MCI performed worse in memory and language domains than T2D-MCI. The amnestic subtype is more frequent among ND-MCI and non-amnestic subtype in T2D-MCI. In T2D-MCI, high HbA1c levels correlate with episodic memory (immediate recall) and T2D duration. Some indexes of episodic memory (immediate recall), attention, and visual-spatial ability correlate with insulin treatment. An association between T2D and non-amnestic MCI is suggested. In the T2D-MCI group, significant associations between insulin treatment and memory (immediate recall), complex figure copy, and attention were found.
Publication Date: 2020-07-08 00:00:00
Journal: Journal of clinical medicine


Long Term Dietary Restriction of Advanced Glycation End-Products (AGEs) in Older Adults with Type 2 Diabetes Is Feasible and Efficacious-Results from a Pilot RCT.
High serum concentrations of advanced glycation end-products (AGEs) in older adults and diabetics are associated with an increased risk of cognitive impairment. The aim of this pilot study was to assess the feasibility of long-term adherence to a dietary intervention designed to decrease intake and exposure to circulating AGEs among older adults with type 2 diabetes. Herein, 75 participants were randomized to either a standard of care (SOC) control arm or to an intervention arm receiving instruction on reducing dietary AGEs intake. The primary outcome was a change in serum AGEs at the end of the intervention. Secondary and exploratory outcomes included adherence to diet and its association with circulating AGEs. Cognitive function and brain imaging were also assessed but were out of the scope of this article ( Identifier: NCT02739971). The intervention resulted in a significant change over time in several serum AGEs compared to the SOC guidelines. Very high adherence (above 80%) to the AGE-lowering diet was associated with a greater reduction in serum AGEs levels. There were no significant differences between the two arms in any other metabolic markers. A long-term dietary intervention to reduce circulating AGEs is feasible in older adults with type 2 diabetes, especially in those who are highly adherent to the AGE-lowering diet.
Publication Date: 2020-10-21 00:00:00
Journal: Nutrients


Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects.
Gestational diabetes (GD) has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. Oxidative stress is strongly associated with neurodegeneration and cognitive disruption. In the offspring brains in a GD experimental rat model, increased oxidative stress in the prenatal and postnatal st age was reported. However, long-term alterations to offspring behavior and oxidative stress, caused by changes in the cerebral cortex and hippocampus, remain unclear. In this study, we evaluated the effect of GD on young and adult male and female rat offspring in metabolic parameters, cognitive behavior, and oxidative stress. GD was induced using streptozotocin in dams. Next, the offspring were evaluated at two and six months of age Anxiety-like behavior was evaluated using the elevated plus maze and open field maze; spatial learning and short-term memory were evaluated using the Morris water maze and radial maze, respectively. We determined oxidative stress biomarkers (reactive oxygen species (ROS), lipid peroxidation and glutathione status) and antioxidant enzymes (superoxide dismutase and catalase) in the brain of offspring. We observed that male GD offspring showed a reduced level of anxiety at both age as they spent less time in the closed arms of the elevated plus maze at adult age ((
Publication Date: 2020-02-07 00:00:00
Journal: Nutrients


Endothelial Cell Metabolic Memory Causes Cardiovascular Dysfunction In Diabetes.
The aim of this study was to identify the molecular mechanism for hyperglycemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes. Hyperglycemia induces increased nuclear factor-κB (NF-κB) signaling, upregulation of miR-27a-3p, downregulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-β (TGF-β) signaling, downregulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs. The observed metabolic memory effects in ECs are blocked by NRF2 activator tert-butylhydroquinone and a miR-27a-3p inhibitor. In vivo, the NRF2 activator and miR-27a-3p inhibitor block cardiac perivascular fibrosis and restore cardiovascular function by decreasing NF-κB signaling, downregulating miR-27a-3p, upregulating NRF2 expression, reducing TGF-β signaling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin (STZ)-induced diabetic mice, whereas insulin alone does not improve cardiac function. Our data indicate that disruption of hyperglycemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signaling pathway of NF-κB/miR-27a-3p/NRF2/ROS/TGF-β/EndMT involved in metabolic memory. Controversy exists on whether high blood glucose (hyperglycemia) induces metabolic memory that may cause long-lasting damaging cardiovascular complications in diabetic patients. Here, we demonstrate that hyperglycemia-induced metabolic memory in endothelial cells causes cardiac perivascular fibrosis and cardiac dysfunction in diabetes in mice, and identify NF-kB/miR-27a-3p/NRF2/ROS/TGF-β-EndMT as the signaling mechanism. We show that disruption of metabolic memory by a NRF2 activator or miR-27a-3p inhibitor is required to achieve therapeutic effect on cardiac dysfunction by insulin treatment of diabetes. Thus, inhibition of metabolic memory is a novel strategy to better prevent cardiovascular complications and improve the clinical outcome of diabetic patients.
Publication Date: 2021-01-24 00:00:00
Journal: Cardiovascular research


Olfactory Dysfunction Mediates Adiposity in Cognitive Impairment of Type 2 Diabetes: Insights From Clinical and Functional Neuroimaging Studies.
Large numbers of people with type 2 diabetes are obese. However, changes in cognition and related brain function in obese people with diabetes have not been characterized. Here, we investigated cognition, olfactory function, and odor-induced brain alterations in these patients and therapeutic effects of glucagon-like peptide 1 receptor agonists (GLP-1Ras) on their psychological behavior and olfactory networks. Cognitive, olfactory, and odor-induced brain activation assessments were administered to 35 obese and 35 nonobese people with type 2 diabetes and 35 control subjects matched for age, sex, and education. Among them, 20 obese individuals with diabetes with inadequate glycemic control and metformin monotherapy received GLP-1Ra treatment for 3 months and were reassessed for metabolic, cognitive, olfactory, and neuroimaging changes. Obese subjects with diabetes demonstrated lower general cognition and olfactory threshold scores, decreased left hippocampal activation, and disrupted seed-based functional connectivity with right insula compared with nonobese subjects with diabetes. Negative associations were found between adiposity and episodic memory and between fasting insulin and processing speed test time in diabetes. Mediation analyses showed that olfactory function and left hippocampus activation mediated these correlations. With 3-month GLP-1Ra treatment, obese subjects with diabetes exhibited improved Montreal Cognitive Assessment (MoCA) score, olfactory test total score, and enhanced odor-induced right parahippocampus activation. Obese subjects with type 2 diabetes showed impaired cognition and dysfunctional olfaction and brain networks, the latter of which mediated adiposity in cognitive impairment of diabetes. GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese subjects with diabetes, providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients.
Publication Date: 2019-06-22 00:00:00
Journal: Diabetes care


Aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats.
Diabetes mellitus (DM) is a leading risk factor for aging-related dementia; however, the underlying mechanisms are not well understood. The present study, utilizing a non-obese T2DN diabetic model, demonstrates that the myogenic response of the middle cerebral artery (MCA) and parenchymal arteriole (PA) and autoregulation of cerebral blood flow (CBF) in the surface and deep cortex were impaired at both young and old ages. The impaired CBF autoregulation was more severe in old than young DM rats, and in the deep than the surface cortex. The myogenic tone of the MCA was enhanced at perfusion pressure in the range of 40-100 mmHg in young DM rats but was reduced at 140-180 mmHg in old DM rats. No change of the myogenic tone of the PA was observed in young DM rats, whereas it was significantly reduced at 30-60 mmHg in old DM rats. Old DM rats had enhanced blood-brain barrier (BBB) leakage and neurodegeneration, reduced vascular density, tight junction, and pericyte coverage on cerebral capillaries in the CA3 region in the hippocampus. Additionally, DM rats displayed impaired functional hyperemia and spatial learning and short- and long-term memory at both young and old ages. Old DM rats had impaired non-spatial short-term memory. These results revealed that impaired CBF autoregulation and enhanced BBB leakage plays an essential role in the pathogenesis of age- and diabetes-related dementia. These findings will lay the foundations for the discovery of anti-diabetic therapies targeting restoring CBF autoregulation to prevent the onset and progression of dementia in elderly DM.
Publication Date: 2020-07-23 00:00:00
Journal: GeroScience

diabetic kidney disease(8)

Cytosine Methylation Studies in Patients with Diabetic Kidney Disease.
Kidney disease is the major cause of morbidity and mortality in patients with diabetes. Poor glycemic control shows the strongest correlation with diabetic kidney disease (DKD) development. A period of poor glycemia increases kidney disease risk even after an extended period of improved glucose control-a phenomenon called metabolic memory. Changes in the epigenome have been proposed to mediate the metabolic memory effect, as epigenome editing enzymes are regulated by substrates of intermediate metabolism and changes in the epigenome can be maintained after cell division. Epigenome-wide association studies (EWAS) have reported differentially methylated cytosines in blood and kidney samples of DKD subjects when compared with controls. Differentially methylated cytosines were enriched on regulatory regions and some correlated with gene expression. Methylation changes predicted the speed of kidney function decline. Site-specific methylome editing tools now can be used to interrogate the functional role of differentially methylated regions. Methylome changes can be detected in blood and kidneys of patients with DKD. Methylation changes can predict future kidney function changes. Future studies shall determine their role in disease development.
Publication Date: 2019-09-01 00:00:00
Journal: Current diabetes reports

risk factors(15)

Association between depressive symptoms, metabolic risk factors, and cognitive function: cross-sectional results from a community study in Quebec, Canada.
To investigate the cross-sectional association between depressive symptoms and metabolic risk factors with cognitive function in a middle-aged population. A stratified subsample of the CARTaGENE (CaG) cohort ( The poorest cognitive performance was observed in the group with both depressive symptoms and MetD, followed by the group with depressive symptoms only, then the group with MetD only and the reference group. Mean (SD) overall cognition scores for the four groups were -0.25 (1.13), -0.13 (1.05), 0.11 (0.90), and 0.15 (0.93), respectively. Linear regression analyses suggested a linear increase in cognitive function across groups. In the logistic regression analyses, the highest risk of poor cognitive function was observed in the comorbid (depressive symptoms and MetD) group (adjusted OR = 1.99, 95% CI 1.46, 2.71). Comorbidity of depressive symptoms and MetD was associated with reduced cognitive performance in middle-aged adults without diabetes. KEY POINTS Poor cognitive function is a major public health concern and can be potentially prevented by targeting its modifiable risk factors Metabolic dysregulation and depression have both been independently associated with poor cognitive function. Comorbidity of metabolic dysregulation and depressive symptoms is associated with an increased risk of poor cognitive function in middle-aged individuals. Future health interventions might benefit by screening for comorbidity in patients with poor cognitive function and by targeting depression and metabolic dysregulation together.
Publication Date: 2020-07-15 00:00:00
Journal: Aging & mental health


Corrigendum: Core Neuropsychological Measures for Obesity and Diabetes Trials: Initial Report.
[This corrects the article DOI: 10.3389/fpsyg.2020.554127.].
Publication Date: 2020-11-27 00:00:00
Journal: Frontiers in psychology

glycemic control(12)

Influence of glycemic control on some real-time biomarkers of free radical formation in type 2 diabetic patients: An EPR study.
The pathology of diabetes is associated with several mechanisms, one of which is oxidative stress (OS). The relationship between OS and diabetic complications has been extensively investigated. OS has been suggested to be involved in the genesis of both macroand microangiopathy. In contrast, the relationship between OS and insulin action is a neglected research area. The aim of this study is to elucidate the effect of glycemic control in type 2 diabetic patients by following the serum levels of some real-time oxidative stress biomarkers. The study group consisted of 53 type 2 diabetic patients (31 with poor glycemic control and 22 with good glycemic control and 24 healthy control subjects. The oxidative stress biomarkers (ROS, Asc• and •NO) were measured by using electron paramagnetic resonance spectroscopy (EPR) methods and compared with clinical parameters. The statistically significantly higher levels of ROS products and •NO in type 2 diabetic patients in both groups compared to controls mean that the oxidation processes take place at the time the survey is performed. Free radical overproduction persists after the normalization of the glucose levels, and oxidative stress may be involved in the "metabolic memory" effect. This is confirmed by the positive correlation between ROS levels/•NO and average blood glucose levels, triglycerides, and total cholesterol. Furthermore, the low level of the ascorbate radical in both diabetes groups compared to controls confirmed an increase in oxidation processes. Higher levels of real-time biomarkers show that intensive insulin treatment does not lead to the expected decrease in oxidative processes involving ROS and •NO, probably due to "metabolic memory".
Publication Date: 2017-12-22 00:00:00
Journal: Advances in clinical and experimental medicine : official organ Wroclaw Medical University

mouse model(14)

Western diet-induced obesity disrupts the diurnal rhythmicity of hippocampal core clock gene expression in a mouse model.
Western diet (WD) feeding disrupts core clock gene expression in peripheral tissues and contributes to WD-induced metabolic disease. The hippocampus, the mammalian center for memory, is also sensitive to WD feeding, but whether the WD disrupts its core clock is unknown. To this end, male mice were maintained on a WD for 16 weeks and diurnal metabolism, gene expression and memory were assessed. WD-induced obesity disrupted the diurnal rhythms of whole-body metabolism, markers of inflammation and hepatic gene expression, but did not disrupt diurnal expression of hypothalamic Bmal1, Npas2 and Per2. However, all measured core clock genes were disrupted in the hippocampus after WD feeding and the expression pattern of genes implicated in Alzheimer's disease and synaptic function were altered. Finally, WD feeding disrupted hippocampal memory in a task- and time-dependent fashion. Our results implicate WD-induced alterations in the rhythmicity of hippocampal gene expression in the etiology of diet-induced memory deficits.
Publication Date: 2020-05-27 00:00:00
Journal: Brain, behavior, and immunity


Diabetic Theory in Anti-Alzheimer's Drug Research and Development. Part 2: Therapeutic Potential of cAMP-Specific Phosphodiesterase Inhibitors.
Alzheimer's Disease (AD) is one of the most prevalent age-related neurodegenerative diseases that affect the cognition, behavior, and daily activities of individuals. Studies indicate that this disease is characterized by several pathological mechanisms, including the accumulation of amyloid beta peptide, hyperphosphorylation of tau protein, impairment of cholinergic neurotransmission, and increase in inflammatory responses within the central nervous system. Chronic neuroinflammation associated with AD is closely related to disturbances in metabolic processes, including insulin release and glucose metabolism. As AD is also called type III diabetes, diverse compounds having antidiabetic effects have been investigated as potential drugs for its symptomatic and disease-modifying treatment. In addition to insulin and oral antidiabetic drugs, scientific attention has been paid to cyclic-3',5'-adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) inhibitors that can modulate the concentration of glucose and related hormones, and exert beneficial effects on memory, mood, and emotional processing. In this review, we present the most recent reports focusing on the involvement of cAMPspecific PDE4, PDE7, and PDE8 in glycemic and inflammatory response controls as well as the potential utility of the PDE inhibitors in the treatment of AD. Besides the results of in vitro and in vivo studies, the review also presents recent reports from clinical trials.
Publication Date: 2020-09-18 00:00:00
Journal: Current medicinal chemistry


New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation.
Conflicting data are reported on the relationship between hyperglycaemia, diabetes and SIRT6 expression. To elucidate hyperglycaemia-induced molecular mechanisms regulating SIRT6 expression, the effect of hyperglycaemia on DNA methylation and SIRT6 expression has been evaluated in human aortic endothelial cells exposed to high glucose. DNA methylation of SIRT6 and any potential clinical implication was also evaluated in type 2 diabetic patients and compared with healthy controls. Endothelial cells exposed to high glucose showed lower methylation levels in SIRT6 promoter and increased SIRT6 and TET2 expression. The high glucose-induced epigenetic changes persisted after 48 h of glucose normalization. Diabetic patients showed lower levels of SIRT6 DNA methylation compared with nondiabetic patients. SIRT6 DNA methylation levels inversely correlated with plasma glucose. Our results firstly demonstrate the involvement of epigenetic mechanisms in regulating SIRT6 expression. Further experiments are necessary to clarify metabolic memory mechanisms driving to diabetic complications and how SIRT6 is potentially involved.
Publication Date: 2020-12-01 00:00:00
Journal: Journal of cellular physiology

cardiovascular disease(13)

The Legacy Effect in the Prevention of Cardiovascular Disease.
The "legacy effect" describes the long-term benefits that may persist for many years after the end of an intervention period, involving different biological processes. The legacy effect in cardiovascular disease (CVD) prevention has been evaluated by a limited number of studies, mostly based on pharmacological interventions, while few manuscripts on dietary interventions have been published. Most of these studies are focused on intensive treatment regimens, whose main goal is to achieve tight control of one or more cardiovascular risk factors. This review aims to summarise the legacy effect-related results obtained in those studies and to determine the existence of this effect in CVD prevention. There is sufficient data to suggest the existence of a legacy effect after intensive intervention on cardiovascular risk factors; however, this effect is not equivalent for all risk factors and could be influenced by patient characteristics, disease duration, and the type of intervention performed. Currently, available evidence suggests that the legacy effect is greater in subjects with moderately-high cardiovascular risk but without CVD, especially in those patients with recent-onset diabetes. However, preventive treatment for CVD should not be discontinued in high-risk subjects, as the level of existing evidence on the legacy effect is low to moderate.
Publication Date: 2020-10-28 00:00:00
Journal: Nutrients


Medicinal plants for diabetes associated neurodegenerative diseases: A systematic review of preclinical studies.
Diabetes mellitus is a metabolic defect with many complications for the patients. Deaths due to diabetes and its complications are increasing, and one of the most serious consequences are the neurological disorders. Chemical treatments have irreversible side effect and therefore the aim of this study is to evaluate the medicinal plants used for treatment of cognitive impairments and neurodegenerative diseases associated with diabetes in 2004-2020 period. Electronic databases used were PubMed, Scopus and Cochrane library. The keywords used were "diabetes," "plant," "herb," "neurodegenerative," "neurodegeneration," "cognitive," "cognition," "Alzheimer," "dementia." The non-English articles, repetitive articles and review studies were excluded. From total of 3,590 results, 58 articles are included in the study. The results show that many chemical treatments considered for this disease simply control hyperglycemia, but cannot improve the complications of diabetes. Herbal medicine could be more effective due to the high antioxidant activity of some medicinal plants. Biologically active substances of medicinal plants can improve the neurological disorders caused by diabetes via several pathways. The most important pathway is related to antioxidant properties. Other pathways include antiinflammatory, anti-apoptotic, neurotoxicity inhibition, neuronal death, increasing the uptake of glucose by cells and improve neurotransmitters levels involved in learning and memory.
Publication Date: 2020-10-21 00:00:00
Journal: Phytotherapy research : PTR


Transient high glucose causes persistent vascular dysfunction and delayed wound healing by the DNMT1-mediated Ang-1/NF-κB pathway.
The progression of diabetic complications does not halt despite termination of hyperglycemia, suggesting a "metabolic memory" phenomenon. However, whether metabolic memory exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that wound healing was delayed and angiogenesis was decreased in diabetic mice, despite normalization of glycemic control. Thus, we hypothesized that transient hyperglycemic spikes may be a risk factor for diabetic wound healing. We showed that transient hyperglycemia caused persistent damage to the vascular endothelium. Transient hyperglycemia directly upregulated DNMT1 expression, leading to the hypermethylation of Ang-1 and reduced Ang-1 expression, which, in turn, induced long-lasting activation of nuclear factor (NF)-κB and subsequent endothelial dysfunction. An in vivo study further showed that inhibition of DNMT1 promoted angiogenesis and accelerated diabetic wound healing by regulating the Ang-1/NF-κB signaling pathway. These results highlight the dramatic and long-lasting effects of transient hyperglycemic spikes on wound healing and suggest that DNMT1 is a novel target for diabetic vascular complications.
Publication Date: 2020-12-02 00:00:00
Journal: The Journal of investigative dermatology

oxidative stress(12)

Vitamin D Deficiency: Effects on Oxidative Stress, Epigenetics, Gene Regulation, and Aging.
Recent advances in vitamin D research indicate that this vitamin, a secosteroid hormone, has beneficial effects on several body systems other than the musculoskeletal system. Both 25 dihydroxy vitamin D [25(OH)
Publication Date: 2019-05-15 00:00:00
Journal: Biology

diabetic nephropathy(9)

Resveratrol prevents diabetic nephropathy by reducing chronic inflammation and improving the blood glucose memory effect in non-obese diabetic mice.
Chronic inflammation plays an important role in the development of diabetic nephropathy Advanced glycation end product receptor (RAGE), nuclear factor kappa B (NF-κB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) are involved in the development of inflammation. Resveratrol is a plant antitoxin; it is believed to have anti-inflammatory effects and can improve blood glucose. We speculate that resveratrol treatment can protect renal function by reducing blood glucose, decreasing the expression of inflammatory factors. Non-obese diabetic (NOD) mice were randomly divided into three groups: T1DM, insulin (INS) and resveratrol (Res) groups. Mice without diabetes were classified as the non-diabetic control group (NOD-C group). The blood glucose (BG) level, blood urea nitrogen (BUN) level, serum creatinine (SCr) level and 24-h urinary microalbumin quantitative (UMA) were measured. The glomerulosclerosis index and basement membrane thickness were calculated under light and electron microscopes. The expression levels of RAGE, NF-кB (P65) and NOX4 in renal tissues were detected by Western blot analysis. We found that resveratrol treatment significantly reduced blood glucose within 28 days of the experiment, but the hypoglycemic effect was not lasting. At the same time, resveratrol reduced BUN, SCr, 24 h UMA and the expression of the inflammatory factors RAGE, NF-кB (P65) and NOX4 and improved the renal pathological structure. We believe that resveratrol improves renal function not only by its anti-inflammatory effect but also by improving the metabolic memory of hyperglycemia.
Publication Date: 2020-01-24 00:00:00
Journal: Naunyn-Schmiedeberg's archives of pharmacology

kidney disease(10)

Epigenetics and epigenomics in diabetic kidney disease and metabolic memory.
The development and progression of diabetic kidney disease (DKD), a highly prevalent complication of diabetes mellitus, are influenced by both genetic and environmental factors. DKD is an important contributor to the morbidity of patients with diabetes mellitus, indicating a clear need for an improved understanding of disease aetiology to inform the development of more efficacious treatments. DKD is characterized by an accumulation of extracellular matrix, hypertrophy and fibrosis in kidney glomerular and tubular cells. Increasing evidence shows that genes associated with these features of DKD are regulated not only by classical signalling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation and non-coding RNAs. These mechanisms can respond to changes in the environment and, importantly, might mediate the persistent long-term expression of DKD-related genes and phenotypes induced by prior glycaemic exposure despite subsequent glycaemic control, a phenomenon called metabolic memory. Detection of epigenetic events during the early stages of DKD could be valuable for timely diagnosis and prompt treatment to prevent progression to end-stage renal disease. Identification of epigenetic signatures of DKD via epigenome-wide association studies might also inform precision medicine approaches. Here, we highlight the emerging role of epigenetics and epigenomics in DKD and the translational potential of candidate epigenetic factors and non-coding RNAs as biomarkers and drug targets for DKD.
Publication Date: 2019-03-22 00:00:00
Journal: Nature reviews. Nephrology

diabetic vascular complications(6)

Epigenetic regulation in diabetic vascular complications.
Cardiovascular disease (CVD), the main complication of diabetes mellitus (DM), accounts for a high percentage of mortality in diabetic patients. Endothelial dysfunction is a major causative event in the pathogenesis of diabetes-related vascular disease and the earliest symptom of vascular injury. Epigenetic modification plays a key role in the initiation, maintenance, and progression of both endothelial dysfunction and diabetes. Epigenetic alterations respond to the environment and mediate the 'legacy effect' of uncontrolled hyperglycaemia early in the disease despite thorough glycaemic control in a phenomenon called metabolic memory. Therefore, an understanding of the integrated system of different epigenetic mechanisms in DM and its vascular complications is urgently needed. This review summarizes aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs). Understanding the connections between these processes and DM may reveal a novel potential therapeutic target for diabetic vascular complications
Publication Date: 2019-10-11 00:00:00
Journal: Journal of molecular endocrinology


The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation-Evidence from In Vivo Studies.
Neurological disorders such as neurodegenerative diseases or traumatic brain injury are associated with cognitive, motor and behavioural changes that influence the quality of life of the patients. Although different therapeutic strategies have been developed and tried until now to decrease the neurological decline, no treatment has been found to cure these pathologies. In the last decades, the implication of the endocannabinoid system in the neurological function has been extensively studied, and the cannabinoids have been tried as a new promising potential treatment. In this study, we aimed to overview the recent available literature regarding in vivo potential of natural and synthetic cannabinoids with underlying mechanisms of action for protecting against cognitive decline and motor impairments. The results of studies on animal models showed that cannabinoids in traumatic brain injury increase neurobehavioral function, working memory performance, and decrease the neurological deficit and ameliorate motor deficit through down-regulation of pro-inflammatory markers, oedema formation and blood-brain barrier permeability, preventing neuronal cell loss and up-regulating the levels of adherence junction proteins. In neurodegenerative diseases, the cannabinoids showed beneficial effects in decreasing the motor disability and disease progression by a complex mechanism targeting more signalling pathways further than classical receptors of the endocannabinoid system. In light of these results, the use of cannabinoids could be beneficial in traumatic brain injuries and multiple sclerosis treatment, especially in those patients who display resistance to conventional treatment.
Publication Date: 2020-07-31 00:00:00
Journal: Journal of clinical medicine


Ghrelin Signaling Affects Feeding Behavior, Metabolism, and Memory through the Vagus Nerve.
Vagal afferent neuron (VAN) signaling sends information from the gut to the brain and is fundamental in the control of feeding behavior and metabolism [1]. Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including affective motivational behaviors and hippocampus (HPC)-dependent memory [2-5]. VANs, located in nodose ganglia, express receptors for various gut-derived peptide signals; however, the function of these receptors with regard to feeding behavior, metabolism, and memory control is poorly understood. We hypothesized that VAN-mediated processes are influenced by ghrelin, a stomach-derived orexigenic hormone, via communication to its receptor (GHSR) expressed on gut-innervating VANs. To examine this hypothesis, rats received nodose ganglia injections of an adeno-associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a control AAV) for RNAi-mediated VAN-specific GHSR knockdown. Results reveal that VAN GHSR knockdown induced various feeding and metabolic disturbances, including increased meal frequency, impaired glucose tolerance, delayed gastric emptying, and increased body weight compared to controls. Additionally, VAN-specific GHSR knockdown impaired HPC-dependent contextual episodic memory and reduced HPC brain-derived neurotrophic factor expression, but did not affect anxiety-like behavior or general activity levels. A functional role for endogenous VAN GHSR signaling was further confirmed by results revealing that VAN signaling is required for the hyperphagic effects of ghrelin administered at dark onset, and that gut-restricted ghrelin-induced increases in VAN firing rate require intact VAN GHSR expression. Collective results reveal that VAN GHSR signaling is required for both normal feeding and metabolic function as well as HPC-dependent memory.
Publication Date: 2020-09-19 00:00:00
Journal: Current biology : CB


Volumetric investigation of the hippocampus in rat offspring due to diabetes in pregnancy-A stereological study.
The brain development during the prenatal period is affected by various factors, including the mother's metabolic condition. It has been revealed that diabetes in pregnancy is associated with structural and functional alterations in offspring's hippocampus Hippocampus as a critical region with well-known roles in learning and memory consolidation, is vulnerable to changes in glucose level. This study was designed to investigate the effects of maternal diabetes during the pregnancy period and insulin therapy on the neuronal density and the volume of different subfields of the hippocampus in rat offspring at postnatal day 14 (P14). Wistar female rats were randomly divided into diabetics (STZ-D), diabetes treated with insulin (STZ-INS) group, and controls (CON). The animals in all groups were mated by non-diabetic male rats. Two weeks after birth, male pups from each group were sacrificed. The Cavalieri method was carried out to estimate the total volume, and the numerical density of the neurons in the hippocampus and its sub regions was measured by the optical dissector technique. Bilateral hippocampal volume decreased in the diabetic group, mainly in the CA1, dentate gyrus (DG) and subiculum areas (P ≤ 0.05), when compared to control and insulin-treated diabetic animals. In all hippocampus sub-regions, maternal diabetes resulted in a significant decrease in the number of cells in comparison with two other groups (P ≤ 0.05 each). These data indicate that diabetes during pregnancy has a negative impact on the development of the hippocampus in the rats. These changes in the volume of hippocampal CA1, DG, and subiculum areas might be at the core of underlying neurocognitive and neurobehavioral impairments observed in the children of diabetic mothers.
Publication Date: 2019-08-24 00:00:00
Journal: Journal of chemical neuroanatomy

diabetic patients(11)

Impaired cognitive processing speed in type 1 diabetic patients who had severe/recurrent hypoglycaemia.
To detect whether adults with type 1 diabetes mellitus (T1DM) have lower cognitive performance than healthy individuals and to detect risk factors for low cognitive performance. Twenty-six adults with T1DM and twenty-six healthy subjects matched for age, gender and educational level were compared for cognitive performance by a chronometric computerized test measuring visuo-spatial working memory (N-Back) and by two validated neuropsychological tests (Mini Mental State Examination, Animal Naming Test). Clinical data about diabetes duration, average daily insulin dosage, glycated haemoglobin, retinopathy, urine albumin-creatinine ratio, previous hypoglycaemic coma and awareness of hypoglycaemia were obtained from medical records. Basal pre-test glycemia and blood pressure were measured for each patient. No differences were found between patients (n = 26) and healthy controls (n = 26) in neuropsychological tests. Within diabetic patients those with impaired awareness of hypoglycaemia (n = 7) or history of coma in the recent 1-3 years (n = 5) had psychomotor slowing at the N-Back test (592 ± 35 vs. 452 ± 21 ms and 619 ± 40 vs. 462 ± 19 ms, respectively; both p < 0.01). The variables related to diabetic severity did not show a relationship with reaction times of the N-Back test. Psychomotor speed slowing is detectable in patients with T1DM who have a history of previous hypoglycaemic episodes or coma.
Publication Date: 2018-08-20 00:00:00
Journal: Journal of diabetes and its complications

older adults(10)

Distinct effects of acute exercise and breaks in sitting on working memory and executive function in older adults: a three-arm, randomised cross-over trial to evaluate the effects of exercise with and without breaks in sitting on cognition.
Sedentary behaviour is associated with impaired cognition, whereas exercise can acutely improve cognition. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cognition in older adults Sedentary overweight/obese older adults with normal cognitive function (n=67, 67±7 years, 31.2±4.1 kg/m Working memory net AUC z-score·hour (95% CI) was improved in EX+BR with a z-score of +28 (-26 to +81), relative to SIT, -25 (-79 to +29, p=0.04 vs EX+BR). Executive function net AUC was improved in EX+SIT, -8 (- 71 to +55), relative to SIT, -80 (-142 to -17, p=0.03 vs EX+SIT). Serum BDNF net AUC ng/mL·hour (95% CI) was increased in both EX+SIT, +171 (-449 to +791, p=0.03 vs SIT), and EX+BR, +139 (-481 to +759, p=0.045 vs SIT), relative to SIT, -227 (-851 to +396). A morning bout of moderate-intensity exercise improves serum BDNF and working memory or executive function in older adults depending on whether or not subsequent sitting is also interrupted with intermittent light-intensity walking. ACTRN12614000737639.
Publication Date: 2019-05-01 00:00:00
Journal: British journal of sports medicine

metabolic control(10)

Cognitive functioning, metabolic control, and treatment type in youth with type 1 diabetes.
There is growing evidence that cognitive functioning plays an important role in self-care behavior and glycemic control in pediatric patients with type 1 diabetes. The aim of this pilot study was to examine whether there were differences in glycemic control and cognitive functioning between youth with T1D treated with continuous subcutaneous insulin infusion and multiple daily injections. The sample consisted of 29 youth diagnosed with type 1 diabetes ages 6-15 years (mean age=11.72 years) receiving care at an outpatient pediatric endocrinology clinic. Youth were administered the Wechsler Abbreviated Scale of Intelligence and Wide Range Assessment of Memory and Learning. Independent samples t-tests were used to compare youth with T1D treated with MDI vs. CSII on glycemic control, verbal memory, visual memory, attention/concentration, and intelligence. Mean intelligence scores for the insulin pump sample were higher than the daily injection sample. This difference was a medium to large effect. After controlling for demographic variables, age of onset for diabetes, and glycemic control, treatment type was still a significant predictor of intelligence demonstrating that CSII was associated with higher intelligence scores. The use of standardized measures of cognitive functioning in routine clinical care may shed some light on the complex interplay between cognitive functioning, treatment type, and glycemic control when managing pediatric patients with T1D.
Publication Date: 2015-01-13 00:00:00
Journal: Journal of pediatric endocrinology & metabolism : JPEM

type 1 diabetic(10)

Region-specific metabolic characterization of the type 1 diabetic brain in mice with and without cognitive impairment.
Type 1 diabetes (T1D) has been reported to cause cognitive decline, but brain metabolic changes during this process are still far from being fully understood. Here, we found that streptozotocin (STZ)-induced T1D mice exhibited impaired learning and memory at 11 weeks after STZ treatment but not at 3 weeks. Therefore, we studied metabolic alterations in six different brain regions of T1D mice with and without cognitive decline, and attempted to identify key metabolic pathways related to diabetic cognitive dysfunction. The results demonstrate that lactate had already increased in all brain regions of T1D mice prior to cognitive decline, but a decreased TCA cycle was only observed in hippocampus, cortex and striatum of T1D mice with cognitive impairment. Reduced N-acetylaspartate and choline were found in all brain regions of T1D mice, irrespective of cognitive decline. In addition, disrupted neurotransmitter metabolism was noted to occur in T1D mice before cognitive deficit. Of note, we found that the level of uridine was significantly reduced in cerebellum, cortex, hypothalamus and midbrain of T1D mice when cognitive decline was presented. Therefore, brain region-specific metabolic alterations may comprise possible biomarkers for the early-diagnosis and monitoring of diabetic cognitive decline. Moreover, down-regulated TCA cycle and pyrimidine metabolism could be closely related to T1D-associated cognitive impairment.
Publication Date: 2020-12-18 00:00:00
Journal: Neurochemistry international

epigenetic mechanisms(12)

Epigenetic Mechanisms in Diabetic Kidney Disease.
Progressive kidney disease is a common companion to both type 1 and type 2 diabetes. However, the majority of people with diabetes do not develop diabetic kidney disease. This may in part be explained by good control of glucose, blood pressure, obesity and other risk factors for kidney disease. It may also be partly due to their genetic makeup or ethnicity. However, the vast majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors or genetics. Epigenetics has recently emerged as an increasingly powerful paradigm to understand and potentially explain complex non-Mendelian conditions-including diabetic kidney disease. Persistent epigenetic changes can be acquired during development or as adaptations to environmental exposure, including metabolic fluctuations associated with diabetes. These epigenetic modifications-including DNA methylation, histone modifications, non-coding RNAs and other changes in chromatin structure and function-individually and co-operatively act to register, store, retain and recall past experiences in a way to shape the transcription of specific genes and, therefore, cellular functions. This review will explore the emerging evidence for the role of epigenetic modifications in programming the legacy of hyperglycaemia for kidney disease in diabetes.
Publication Date: 2016-02-26 00:00:00
Journal: Current diabetes reports

dna methylation(14)

DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes.
Metabolic memory, the persistent benefits of early glycaemic control on preventing and/or delaying the development of diabetic complications, has been observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but the underlying mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycaemic history, and with subsequent development of complications over an 18-yr period in the blood DNA of 499 randomly selected DCCT participants with type 1 diabetes who are also followed up in EDIC. We demonstrate the associations between DNAme near the closeout of DCCT and mean HbA1c during DCCT (mean-DCCT HbA1c) at 186 cytosine-guanine dinucleotides (CpGs) (FDR < 15%, including 43 at FDR < 5%), many of which were located in genes related to complications. Exploration studies into biological function reveal that these CpGs are enriched in binding sites for the C/EBP transcription factor, as well as enhancer/transcription regions in blood cells and haematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68-97% of the association of mean-DCCT HbA1c with the risk of complications during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycaemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.
Publication Date: 2020-07-23 00:00:00
Journal: Nature metabolism


Epidermal Growth Factor in Healing Diabetic Foot Ulcers: From Gene Expression to Tissue Healing and Systemic Biomarker Circulation.
Lower-extremity diabetic ulcers are responsible for 80% of annual worldwide nontraumatic amputations. Epidermal growth factor (EGF) reduction is one of the molecular pillars of diabetic ulcer chronicity, thus EGF administration may be considered a type of replacement therapy. Topical EGF ad-ministration to improve and speed wound healing began in 1989 on burn patients as part of an acute-healing therapy. Further clinical studies based on topically administering EGF to different chronic wounds resulted in disappointing out-comes. An analysis of the literature on unsuccessful clinical trials identifi ed a lack of knowledge concerning: (I) molecular and cellular foundations of wound chronicity and (II) the phar-macodynamic requisites governing EGF interaction with its receptor to promote cell response. Yet, EGF intra- and perile-sional infi ltration were shown to circumvent the pharmacody-namic limitations of topical application. Since the fi rst studies, the following decades of basic and clinical research on EGF therapy for problem wounds have shed light on potential uses of growth factors in regenerative medicine. EGF's molecular and biochemical effects at both local and systemic levels are diverse: (1) downregulation of genes encoding infl ammation mediators and increased expression of genes involved in cell proliferation, angiogenesis and matrix secretion; (2) EGF in-tervention positively impacts both mesenchymal and epithelial cells, reducing infl ammation and stimulating the recruitment of precursor circulating cells that promote the formation of new blood vessels; (3) at the subcellular level, upregulation of the EGF receptor with subsequent intracellular traffi cking, includ-ing mitochondrial allocation along with restored morphology of multiple organelles; and (4) local EGF infi ltration resulting in a systemic, organismal repercussion, thus contributing to attenuation of circulating infl ammatory and catabolic reac-tants, restored reduction-oxidation balance, and decreased toxic glycation products and soluble apoptogenic effectors. It is likely that EGF treatment may rearrange critical epigenetic drivers of diabetic metabolic memory. KEYWORDS Epidermal Growth Factor, diabetes, diabetes complications, wound healing, diabetic foot, amputation, ulcer, Cuba.
Publication Date: 2020-08-20 00:00:00
Journal: MEDICC review


Realising the long-term promise of insulin therapy: the DCCT/EDIC study.
The introduction of insulin in the treatment of juvenile-onset, now type 1, diabetes mellitus transformed a rapidly fatal disease into a chronic degenerative one. During the insulin-treatment era, long-term microvascular and cardiovascular complications proved to be the bane of existence for people with type 1 diabetes, leading to blindness, kidney failure, amputations, cardiovascular disease (CVD) and premature mortality. The nascent understanding of the link between non-physiologically regulated glucose levels and these complications led to the development of new treatment tools in the 1970s and 1980s that facilitated the delivery of insulin to achieve glucose levels closer to non-diabetic levels. These therapeutic advances set the stage for definitive testing of the glucose hypothesis. The Diabetes Control and Complications Trial (DCCT), supported by the National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health (NIH), definitively established the benefits and risks of intensive therapy that substantially lowered mean blood glucose levels, measured by HbA
Publication Date: 2021-02-08 00:00:00
Journal: Diabetologia


Betaine Alleviates Cognitive Deficits in Diabetic Rats via PI3K/Akt Signaling Pathway Regulation.
Diabetes mellitus is a metabolic disease which also causes cognitive deficits Betaine (N,N,N-trimethylglycine), also known as trimethylglycine, has been shown to ameliorate diabetic symptoms in diabetic animals and improve cognitive ability in Alzheimer disease (AD) animals. However, the effects of betaine on cognitive deficits in diabetic animals have not been described yet. Therefore, in the current study, the effects of betaine on cognition in diabetic rats were evaluated. We established a diabetic rat model by injecting streptozotocin (STZ) into rats and administrated betaine to these diabetic rats. We monitored the metabolism index, and glucose and insulin levels in blood and cerebrospinal fluid. We measured inflammatory cytokine levels, including TNF-α, IL-1β, and IL-6, in serum and hippocampus. We also monitored oxidative stress in the hippocampus by measuring malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. We measured the learning and memory ability of diabetic rats using the Morris water and Y maze tests and tested the phosphatidylinositol 3-kinase (PI3K)/Akt activation and p-mTOR level in the hippocampus. Betaine improved glucose metabolism and suppressed the production of inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Also, betaine decreased MDA concentration and increased SOD activity in the hippocampus of diabetic rats. Betaine ameliorated cognitive deficits in diabetic rats, and it promoted PI3K expression and Akt activation and decreased p-mTOR expression. Betaine alleviates cognitive deficits in STZ-induced diabetic rats via regulating the PI3K/Akt signaling pathway.
Publication Date: 2020-07-24 00:00:00
Journal: Dementia and geriatric cognitive disorders


Vitamin D: a Review of its Effects on Epigenetics and Gene Regulation.
Vitamin D is a secosteroid hormone with known beneficial effects on several body systems other than the musculoskeletal system. Both 25 dihydroxy vitamin D [25(OH)2D] and its active hormonal form, 1,25-dihydroxyvitamin D [1,25(OH)2D] are essential for hu-man physiological functions, including damping down inflammation and the excessive intracellular oxidative stresses. In the present study we set out to review all available literature on vitamin D and the role it plays in epigenetics and gene regulation We searched the PubMed/Medline electronic database for studies published in the English language up to January 2020. The Medical Subject Headings (MeSH) database was searched with the keywords 'vitamin D', 'DNA methylation', 'nutritional supplements', 'epigenome' and 'pregnancy'. Observational studies, supplementation studies, and meta-analyses dealing with the effect of vitamin D on epigenetics and gene regula-tion were included in the review. The obtained information from the databases such as PubMed, Google Scholar, and ResearchGate was analysed and summarized. We found that hypovitaminosis D increases the incidence and severity of several age-related common diseases such as the oxidative stress-associated metabolic disorders. These include obesity, insulin resistance, type 2 diabetes, hypertension, pregnancy complications, memory disorders, osteoporosis, autoimmune diseases, certain cancers, and systemic inflammatory diseases. New understandings of vitamin D-related advances in metabolomics, transcriptomics, epigenetics, in relation to its ability to control oxidative stress in conjunc-tion with micronutrients, vitamins, and antioxidants, following normalization of serum 25(OH)D and tissue 1,25(OH)2D concentra-tions, are likely to promise better cost-effective clinical outcomes in humans. There is a strong reciprocity between the vitamin D system and epigenetic mechanisms. The vitamin D system is, on the one hand regu-lated by epigenetic mechanisms and, on the other hand, is involved in regulating epigenetic events.
Publication Date: 2021-01-09 00:00:00
Journal: Folia medica

adipose tissue(10)

Adipose Tissue in Persons With HIV Is Enriched for CD4
Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4
Publication Date: 2019-04-04 00:00:00
Journal: Frontiers in immunology

gene expression(12)

Maternal high-fat diet results in cognitive impairment and hippocampal gene expression changes in rat offspring.
Consumption of a high-fat diet has long been known to increase risk for obesity, diabetes, and the metabolic syndrome. Further evidence strongly suggests that these same metabolic disorders are associated with an increased risk of cognitive impairment later in life. Now faced with an expanding global burden of obesity and increasing prevalence of dementia due to an aging population, understanding the effects of high-fat diet consumption on cognition is of increasingly critical importance. Further, the developmental origins of many adult onset neuropsychiatric disorders have become increasingly clear, indicating a need to investigate effects of various risk factors, including diet, across the lifespan. Here, we use a rat model to assess the effects of maternal diet during pregnancy and lactation on cognition and hippocampal gene expression of offspring. Behaviorally, adult male offspring of high-fat fed dams had impaired object recognition memory and impaired spatial memory compared to offspring of chow-fed dams. In hippocampus, we found decreased expression of Insr, Lepr, and Slc2a1 (GLUT1) among offspring of high-fat fed dams at postnatal day 21. The decreased expression of Insr and Lepr persisted at postnatal day 150. Together, these data provide additional evidence to suggest that maternal exposure to high-fat diet during pregnancy and lactation can have lasting effects on the brain, behavior, and cognition on adult offspring.
Publication Date: 2019-05-06 00:00:00
Journal: Experimental neurology


Effects of alpha-mangostin on memory senescence induced by high glucose in human umbilical vein endothelial cells.
Hyperglycemia induces cellular senescence in various body cells, such as vascular endothelial cells. Since the vessels are high y distributed in the body and nourish all tissues, vascular damages cause diabetes complications such as kidney failure and visual impairment. Alpha-mangostin is a xanthone found in mangosteen fruit with protective effects in metabolic syndrome and diabetes. This paper has investigated the protective effect of this xanthone against high glucose-induced memory senescence in human vascular endothelial cells (HUVECs) in the presence of metformin, as a positive control. To induce the memory senescence model, HUVECs, after three days incubation with high glucose, were incubated with normal glucose for another three days, and for whole six days, cells were treated with metformin (50 µM) or alpha-mangostin (1.25 µM). On the last day, cell viability by MTT assay, oxidative stress by fluorimetric assay, the number of senescent cells by SA beta-galactosidase staining kit, and secretory interleukin-6 by ELISA kit were measured. SIRT1 and P53 proteins were also evaluated by Western blotting. Metformin and alpha-mangostin significantly increased cell viability, decreased reactive oxygen species, and senescence-associated beta-galactosidase in HUVECs incubated in metabolic memory condition. Generally, metabolic memory increased p53 and acetyl-P53 and decreased SIRT1 proteins in HUVECs, which were reversed by alpha-mangostin and metformin. These data exhibit that alpha-mangostin, comparable to metformin, protects endothelial cells against metabolic memory-induced senescence, which is likely via SIRT1.
Publication Date: 2020-11-06 00:00:00
Journal: Iranian journal of basic medical sciences

blood glucose(12)

Deep Physiological Model for Blood Glucose Prediction in T1DM Patients.
Accurate estimations for the near future levels of blood glucose are crucial for Type 1 Diabetes Mellitus (T1DM) patients in order to be able to react on time and avoid hypo and hyper-glycemic episodes. Accurate predictions for blood glucose are the base for control algorithms in glucose regulating systems such as the artificial pancreas. Numerous research studies have already been conducted in order to provide predictions for blood glucose levels with particularities in the input signals and underlying models used. These models can be categorized into two major families: those based on tuning glucose physiological-metabolic models and those based on learning glucose evolution patterns based on machine learning techniques. This paper reviews the state of the art in blood glucose predictions for T1DM patients and proposes, implements, validates and compares a new hybrid model that decomposes a deep machine learning model in order to mimic the metabolic behavior of physiological blood glucose methods. The differential equations for carbohydrate and insulin absorption in physiological models are modeled using a Recurrent Neural Network (RNN) implemented using Long Short-Term Memory (LSTM) cells. The results show Root Mean Square Error (RMSE) values under 5 mg/dL for simulated patients and under 10 mg/dL for real patients.
Publication Date: 2020-07-17 00:00:00
Journal: Sensors (Basel, Switzerland)


Hyperglycemic memory in the rat bladder detrusor is associated with a persistent hypomethylated state.
Hyperglycemic memory is associated with several complications of diabetes. Although there is some physiological evidence that this phenomenon occurs with diabetic bladder dysfunction (DBD), there have been no studies in bladder that provide evidence of hyperglycemic memory at the molecular/biochemical level. In the present studies, we determined the effects of long-term diabetes on the metabolome of bladder detrusor in a rat model of streptozotocin-induced type-1-diabetes and the ability of insulin treatment to normalize metabolic changes. These studies demonst rat d that although insulin reversed a majority of the metabolic changes caused by diabetes, with long-term diabetes there was a persistent decrease in the methylation index (indicated by a reduced rat o of S-adenosylmethionine to S-adenosyl homocysteine) after insulin treatment. We confirmed a "hypomethylated environment" develops in diabetic detrusor by demonst rat ng an overall reduction in methylated detrusor DNA that is only partially reversed with glycemic control. Furthermore, we confirmed that this hypomethylated environment is associated with epigenetic changes in the detrusor genome, which are again mostly, but not completely, reversed with glycemic control. Overall our studies provide strong molecular evidence for a mechanism by which diabetes alters methylation status and gene expression in the detrusor genome, and that these epigenetic modifications contribute to hyperglycemic memory. Our work suggests novel treatment st rat gies for diabetic patients who have attained glycemic control but continue to experience DBD. For example, epigenomic data can be used to identify "actionable gene targets" for its treatment and would also support a rat onale for approaches that target the hypomethylation index.
Publication Date: 2020-11-18 00:00:00
Journal: Physiological reports

glucose metabolism(11)

"Gut Microbiota-Circadian Clock Axis" in Deciphering the Mechanism Linking Early-Life Nutritional Environment and Abnormal Glucose Metabolism.
The prevalence of diabetes mellitus (DM) has been increasing dramatically worldwide, but the pathogenesis is still unknown. A growing amount of evidence suggests that an abnormal developmental environment in early life increases the risk of developing metabolic diseases in adult life, which is referred to as the "metabolic memory" and the Developmental Origins of Health and Disease (DOHaD) hypothesis. The mechanism of "metabolic memory" has become a hot topic in the field of DM worldwide and could be a key to understanding the pathogenesis of DM. In recent years, several large cohort studies have shown that shift workers have a higher risk of developing type 2 diabetes mellitus (T2DM) and worse control of blood glucose levels. Furthermore, a maternal high-fat diet could lead to metabolic disorders and abnormal expression of clock genes and clock-controlled genes in offspring. Thus, disorders of circadian rhythm might play a pivotal role in glucose metabolic disturbances, especially in terms of early adverse nutritional environments and the development of metabolic diseases in later life. In addition, as a peripheral clock, the gut microbiota has its own circadian rhythm that fluctuates with periodic feeding and has been widely recognized for its significant role in metabolism. In light of the important roles of the gut microbiota and circadian clock in metabolic health and their interconnected regulatory relationship, we propose that the "gut microbiota-circadian clock axis" might be a novel and crucial mechanism to decipher "metabolic memory." The "gut microbiota-circadian clock axis" is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life.
Publication Date: 2019-09-20 00:00:00
Journal: International journal of endocrinology


Alzheimer's Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α.
Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Mutations in genes encoding proteins involved in amyloid-β peptide (Aβ) production are responsible for inherited AD cases. The amyloid cascade hypothesis was proposed to explain the pathogeny. Despite the fact that Aβ is considered as the main culprit of the pathology, most clinical trials focusing on Aβ failed and suggested that earlier interventions are needed to influence the course of AD. Therefore, identifying risk factors that predispose to AD is crucial. Among them, the epsilon 4 allele of the
Publication Date: 2020-05-20 00:00:00
Journal: Cells


Epigenetics and Cellular Metabolism.
Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.
Publication Date: 2016-10-04 00:00:00
Journal: Genetics & epigenetics


Strain and sex-based glucocentric & behavioral differences between KK/HlJ and C57BL/6J mice.
Small-animal models are the most widely used preclinical model for studying the etiology, pathology and treatment of diabetes, prediabetes and diabetic comorbidities. Diabetic patients are burdened with higher rates of depression, anxiety and cognitive decline due to inadequate control of blood glucose levels, vascular damage and aberrant CNS insulin signaling. The C57BL/6J model is amongst the most widely used mouse model due to its susceptibility to diet-induced obesity (DIO). This strain has also been well-characterized in behavioral research studies. However the C57BL/6J model has a number of limitations: [1] overt fasting hyperglycemia can only be induced by dietary manipulation and/or chemical ablation of the pancreatic beta cells. [2] There is heterogeneity in the obesogenic response to hypercaloric feeding as well as sex-dependent differences, with males being more responsive. The KK inbred strain has been used to study aspects of the metabolic syndrome and prediabetes due to inherent glucose intolerance, hyperinsulinemia and insulin resistance. However KK/HlJ mice are less well-characterized and there have been fewer behavioral studies reported. The aim of this study was to examine differences in male and female glucocentric parameters between KK/HlJ and C57BL/6J mice, and to compare their performance in a variety of standard behavioral tests relating to general, anxiogenic and cognitive paradigms. Strain differences in male and female KK/HlJ and C57BL/6J mouse adiposity, glucose and insulin parameters were studied together with group differences in standard Open Field, Object Recognition, Elevated Plus Maze, Light-Dark Transition, Porsolt test, Marble Burying, Social Recognition and Morris Water Maze tests. Correlations between behavioral variables were analyzed. In addition to being uniformly larger, hyperinsulinemic and more insulin intolerant than C57BL/6J mice, we observed marked strain and sex-differences in KK/HlJ behavior. KK/HlJ mice exhibited less locomotor and vertical exploratory behavior in comparison to C57BL/6J, whereas object exploration and novel object discrimination were superior in KK/HlJ mice. Female KK/HlJ mice were faster swimmers, whereas the males exhibited greater spatial cognition and place-learning during the MWM test.
Publication Date: 2019-08-11 00:00:00
Journal: Physiology & behavior


Brain microstructural abnormalities in type 2 diabetes mellitus: A systematic review of diffusion tensor imaging studies.
Type 2 diabetes mellitus (T2DM) is associated with deficits in the structure and function of the brain. Diffusion tensor imaging (DTI) is a highly sensitive method for characterizing cerebral tissue microstructure. Using PRISMA guidelines, we identified 29 studies which have demonstrated widespread brain microstructural impairment and topological network disorganization in patients with T2DM. Most consistently reported structures with microstructural abnormalities were frontal, temporal, and parietal lobes in the lobar cluster; corpus callosum, cingulum, uncinate fasciculus, corona radiata, and internal and external capsules in the white matter cluster; thalamus in the subcortical cluster; and cerebellum. Microstructural abnormalities were correlated with pathological derangements in the endocrine profile as well as deficits in cognitive performance in the domains of memory, information-processing speed, executive function, and attention. Altogether, the findings suggest that the detrimental effects of T2DM on cognitive functions might be due to microstructural disruptions in the central neural structures.
Publication Date: 2019-08-12 00:00:00
Journal: Frontiers in neuroendocrinology


Abnormal DNA Methylation Induced by Hyperglycemia Reduces CXCR 4 Gene Expression in CD 34
Background CD 34
Publication Date: 2019-04-26 00:00:00
Journal: Journal of the American Heart Association

cognitive performance(10)

Associations between cognitive performance and Mediterranean dietary pattern in patients with type 1 or type 2 diabetes mellitus.
Diabetes mellitus has been associated with impaired cognitive performance particularly in verbal memory. Mediterranean diets (MedD) may lead to improvements in overall and single cognitive functions. We hypothesised that adherence to MedD associates with better performance in verbal memory in patients with type 1 or type 2 diabetes. Thus, we performed a cross-sectional analysis including patients with recently diagnosed type 1 (n = 75) or type 2 diabetes (n = 118), metabolically healthy individuals (n = 41) and individuals with type 1 (n = 44) or type 2 diabetes (n = 62) of at least five years after diagnosis. Participants underwent comprehensive metabolic phenotyping and cognitive testing. Adherence to the Modified Mediterranean diet scale (MMDS) was computed from a food frequency questionnaire. Among patients with type 2 diabetes with a known diabetes duration ≥5 years, closer adherence to the MMDS was associated with higher score in verbal memory after adjustment for potential confounders (P = 0.043). Adherence to the MMDS did not relate to verbal memory in recently diagnosed type 2 diabetes (P = 0.275), recently diagnosed or longer-standing type 1 diabetes (P = 0.215 and P = 0.626, respectively) or metabolically healthy individuals (P = 0.666). In conclusion, closer adherence to MedD may exert beneficial effects on cognitive performance in the course of type 2 diabetes.
Publication Date: 2020-04-03 00:00:00
Journal: Nutrition & diabetes


Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21.
A viewpoint considering Alzheimer's disease (AD) as "type 3 diabetes" emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete.
Publication Date: 2020-07-30 00:00:00
Journal: Theranostics

endothelial cells(7)

Resveratrol inhibits high-glucose-induced inflammatory "metabolic memory" in human retinal vascular endothelial cells through SIRT1-dependent signaling.
Diabetes induces vascular endothelial damage and this study investigated high-glucose-induced inflammation "metabolic memory" of human retinal vascular endothelial cells (HRVECs), the effects of resveratrol on HRVECs, and the underlying signaling. HRVECs were grown under various conditions and assayed for levels of sirtuin 1 (SIRT1); acetylated nuclear factor κB (Ac-NF-κB); NOD-like receptor family, pyrin domain containing 3 (NLRP3); and other inflammatory cytokines; and cell viability. A high glucose concentration induced HRVEC inflammation metabolic memory by decreasing SIRT1 and increasing Ac-NF-κB, NLRP3, caspase 1, interleukin-1β, inducible nitric oxide synthase, and tumor necrosis factor α, whereas exposure of HRVECs to a high glucose medium for 4 days, followed by a normal glucose concentration for an additional 4 days, failed to reverse these changes. A high glucose concentration also significantly reduced HRVEC viability. In contrast, resveratrol, a selective SIRT1 activator, markedly enhanced HRVEC viability and reduced the inflammatory cytokines expressions. In addition, high glucose reduced AMP-activated protein kinase (AMPK) phosphorylation and retained during the 4 days of the reversal period of culture. The effects of resveratrol were abrogated after co-treatment with the SIRT1 inhibitor nicotinamide and the AMPK inhibitor compound C. In conclusion, resveratrol was able to reverse high-glucose-induced inflammation "metabolic memory" of HRVECs by activation of the SIRT1/AMPK/NF-κB pathway.
Publication Date: 2019-10-23 00:00:00
Journal: Canadian journal of physiology and pharmacology


Metabolic Syndrome and Cardiovascular Disease Impacts on the Pathophysiology and Phenotype of HIV-Associated Neurocognitive Disorders.
Evidence from epidemiological studies on the general population suggests that midlife cardiovascular disease (CVD) and/or metabolic syndrome (MetS) are associated with an increased risk of cognitive impairment and dementia later in life. In the modern combined antiretroviral therapy (cART) era, as in the general population, CVD and MetS were strongly and independently associated with poorer cognitive performances of sustained immunovirologically controlled persons living with human immunodeficiency viruses (PLHIVs). Those findings suggest that CV/metabolic comorbidities could be implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND) and might be more important than factors related to HIV infection or its treatment, markers of immunocompetence, or virus replication. The association between CVD/MetS and cognition decline is driven by still not well-understood mechanisms, but risk might well be the consequence of increased brain inflammation and vascular changes, notably cerebral small-vessel disease. In this review, we highlight the correspondences observed between the findings concerning CVD and MetS in the general population and virus-suppressed cART-treated PLHIVs to evaluate the real brain-aging processes. Indeed, incomplete HIV control mainly reflects HIV-induced brain damage described during the first decades of the pandemic. Given the growing support that CVD and MetS are associated with HAND, it is crucial to improve early detection and assure appropriate management of these conditions.
Publication Date: 2020-01-29 00:00:00
Journal: Current topics in behavioral neurosciences

1 diabetic rats(4)

Differential change in cortical and hippocampal monoamines, and behavioral patterns in streptozotocin-induced type 1 diabetic rats.
Diabetes mellitus (DM) is a widespread metabolic disorder worldwide. Clinical physicians have found diabetic patients have mild to middle cognitive dysfunction and an alteration of brain monoaminergic function. This study explored the change in various patterns of behavioral models and brain monoamine function under streptozotocin (STZ)-induced type 1 diabetes. We established a type 1 DM model via intravenous injection with STZ (65 mg/kg) in rats. Three weeks after the STZ injection, various behavioral measurements including the inhibitory avoidance test, active avoidance test and Morris water maze were conducted. Finally, all rats were dissected and the concentrations of monoamines and their metabolites in cortex and hippocampus were measured by high performance liquid chromatography with electrochemical detection. We found that STZ induced type 1 diabetes (hyperglycemia and lack of insulin) in rats. STZ-induced diabetic rats had cognitive impairment in acquisition sessions and long-term retention of the active avoidance test. STZ-induced diabetic rats also had cognitive impairment in spatial learning, reference and working memory of the Morris water maze. STZ significantly reduced concentrations of norepinephrine (NE) in the cortex and dopamine (DA) in the hippocampus, but increased concentrations of DA and serotonin (5-HT) in the cortex 35 days after injection. The concentration of 5-HT in the hippocampus was also significantly increased. The data suggested that this cognitive impairment after a short-term period of STZ injection might be related to cortical NE dysfunction, differential alteration of cortical and hippocampal DA function, and brain 5-HT hyperfunction.
Publication Date: 2018-12-14 00:00:00
Journal: Iranian journal of basic medical sciences

type ii diabetes(6)

The Improving Effect of HL271, a Chemical Derivative of Metformin, a Popular Drug for Type II Diabetes Mellitus, on Aging-induced Cognitive Decline.
In recent years, as the aging population grows, aging-induced cognitive impairments including dementia and Alzheimer's disease (AD) have become the biggest challenges for global public health and social care. Therefore, the development of potential therapeutic drugs for aging-associated cognitive impairment is essential. Metabolic dysregulation has been considered to be a key factor that affects aging and dementia. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a primary sensor of cellular energy states and regulates cellular energy metabolism. Metformin (1,1-dimethylbiguanide hydrochloride) is a well-known AMPK activator and has been widely prescribed for type 2 diabetes mellitus (T2DM). Since the incidence of T2DM and dementia increases with aging, metformin has been considered to be one of the most promising drugs to target dementia and its related disorders. To that end, here, we tested the efficacy of metformin and HL271, a novel metformin derivative, in aging-induced cognitive decline. Water (control), metformin (100 mg/kg) or HL271 (50 mg/kg) were orally administered to aged mice for two months; then, the mice were subjected to behavioral tests to measure their cognitive function, particularly their contextual, spatial and working memory. AMPK phosphorylation was also measured in the drug-treated mouse brains. Our results show that oral treatment with HL271 (50 mg/kg) but not metformin (100 mg/kg) improved cognitive decline in aged mice. AMPK activation was correlated with behavior recovery after aging-induced cognitive decline. Taken together, these results suggest that the newly synthesized AMPK activator, HL271, could be a potential therapeutic agent to treat age-related cognitive decline.
Publication Date: 2018-03-15 00:00:00
Journal: Experimental neurobiology

understanding metabolic memory(3)

Response to Comment on Miller and Orchard: Understanding Metabolic Memory: A Tale of Two Studies. Diabetes 2020;69:291-299.
Publication Date: 2020-06-21 00:00:00
Journal: Diabetes

cognitive deficits(12)

Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is a global health problem without effective methods to alleviate the disease progression. Amyloid β-protein (Aβ) is widely accepted as a key biomarker for AD. Metabolic syndromes, including obesity and insulin resistance, are key high risk factors for AD. Akkermansia muciniphila (Akk), the only representative human gut microbe in the genus Verrucomicrobia, can prevent the weight gain caused by a high-fat diet, repair the damaged integrity of the intestinal epithelium barrier, reduce endotoxin levels in blood and improve insulin resistance. The aim of this study is to explore the impact of Akk administration in AD model mice in different diets. APP/PS1 mice were fed either a normal chow diet or a high-fat diet and were treated with Akk by gavage each day for 6 months. The impacts of Akk on glucose metabolism, intestinal barrier and lipid metabolism in the mouse model of AD were determined. Changes in brain pathology and neuroethology were also analyzed. Akk effectively reduced the fasting blood glucose and serum diamine oxidase levels, and alleviated the reduction of colonic mucus cells in APP/PS1 mice. After treatment with Akk, the APP/PS1 mice showed obviously reduced blood lipid levels, improved hepatic steatosis and scapular brown fat whitening. Moreover, Akk promoted the reduction of Aβ 40-42 levels in the cerebral cortex of APP/PS1 mice, shortened the study time and improved the completion rate in Y-maze tests. Akk effectively improved glucose tolerance, intestine barrier dysfunction and dyslipidemia in AD model mice. Our study results suggested that Akk could delay the pathological changes in the brain and relieve impairment of spatial learning and memory in AD model mice, which provides a new strategy for prevention and treatment of AD.
Publication Date: 2020-04-24 00:00:00
Journal: Nutrition & diabetes


Proteotoxicity and mitochondrial dynamics in aging diabetic brain.
Impaired neuronal proteostasis is a salient feature of both aging and protein misfolding disorders. Amyloidosis, a consequence of this phenomena is observed in the brains of diabetic patients over the chronic time period. These toxic aggregates not only cause age-related decline in proteostasis, but also dwindle its ability to increase or restore the chaperones in response to any stressful condition. Mitochondria acts as the main source of energy regulation and many metabolic disorders such as diabetes have been associated with altered oxidative phosphorylation (OxPhos) and redox imbalance in the mitochondria. The mitochondrial unfolded protein response (UPR
Publication Date: 2020-05-26 00:00:00
Journal: Pharmacological research


Pioglitazone improves working memory performance when administered in chronic TBI.
Traumatic brain injury (TBI) is a leading cause of long-term disability in the United States. Even in comparatively mild injuries, cognitive and behavioral symptoms can persist for years, and there are currently no established strategies for mitigating symptoms in chronic injury. A key feature of TBI-induced damage in acute and chronic injury is disruption of metabolic pathways. As neurotransmission, and therefore cognition, are highly dependent on the supply of energy, we hypothesized that modulating metabolic activity could help restore behavioral performance even when treatment was initiated weeks after TBI. We treated rats with pioglitazone, a FDA-approved drug for diabetes, beginning 46 days after lateral fluid percussion injury and tested working memory performance in the radial arm maze (RAM) after 14 days of treatment. Pioglitazone treated TBI rats performed significantly better in the RAM test than untreated TBI rats, and similarly to control animals. While hexokinase activity in hippocampus was increased by pioglitazone treatment, there was no upregulation of either the neuronal glucose transporter or hexokinase enzyme expression. Expression of glial markers GFAP and Iba-1 were also not influenced by pioglitazone treatment. These studies suggest that targeting brain metabolism, in particular hippocampal metabolism, may be effective in alleviating cognitive symptoms in chronic TBI.
Publication Date: 2019-09-13 00:00:00
Journal: Neurobiology of disease

metabolic disease(6)

Shared signaling pathways in Alzheimer's and metabolic disease may point to new treatment approaches.
'A peculiar severe disease process of the cerebral cortex' are the exact words used by A. Alzheimer in 1906 to describe a patient's increasingly severe condition of memory loss, changes in personality, and sleep disturbance. A century later, this 'peculiar' disease has become widely known as Alzheimer's disease (AD), the world's most common neurodegenerative disease, affecting more than 35 million people globally. At the same time, its pathology remains unclear and no successful treatment exists. Several theories for AD etiology have emerged throughout the past century. In this review, we focus on the metabolic mechanisms that are similar between AD and metabolic disease , based on the results from genome-wide association studies. We discuss signaling pathways involved in both types of disease and look into new optogenetic methods to study the in vivo mechanisms of AD.
Publication Date: 2020-08-28 00:00:00
Journal: The FEBS journal


The Multiparametric Analysis of Mitochondrial Dynamics in T Cells from Cryopreserved Peripheral Blood Mononuclear Cells (PBMCs).
The analysis of mitochondrial dynamics within immune cells allows us to understand how fundamental metabolism influences immune cell functions, and how dysregulated immunometabolic processes impact biology and disease pathogenesis. For example, during infections, mitochondrial fission and fusion coincide with effector and memory T-cell differentiation, respectively, resulting in metabolic reprogramming. As frozen cells are generally not optimal for immunometabolic analyses, and given the logistic difficulties of analysis on cells within a few hours of blood collection, we have optimized and validated a simple cryopreservation protocol for peripheral blood mononuclear cells, yielding >95% cellular viability, as well as preserved metabolic and immunologic properties. Combining fluorescent dyes with cell surface antibodies, we demonstrate how to analyze mitochondrial density, membrane potential, and reactive oxygen species production in CD4 and CD8 T cells from cryopreserved clinical samples.
Publication Date: 2020-08-19 00:00:00
Journal: Methods in molecular biology (Clifton, N.J.)

bariatric surgery(7)

Skin Autofluorescence and Carotid Intima-Media Thickness Evaluation Following Bariatric Surgery in Patients with Severe Obesity.
Advanced glycation end product (AGE) is a marker of metabolic memory. Accumulated AGEs in skin collagen measured with skin autofluorescence (SAF) was found to be associated with subclinical atherosclerosis. We aimed to evaluate SAF and carotid intima-media thickness (CIMT) and its association with clinical and biochemical parameters in severely obese patients before and after bariatric surgery In this observational study, 432 morbid obese patients evaluated before and after 6 and 12 months of bariatric surgery for metabolic and anthropometric parameters, CIMT and SAF. SAF was assessed in the forearm with an AGE Reader. SAF measurements were higher in diabetic (2.04 ± 0.52 AU) obese patients compared to non-diabetic (1.78 ± 0.40 AU) obese patients (p < 0.0001). Although bariatric surgery induced weight loss resulted in a decrease in CIMT in the 6th and 12th months compared to baseline, weight loss and metabolic improvements were not associated with a parallel decrease in SAF measurements. SAF measurements were positively correlated with body mass index (r 0.527, p < 0.0001), HbA1c (r 0.362, p < 0.0001), and CIMT (r 0.319, p < 0.0001). Multivariate analysis showed the presence of diabetes (but not BMI, age, and sex) was independently associated with SAF (R Bariatric surgery induced weight loss and metabolic improvement were found to be associated with improvement in CIMT, while skin AGE accumulation was not regressed in the first year of surgery.
Publication Date: 2020-10-31 00:00:00
Journal: Obesity surgery


Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer's Disease.
As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer's disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body's diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain's metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-
Publication Date: 2020-02-23 00:00:00
Journal: Journal of diabetes research

db db mice(5)

Explore of the beneficial effects of Huang-Lian-Jie-Du Decoction on diabetic encephalopathy in db/db mice by UPLC-Q-Orbitrap HRMS/MS based untargeted metabolomics analysis.
Diabetic encephalopathy (DE) is a severe diabetic complication with cognitive dysfunction. Huang-Lian-Jie-Du Decoction (HLJDD), a famous traditional Chinese formula, is effective for the treatment of diabetes mellitus and Alzheimer's disease in clinical practices, however, the therapeutic effects and the underlying mechanisms of HLJDD on DE is unclear yet. With this purpose, behavior test, brain histological and biochemical analysis were estimated to assess the beneficial effects of HLJDD on DE. Plasma samples were collected for metabolomics analysis based on UPLC-Q-Orbitrap HRMS/MS and chemometric analysis. As a result, morris water maze test revealed that HLJDD could effectively improve the learning and memory abilities in db/db mice. Brain histological and biochemical analysis indicated that HLJDD could protect against neurodegeneration and oxidative stress in db/db mice. Meanwhile, a total of 21 potential biomarkers with significant differences were identified between Model group and Control group using untargeted metabolomics strategy. Among them, 11 metabolites showed a trend towards the normal levels after HLJDD intervention. These metabolites principally involved in glycerophospholipid metabolism, fatty acid β-oxidation, linoleic acid metabolism, glucose metabolism and glutathione metabolism based on the metabolic pathway analysis, which were regulated in DE model mice after HLJDD intervention. Generally, the results demonstrated that HLJDD had beneficial effects on DE, which could be mediated via ameliorating the metabolic disorders.
Publication Date: 2020-10-12 00:00:00
Journal: Journal of pharmaceutical and biomedical analysis

1 diabetes mellitus(4)

[A 20-year prospective follow-up study to evaluate the development of retinopathy and nephropathy after the onset of type 1 diabetes mellitus: Contribution of glycemic control and metabolic memory].
To assess the time course of changes in the level of glycated hemoglobin (HbA1c) for 20 years after the onset of type 1 diabetes mellitus (T1DM) and to compare its correlation with the development of microvascular complications, such as diabetic retinopathy (DR) and diabetic nephropathy (DN). A total of 187 children with new-onset T1DM were registered in Moscow in 1994. During the 20-year follow-up study, these patients underwent regular check-ups at the Endocrinology Research Center, Ministry of Health of the Russian Federation, which included assessment of physical data, HbA1c 2-4 times a year, biochemical blood and albuminuria tests (once per year), and ophthalmologic examination (twice a year). A total of 155 people fully completed the 20-years follow-up study. During the 20-year follow-up period after the onset of T1DM, 86 of the 155 patients developed microvascular complications: DR and DN in 86 (55.5%) and 24 (15.5%) cases, respectively; while DR concurrent with DN were noted in 20 patients. By the time of their last visit, 69 (44.5%) patients had no evidence suggesting the presence of microvascular complications. The level of HbA1c at the onset of the disease in patients who later developed the complications was higher than in those without complications (10.2±0.6 and 8.5±0.2%, respectively (p = 0.003). The statistically significant differences in HbA1c levels between the groups persisted during subsequent 15 years of follow-up, averaging 9.2±1.5, 9.7±0.9, and 8.1±0.7% after 5, 10, and 15 years, respectively, in the complication group and 7.1±0.3, 8.1±0.4, and 7.2±0.2% in the non-complication group (p < 0.01). Over the last 5 years of the follow-up, the mean HbA1c level between the groups was not significantly different, which at the end of the 20-year follow-up period was 7.8±0.3 and 7.4±0.6%, respectively (p > 0.05). The mean duration of T1DM, in which DR developed, was 9.6±6.2, 11.0±2.0, and 13.6±4.6 years for the non-proliferative, pre-proliferative, and proliferative stages, respectively. That of T1DM, in which DN developed, was 11.8±0.6 years for microalbuminuria and 16.1±1.3 years for macroalbuminuria. The 20-year clinical follow-up of patients who had fallen ill with T1DM in childhood showed that diabetic microangiopathies developed with the long-term preservation of poor blood glucose control (BGC) starting at the onset of the disease. At the same time, the complications progressed to more severe stages, despite a clear trend toward better BGC. This may be suggestive of the negative metabolic memory phenomenon, which necessitates stable BGC, starting at the onset of the disease, for the prevention of microvascular complications. Цель исследования. Оценка динамики уровня гликированного гемоглобина (HbA1c) в течение 20 лет от момента дебюта сахарного диабета 1-го типа (СД-1) и сопоставление ее с развитием микрососудистых осложнений - диабетической ретинопатии (ДР) и нефропатии (ДН). Материалы и методы. В 1994 г. в Москве с впервые выявленным СД-1 зарегистрированы 187 детей. В течение 20 лет наблюдения эти пациенты проходили регулярное обследование в ФГБУ 'Эндокринологический научный центр' (ЭНЦ) МЗ РФ, включавшее оценку физических данных, уровня HbA1c 2-4 раза в год, биохимическое исследование крови и альбуминурии (1 раз в год), осмотр офтальмолога (2 раза в год). Полностью 20-летний период наблюдения закончили 155 человек. Результаты. За период 20-летнего наблюдения от момента дебюта СД-1 микрососудистые осложнения развились у 86 из 155 больных: ДР у 86 (55,5%), ДН у 24 (15,5%), при этом сочетание ДР и ДН отмечалось у 20 больных. У 69 (44,5%) пациентов к моменту последнего визита данные, подтверждающие наличие микрососудистых осложнений, отсутствовали. Уровень HbA1c в дебюте заболевания у пациентов, у которых позже развились осложнения, был выше, чем в группе пациентов без осложнений, - 10,2±0,6 и 8,5±0,2% соответственно (p=0,003). Статистически значимые различия уровня HbA1c между группами сохранялись в течение последующих 15 лет наблюдения, составляя в среднем 9,2±1,5, 9,7±0,9 и 8,1±0,7% через 5, 10 и 15 лет соответственно в группе больных с осложнениями и 7,1±0,3, 8,1±0,4 и 7,2±0,2% в группе без осложнений (р<0,01). В течение последних 5 лет наблюдения средний уровень HbA1c между группами статистически значимо не различался, составляя на конец 20-летнего наблюдения 7,8±0,3 и 7,4±0,6% соответственно (р>0,05). Средняя длительность СД-1, при которой развилась ДР, составила для непролиферативной стадии 9,6±6,2 года, для препролиферативной стадии - 11±2 года, для пролиферативной стадии - 13,6±4,6 года. Средняя длительность СД-1, при которой развилась ДН, составила для стадии микроальбуминурии 11,8±0,6 года, для стадии макроальбуминурии - 16,1±1,3 года. Заключение. 20-Летнее клиническое наблюдение за пациентами, заболевшими СД-1 в детском возрасте, показало, что диабетические микроангиопатии развиваются при длительном сохранении неудовлетворительного контроля уровня глюкозы в крови (УГК), начиная с дебюта заболевания. При этом прогрессирование осложнений до более тяжелых стадий происходит, несмотря на отчетливую тенденцию к улучшению контроля УГК. Это может свидетельствовать о феномене 'негативной метаболической памяти', что обусловливает необходимость стабильного контроля УГК, начиная с дебюта заболевания, для профилактики микрососудистых осложнений.
Publication Date: 2017-11-25 00:00:00
Journal: Terapevticheskii arkhiv

diabetic metabolic memory(4)

Response to letter "DPP-4 inhibition as a therapeutic strategy to ameliorate diabetic metabolic memory".
Publication Date: 2017-09-26 00:00:00
Journal: International journal of cardiology

location location(1)

Location, location, location: Beneficial effects of autologous fat transplantation.
Visceral adiposity is a risk factor for cardiovascular disorders, type 2 diabetes mellitus (T2D) and associated metabolic diseases. Sub-cutaneous fat is believed to be intrinsically different from visceral fat. To understand molecular mechanisms involved in metabolic advantages of fat transplantation, we studied a rat model of diet-induced adiposity. Adipokine genes (Adiponectin, Leptin, Resistin and Visfatin) were expressed at 10,000 to a million-fold lower in visceral fat depot as compared to peripheral (thigh/chest) fat depots. Interestingly, autologous transplantation of visceral fat to subcutaneous sites resulted in increased gene transcript abundance in the grafts by 3 weeks post-transplantation, indicating the impact of local (residence) factors influencing epigenetic memory. We show here that active transcriptional state of adipokine genes is linked with glucose mediated recruitment of enzymes that regulate histone methylation. Adipose depots have "residence memory" and autologous transplantation of visceral fat to sub-cutaneous sites offers metabolic advantage.
Publication Date: 2012-02-23 00:00:00
Journal: Scientific reports

high glucose(9)

Characteristic Metabolic Alterations Identified in Primary Neurons Under High Glucose Exposure.
Cognitive dysfunction is a central nervous system (CNS) complication of diabetes mellitus (DM) that is characterized by impaired memory and cognitive ability. An in-depth understanding of metabolic alterations in the brain associated with DM will facilitate our understanding of the pathogenesis of cognitive dysfunction. The present study used an
Publication Date: 2018-08-02 00:00:00
Journal: Frontiers in cellular neuroscience


Ginsenoside Rb1 Improves Cognitive Impairment Induced by Insulin Resistance through Cdk5/p35-NMDAR-IDE Pathway.
The relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) has attracted wide attention. Studies have reported that ginsenoside Rb1 can improve human cognitive ability and glucose tolerance during the development of diabetes. The mechanism behind the improvement in cognitive ability and glucose tolerance still remains unclear. In this study, streptozotocin- (STZ-) injected mice were used as models to explore the mechanisms behind the cognitive improvement of ginsenoside Rb1. According to the results of behavioral tests, ginsenoside Rb1 improved memory and cognitive ability of STZ-lesioned mice. In addition to that, ginsenoside Rb1 also relieved glucose intolerance induced by STZ injection by enhancing insulin sensitivity. These beneficial effects of ginsenoside Rb1 is most likely mediated by upregulating the expression of NMDAR1 and IDE in the hippocampus through inhibiting the activity of Cdk5/p35. This work will be of great importance in illustrating the mechanisms of ginsenoside Rb1 for improving cognitive ability, as well as revealing the relationship between diabetes and AD.
Publication Date: 2020-06-19 00:00:00
Journal: BioMed research international


Western Diet Accelerates the Impairment of Odor-Related Learning and Olfactory Memory in the Mouse.
Olfactory dysfunction could be an early indicator of cognitive decline in type 2 diabetes (T2D). However, whether obesity affects olfaction in people with T2D is unclear. This question needs to be addressed, because most people with T2D are obese. Importantly, whether different contributing factors leading to obesity (e.g., different components of diet or gain in weight) affect specific olfactory functions and underlying mechanisms is unknown. We examined whether two T2D-inducing obesogenic diets, one containing a high proportion of fat (HFD) and one with moderate fat and high sugar (Western diet, WD), affect odor detection/discrimination, odor-related learning and olfactory memory in the mouse. We also investigated whether the diets impair adult neurogenesis, GABAergic interneurons, and neuroblasts in the olfactory system. Here, we further assessed olfactory cortex volume and cFos expression-based neuronal activity. The WD-fed mice showed declined odor-related learning and olfactory memory already after 3 months of diet intake (
Publication Date: 2020-10-16 00:00:00
Journal: ACS chemical neuroscience

memory impairment(10)

Insulin resistance is associated with verbal memory impairment in bipolar disorders.
Cognitive impairment contributes to deterioration in social, family and work functioning in Bipolar Disorder (BD). Cognitive deficits are present not only during, but also outside of mood episodes. Insulin resistance (IR) impairs cognitive functioning and is frequent in participants with BD. Thus, we hypothesized that IR might contribute to cognitive deficits in remitted BD participants. We acquired biochemical (fasting insulin, glucose, lipids) cognitive (California Verbal Learning Test, Digit Span) measures from 100 euthymic participants with BD type I or II. IR was diagnosed using HOMA-IR. BD participants with IR displayed worse composite verbal memory score (-0.38 vs 0.17; F(1, 8.23)=17.90; p = 0.003), while composite working memory scores were comparable in patients with or without IR (-0.20 vs 0.07; F(1, 6.05)=1.64; p = 0.25). Insulin resistance remained significantly associated with composite verbal memory scores (F(1, 47.99)=9.82, p = 0.003) even when we controlled for levels of lipids. The association between IR and verbal memory was not confounded by exposure to antipsychotics, which were not associated with worse cognitive performance (F(1, 2.07)=5.95, p = 0.13). The main limitation is the cross-sectional design, which does not allow us to rule out reverse causation. We demonstrated that among remitted BD participants without diabetes mellitus, IR was significantly associated with verbal memory performance, even when we controlled for other relevant metabolic or treatment variables. These findings raise the possibility that early detection and treatment of IR, which is reversible, could possibly improve cognitive functioning in at least some BD participants.
Publication Date: 2020-02-15 00:00:00
Journal: Journal of affective disorders

ca 2(2)

Effects of caloric restriction on O-GlcNAcylation, Ca(2+) signaling, and learning impairment in the hippocampus of ob/ob mice.
Diabetes may adversely affect cognitive function and, conversely, caloric restriction (CR) increases longevity and improves memory. To shed light on the unknown underlying mechanisms involved in these observations, we examined the effects of CR on serum metabolic parameters and hippocampal protein expression in the ob/ob mice model of obesity-induced diabetes. We found that CR reduced hepatic steatosis and insulin resistance in ob/ob mice. In addition, CR increased the levels of hippocampal O-linked-N-acetylglucosamine (O-GlcNAc) and GlcNAc transferase and decreased the expression of calcium/calmodulin-dependent protein kinase II, lipocalin-2, and phosphorylated tau. Furthermore, CR lessened the learning deficits that are typically seen in ob/ob mice. These findings indicate that CR may reverse obesity-related brain glucose impairment and intracellular Ca(2+) dysfunction and relieve learning impairment associated with diabetes.
Publication Date: 2016-06-19 00:00:00
Journal: Neurobiology of aging


Outcomes and clinical implications of intranasal insulin administration to the central nervous system.
Insulin signaling in the brain plays a critical role in metabolic control and cognitive function. Targeting insulinergic pathways in the central nervous system via peripheral insulin administration is feasible, but associated with systemic effects that necessitate tight supervision or countermeasures. The intranasal route of insulin administration, which largely bypasses the circulation and thereby greatly reduces these obstacles, has now been repeatedly tested in proof-of-concept studies in humans as well as animals. It is routinely used in experimental settings to investigate the impact on eating behavior, peripheral metabolism, memory function and brain activation of acute or long-term enhancements in central nervous system insulin signaling. Epidemiological and experimental evidence linking deteriorations in metabolic control such as diabetes with neurodegenerative diseases imply pathophysiological relevance of dysfunctional brain insulin signaling or brain insulin resistance, and suggest that targeting insulin in the brain holds some promise as a therapy or adjunct therapy. This short narrative review gives an overview over recent findings on brain insulin signaling as derived from human studies deploying intranasal insulin, and evaluates the potential of therapeutic interventions that target brain insulin resistance.
Publication Date: 2019-03-20 00:00:00
Journal: Experimental neurology


A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort.
Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers. This study analyzed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV). On the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively. This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort Further studies in independent cohort are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.
Publication Date: 2020-01-01 00:00:00
Journal: Alzheimer's & dementia (New York, N. Y.)


Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits.
Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8
Publication Date: 2020-10-18 00:00:00
Journal: Nature communications


Mitochondrial activity in different regions of the brain at the onset of streptozotocin-induced diabetes in rats.
Diabetes affects a variety of tissues including the central nervous system; moreover, some evidence indicates that memory and learning processes are disrupted. Also, oxidative stress triggers alterations in different tissues including the brain. Recent studies indicate mitochondria dysfunction is a pivotal factor for neuron damage. Therefore, we studied mitochondrial activity in three brain regions at early type I-diabetes induction. Isolated mitochondria from normal hippocampus, cortex and cerebellum revealed different rates of oxygen consumption, but similar respiratory controls. Oxygen consumption in basal state 4 significantly increased in the mitochondria from all three brain regions from diabetic rats. No relevant differences were observed in the activity of respiratory complexes, but hippocampal mitochondrial membrane potential was reduced. However, ATP content, mitochondrial cytochrome c, and protein levels of β-tubulin III, synaptophysin, and glutamine synthase were similar in brain regions from normal and diabetic rats. In addition, no differences in total glutathione levels were observed between normal and diabetic rat brain regions. Our results indicated that different regions of the brain have specific metabolic responses. The changes in mitochondrial activity we observed at early diabetes induction did not appear to cause metabolic alterations, but they might appear at later stages. Longer-term streptozotocin treatment studies must be done to elucidate the impact of hyperglycemia in brain metabolism and the function of specific brain regions.
Publication Date: 2018-07-10 00:00:00
Journal: Molecular biology reports

central nervous system(4)

Early-Stage Alzheimer's Disease Is Associated with Simultaneous Systemic and Central Nervous System Dysregulation of Insulin-Linked Metabolic Pathways.
Brain insulin resistance is a well-recognized abnormality in Alzheimer's disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity. This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related. Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and 21 controls using a multiplex ELISA platform. In MCI/AD, both the CSF and serum samples had significantly elevated mean levels of C-peptide and an incretin, and reduced expression of Visfatin, whereas only CSF showed significant reductions in insulin and leptin and only serum had increased glucagon, PAI-1, and ghrelin. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different. In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors.
Publication Date: 2019-02-19 00:00:00
Journal: Journal of Alzheimer's disease : JAD

magnetic resonance imaging(4)

Telmisartan-mediated metabolic profile conferred brain protection in diabetic hypertensive rats as evidenced by magnetic resonance imaging, behavioral studies and histology.
Type 2 diabetes and hypertension are associated with cognitive dysfunction that includes pathological changes in brain tissue. It was speculated that the beneficial hypotensive effect of telmisartan, an angiotensin receptor 1 blocker, and its unique hypoglycemic effect due to its PPARγ-activation, could ameliorate the ​ pathological changes in the brain​ that accompany​ these diseases. We examined the effect of telmisartan on brain changes in magnetic resonance imaging (MRI) T2-weighted scans, and behavioral and histological findings in the Cohen-Rosenthal Diabetic Hypertensive (CRDH) rat. Baseline and post-treatment values with telmisartan/vehicle (3 months) of blood pressure, blood glucose levels, behavioral tests, brain MRI scanning and immunohistological staining were obtained. Telmisartan significantly lowered blood pressure and blood glucose levels; induced consistent T2 reduction in specific gray and white regions including hippocampus, corpus callosum, amygdala and cortical regions; and significantly improved performance on behavioral tasks. Immunohistological analysis of the brain revealed significant amelioration of diabetes/hypertension-induced changes in white matter regions and microglia, evidenced by preserved myelin (LBF marker), and improved microglial neuronal markers GFAP, GAP43 and Iba1 expression. In conclusion, the behavioral performance, longitudinal MRI study and histology staining revealed the protective effects of telmisartan on brain microstructure and cognitive function.
Publication Date: 2016-07-16 00:00:00
Journal: European journal of pharmacology

advanced glycation end-products(5)

The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review.
Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. BODY: Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of "metabolic memory." AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.
Publication Date: 2018-11-25 00:00:00
Journal: Molecular medicine (Cambridge, Mass.)

epigenetic modifications(8)

Targeting epigenetic modifications as a potential therapeutic option for diabetic retinopathy.
Diabetic retinopathy (DR) is the leading cause of visual impairment in adults of working age (20-65 years) in developed countries. The metabolic memory phenomena (persistent effect of a glycemic insult even after retrieved) associated with it has increased the risk of developing the complication even after the termination of the glycemic insult. Hence, the need for finding early diagnosis and treatment options has been of great concern. Epigenetic modifications which generally occur during the beginning stages of the disease are responsible for the metabolic memory effect. Therefore, the therapy based on the reversal of the associated epigenetic mechanism can bring new insight in the area of early diagnosis and treatment mechanism. This review discusses the diabetic retinopathy, its pathogenesis, current treatment options, need of finding novel treatment options, and different epigenetic alterations associated with DR. However, the main focus is emphasized on various epigenetic modifications particularly DNA methylation which are responsible for the initiation and progression of diabetic retinopathy and the use of different epigenetic inhibitors as a novel therapeutic option for DR.
Publication Date: 2019-09-19 00:00:00
Journal: Journal of cellular physiology


Role of Advanced Glycation Endproduct (AGE)-Receptor for Advanced Glycation Endproduct (RAGE) Axis in Cardiovascular Disease and Its Therapeutic Intervention.
Despite the early loss of glycemic differences between the original intensive therapy group and conventional treatment in the DCCT/EDIC and UKPDS 80 trials, a continued reduction in microvascular risk and risk reductions for emergency myocardial infarction and all-cause death were observed 10-30 years after the end of these trials. These observations demonstrated that so-called "metabolic memory" could cause chronic abnormalities in diabetic vessels that are not easily reversed, even by subsequent improvement in blood glucose levels, thus suggesting a long-term beneficial influence of early metabolic control; that is, legacy effects on the risk of vascular complications and death in patients with both type 1 and type 2 diabetes. Formation and accumulation of advanced glycation endproducts (AGEs) are known to progress at an accelerated rate under diabetes. Furthermore, AGEs are hardly degraded and remain for a long time in diabetic vessels even after glycemic control is improved. Therefore, AGEs could explain why former cumulative diabetic exposure could contribute to current progression of vascular complications in diabetes. Here, the clinical utility of measurement of serum and tissue accumulation levels of AGEs for evaluating the prevalence and severity of numerous types of cardiovascular disease is reviewed and novel therapeutic strategies that could target the AGE- RAGE axis in CVD are discussed.
Publication Date: 2019-08-02 00:00:00
Journal: Circulation journal : official journal of the Japanese Circulation Society


Lack of the E3 Ubiquitin Ligase March1 Affects CD8 T Cell Fate and Exacerbates Insulin Resistance in Obese Mice.
Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. However, the mechanisms that trigger the underlying adipose tissues inflammation are not completely understood. Here, we show that the E3 ubiquitin ligase March1 controls the phenotypic and functional properties of CD8
Publication Date: 2020-09-26 00:00:00
Journal: Frontiers in immunology

spatial memory(7)

Hyperglycemia induces RAGE-dependent hippocampal spatial memory impairments.
Diabetes is a prevalent metabolic disorder that has long been associated with changes in different regions of the brain, including the hippocampus. Changes in hippocampal synaptic plasticity and subsequent impairment in cognitive functions such as learning and memory, are well documented in animal models of type 1 and type 2 diabetes. It is known that RAGE contributes to peripheral micro- and macro-vascular complications of diabetes. However, it is still unknown if RAGE plays a similar role in the development of CNS complications of diabetes. Therefore, we hypothesize that RAGE contributes to cognitive dysfunction, such as learning and memory impairments, in a mouse model of STZ-induced hyperglycemia. Control and STZ-induced hyperglycemic mice from WT and RAGE-KO groups were used for the behavioral experiments. While STZ-induced hyperglycemia decreased locomotor activity in the open field (OF) test, it did not affect the recognition memory in the novel object recognition (NOR) test in either genotype. Spatial memory however, was impaired in STZ-induced hyperglycemic mice in WT but not in RAGE-KO group in both the Barnes maze (BM) and the Morris water maze (MWM) tests. Consistently, the RAGE antagonist FPS-ZM1 protected WT STZ-induced hyperglycemic mice from spatial memory impairment in the BM test. Our findings indicate that the parameters associated with locomotor activity and recognition memory were independent of RAGE in STZ-induced hyperglycemic mice. In contrast, the parameters associated with hippocampal-dependent spatial memory were dependent on RAGE expression.
Publication Date: 2020-12-15 00:00:00
Journal: Physiology & behavior


Glucagon-like peptide 1 (GLP-1).
The glucagon-like peptide-1 ( GLP-1 is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1 based pharmacotherapies are in clinical evaluation for the treatment of obesity. In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.
Publication Date: 2019-11-27 00:00:00
Journal: Molecular metabolism

dcct edic(4)

Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
To examine whether cardiovascular autonomic neuropathy (CAN) is an independent risk factor of cardiovascular disease (CVD) events during DCCT/EDIC. Standardized cardiovascular autonomic reflex tests (R-R response to paced breathing, Valsalva maneuver, postural changes in blood pressure) were performed at DCCT baseline, every 2 years throughout DCCT, and at two time points in EDIC. CVD events were ascertained throughout the study and adjudicated by a review committee. Cox proportional hazards models were used to estimate the effect of CAN at DCCT closeout on subsequent CVD risk. There were 299 adjudicated CVD events in 165 participants following the DCCT closeout assessment: 132 of 1,262 subjects (10%) without CAN at DCCT closeout who experienced 244 CVD events versus 33 of 131 subjects (25%) with CAN at DCCT closeout who experienced 55 events (hazard ratio 2.79, 95% CI 1.91-4.09 for time to first CVD event). The cumulative incidence of the first occurrence of any CVD event during EDIC was significantly higher in participants with CAN at DCCT closeout compared with those without CAN. The association remained marginally significant after adjustment for multiple risk factors, including the EDIC updated mean HbA In the DCCT/EDIC cohort, individuals diagnosed with CAN at DCCT closeout experienced a higher long-term risk of CVD events during follow-up in EDIC. This association was not independent of historic glycemic exposure and its metabolic memory effect, the principal determinant of both long-term CVD risk and CAN in type 1 diabetes.
Publication Date: 2016-11-03 00:00:00
Journal: Diabetes care

case study(5)

AMPK induced memory improvements in the diabetic population: A case study.
Diabetics in mid-life carry a 1.5 times higher risk of developing Alzheimer's disease than those diagnosed with diabetes (T2D) later in life [1]. Recent research points to accelerated cognitive decline within a range of 20%-50% for middle-aged diabetics as compared to non-diabetic populations [2,3]. Metabolic syndrome (MetS), a type 2 diabetes (T2D) precursor, is also linked to MCI and AD pathologies via hypo-metabolic brain circuitry that inhibits glucose metabolism and attenuates cognitive function [4]. Dysregulation of intracellular and extracellular signaling as mediated by the mTOR and AMPK pathways is the result. These critical nutrient sensing pathways modulate epigenetic shifts in the genome by channeling fuel substrates either towards mitochondrial fatty acid oxidation (AMPK) or cytosolic glycolysis and substrate level phosphorylation (mTOR) [5]. This case study was designed to examine the link between peripheral insulin resistance and early stage memory loss in a type 2 diabetic male. Reactivating the AMPK pathway via induced and controlled nutritional ketosis combined with high intensity interval training (HIIT) (in order to inhibit mTOR signaling) were primary features of the 10 week intervention. Post intervention results revealed statistically significant reductions in HgA1c, fasting insulin and HOMA-IR (homeostatic model assessment of insulin resistance). Restoring peripheral and hypothalamic insulin sensitivity by way of AMPK activation may restore memory function, improve neuroplasticity, and normalize MetS biomarkers (Demetrius and Driver, 2014; [4,6]).
Publication Date: 2018-05-12 00:00:00
Journal: Diabetes & metabolic syndrome

hippocampal neurogenesis(4)

Effect of Metformin on Adult Hippocampal Neurogenesis: Comparison with Donepezil and Links to Cognition.
Recent studies have uncovered evidence suggesting that interference with hippocampal adult neurogenesis contributes to neurodegeneration in Alzheimer's disease (AD). Evidence supporting that AD is a metabolic disease with derangements in brain glucose utilization implies the use of anti-diabetics as an alternate therapeutic strategy. The present study drew comparison between the pro-neurogenic potential of metformin and donepezil in AlCl
Publication Date: 2017-04-06 00:00:00
Journal: Journal of molecular neuroscience : MN

quebec canada(2)

epigallocatechin-3-gallate egcg(2)

Epigallocatechin-3-Gallate (EGCG) Improves Cognitive Deficits Aggravated by an Obesogenic Diet Through Modulation of Unfolded Protein Response in APPswe/PS1dE9 Mice.
Epigallocatechin-3-gallate (EGCG), a catechin found in green tea, has been previously investigated for its neuroprotective effects in vitro and in vivo. In the present study, we aimed to evaluate its possible beneficial effects in a well-established preclinical mixed model of familial Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) based on the use of transgenic APPswe/PS1dE9 (APP/PS1) mice fed with a high fat diet (HFD). C57BL/6 wild-type (WT) and APP/PS1 mice were used in this study. APP/PS1 mice were fed with a palmitic acid-enriched HFD (APP/PS1 HFD) containing 45% of fat mainly from hydrogenated coconut oil. Intraperitoneal glucose tolerance tests (IP-GTT) and insulin tolerance tests (IP-ITT) were performed. Western blot analyses were performed to analyse protein expression, and water maze and novel object recognition test were done to evaluate the cognitive process. EGCG treatment improves peripheral parameters such as insulin sensitivity or liver insulin pathway signalling, as well as central memory deficits. It also markedly increased synaptic markers and cAMP response element binding (CREB) phosphorylation rates, as a consequence of a decrease in the unfolded protein response (UPR) activation through the reduction in the activation factor 4 (ATF4) levels and posterior downregulation of protein tyrosine phosphatase 1B (PTP1B). Moreover, EGCG significantly decreased brain amyloid β (Aβ) production and plaque burden by increasing the levels of α-secretase (ADAM10). Also, it led to a reduction in neuroinflammation, as suggested by the decrease in astrocyte reactivity and toll-like receptor 4 (TLR4) levels. Collectively, evidence suggests that chronic EGCG prevents distinct neuropathological AD-related hallmarks. This study also provides novel insights into the metabolic and neurobiological mechanisms of EGCG against cognitive loss through its effects on UPR function, suggesting that this compound may be a promising disease-modifying treatment for neurodegenerative diseases.
Publication Date: 2019-12-16 00:00:00
Journal: Molecular neurobiology

randomized controlled(2)

[Randomized, controlled clinical trials with observational follow-up investigations for evaluating efficacy of antihyperglycaemic treatment. II. Features of and lessons from the follow-up investigations].
Although the outcomes of the follow-up investigation period of the randomized clinical studies for evaluating the efficacy of a treatment or an antidiabetic drug may be confounded or potentially biased by several factors, the results are widely accepted by the diabetes community. In line with the theory of metabolic memory or metabolic legacy, early and intensive antihyperglycaemic treatment should be provided for all diabetic patients as this strategy can result in beneficial effects even in the long run. The recent cardiovascular safety trials with new, innovative antidiabetic drugs differ in several aspects from the former efficacy studies. Ten cardiovascular safety trials were completed so far enabling to define their unique and common features. It can be anticipated that the era of randomized, controlled efficacy studies with observational follow-up investigations came to an end in diabetes research. Nowadays, cardiovascular safety trials are in the focus of clinical research in diabetology and results of several ongoing studies are expected with interest in the near future. Orv Hetil. 2018; 159(16): 615-619.
Publication Date: 2018-04-17 00:00:00
Journal: Orvosi hetilap

hippocampal synaptic plasticity(4)

Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance.
Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders.
Publication Date: 2015-08-25 00:00:00
Journal: Biochimica et biophysica acta


Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors.
Interleukin-18 (IL-18) is an inflammatory cytokine linked to major depressive disorder (MDD). MDD is closely related to metabolic disorders, such as diabetes mellitus (DM) and obesity. Moreover, DM is associated with cognitive impairment and promotes apoptosis of hippocampal cells by activating pro-apoptotic and inhibiting anti-apoptotic factors. IL-18-deficient (Il18
Publication Date: 2019-04-15 00:00:00
Journal: Neuroscience


Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?
Type 2 diabetes (T2D) is a metabolic disease with impact on brain function through mechanisms that include glucose toxicity, vascular damage and blood-brain barrier (BBB) impairments, mitochondrial dysfunction, oxidative stress, brain insulin resistance, synaptic failure, neuroinflammation, and gliosis. Rodent models have been developed for investigating T2D, and have contributed to our understanding of mechanisms involved in T2D-induced brain dysfunction. Namely, mice or rats exposed to diabetogenic diets that are rich in fat and/or sugar have been widely used since they develop memory impairment, especially in tasks that depend on hippocampal processing. Here we summarize main findings on brain energy metabolism alterations underlying dysfunction of neuronal and glial cells promoted by diet-induced metabolic syndrome that progresses to a T2D phenotype.
Publication Date: 2020-04-09 00:00:00
Journal: Frontiers in neuroscience

glucagon-like peptide 1(3)

Alleviation of Depression by Glucagon-Like Peptide 1 Through the Regulation of Neuroinflammation, Neurotransmitters, Neurogenesis, and Synaptic Function.
Depression has emerged as a major cause of mortality globally. Many studies have reported risk factors and mechanisms associated with depression, but it is as yet unclear how these findings can be applied to the treatment and prevention of this disorder. The onset and recurrence of depression have been linked to diverse metabolic factors, including hyperglycemia, dyslipidemia, and insulin resistance. Recent studies have suggested that depression is accompanied by memory loss as well as depressive mood. Thus, many researchers have highlighted the relationship between depressive behavior and metabolic alterations from various perspectives. Glucagon-like peptide-1 (GLP-1), which is secreted from gut cells and hindbrain areas, has been studied in metabolic diseases such as obesity and diabetes, and was shown to control glucose metabolism and insulin resistance. Recently, GLP-1 was highlighted as a regulator of diverse pathways, but its potential as the therapeutic target of depressive disorder was not described comprehensively. Therefore, in this review, we focused on the potential of GLP-1 modulation in depression.
Publication Date: 2020-09-15 00:00:00
Journal: Frontiers in pharmacology


Effects of "metabolic memory" on erectile function in diabetic men: A retrospective case-control study.
This study was performed to explore the effects of metabolic memory on diabetic erectile dysfunction (ED), especially the severity and response to treat men . Through medical records and follow-up by telephone, 67 patients meeting the criteria with a clinical diagnosis of ED and a diabetic history of more than 5 years were enrolled for erectile function analysis. They were divided into a glycemic control group, a glycemic non-control group and a metabolic memory group according to glycemic levels and treat men s for diabetes in the past 5 years, and they were treated with phosphodiesterase type 5 (PDE5) inhibitors for 4 weeks. Erectile function and efficacy were assessed by the International Index for Erectile Function (IIEF), the Erection Hardness Score (EHS), and the Sexual Encounter Profile (SEP). The patients in the glycemic control group performed better in erectile function than those in the other groups. The patients in the glycemic control group received a significantly greater score on both the EHS and the five domains of the IIEF than did the patients in the glycemic non-control group and the metabolic memory group (all P < .001). There were also statistically significant differences favoring the glycemic control group (P < .05) in SEP2 and SEP3 success rates. However, there were no significant differences between the metabolic memory group and the glycemic non-control group in these erectile function assess men s (P > .05). Significant negative correlations were seen between HbA1c levels at the time of consultation and the scores on the IIEF-EF and the EHS (Pearson r-values of -0.338 with P = .005 and -0.273 with P = .025, respectively). HbA1c levels at the first diagnosis of diabetes mellitus (DM) were also significantly negatively correlated with scores on the IIEF-EF and the EHS with greater Pearson correlation coefficients (Pearson r-values of -0.478 with P < .001 and -0.392 with P = .001, respectively). Significant improve men s on each of the erectile function assess men s were observed among diabetic patients with ED, but no significant difference in efficacy was observed between each group. The pheno men n of metabolic memory did have a significant influence on ED in men with diabetes, associated with the severity of ED but not the response to medical treat men . Early hyperglycemia exposure would have long-term disadvantageous effects on erectile function in diabetic patients with ED, which would be sustained even after the patients achieve better glycemic control. In this report, we looked at the erectile functions of 67 patients with a clinical diagnosis of ED and a diabetic history of more than 5 years. We found that early hyperglycemia exposure would have long-term disadvantageous effects on erectile function in diabetic patients with ED, which would be sustained even after the patients achieve better glycemic control. We further found that the effects were associated with the severity of ED but not the response to medical treat men in men with diabetes.
Publication Date: 2020-10-07 00:00:00
Journal: Andrology

advanced glycation endproduct(2)

Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease.
Skin autofluorescence (SAF) is a new method to noninvasively assess accumulation of advanced glycation endproduct (AGEs) in a tissue with low turnover. Recent progress in the clinical application of SAF as a risk marker for diabetic nephropathy as well as cardiovascular disease in nondiabetic end-stage kidney disease, less advanced chronic kidney disease, and renal transplant recipients is reviewed. Experimental studies highlight the fundamental role of the interaction of AGEs with the receptor for AGEs (RAGEs), also called the AGE-RAGE axis, in the pathogenesis of vascular and chronic kidney disease. SAF predicts (cardiovascular) mortality in renal failure and also chronic renal transplant dysfunction. Long-term follow-up results from the Diabetes Control and Complications Trial and UK Prospective Diabetes Study suggest that AGE accumulation is a key carrier of metabolic memory and oxidative stress. Short-term intervention studies in diabetic nephropathy with thiamine, benfotiamine and angiotensin-receptor blockers aimed at reducing AGE formation have reported mixed results. SAF is a noninvasive marker of AGE accumulation in a tissue with low turnover, and thereby of metabolic memory and oxidative stress. SAF independently predicts cardiovascular and renal risk in diabetes, as well as in chronic kidney disease. Further long-term studies are required to assess the potential benefits of interventions to reduce AGE accumulation.
Publication Date: 2010-09-17 00:00:00
Journal: Current opinion in nephrology and hypertension

diabetic encephalopathy(5)

Berberine Alleviates Tau Hyperphosphorylation and Axonopathy-Associated with Diabetic Encephalopathy via Restoring PI3K/Akt/GSK3β Pathway.
Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes. The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models. High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro. Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3β signaling pathway in T2D rats. In vitro, berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3β in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway. Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway.
Publication Date: 2018-09-04 00:00:00
Journal: Journal of Alzheimer's disease : JAD


Prenatal high sucrose intake affected learning and memory of aged rat offspring with abnormal oxidative stress and NMDARs/Wnt signaling in the hippocampus.
Maternal over-nutrition may predispose offspring to obesity, type 2 diabetes and other adult diseases. The present study investigated long-term impact of prenatal high sucrose (HS) diets on cognitive capabilities in aged rat offspring. The fasting plasma glucose concentration did not differ between the control and HS groups. However, the fasting plasma insulin and insulin resistance index values were significantly increased in HS offspring that showed abnormal glucose tolerance test. HS offspring exhibited increased escape latency and swimming path length to the platform, and reduced time in the target quadrant and the number of crossing the platform, as compared with the control group. The expression of Grin2b/NR2B, Wnt2, Wnt3a and active form of β-catenin protein were decreased, and Dickkopf-related protein 1 was increased in the HS group. In addition, the levels of lipid peroxidation biomarker thiobarbituricacid reactive substance, nicotinamide adenine dinucleotide phosphate oxidases 2 and superoxide dismutase 1 were significantly increased, and the activity of catalase was decreased in the hippocampus in the HS group. The results demonstrate that prenatal HS-induced metabolic changes cause cognitive deficits in aged rat offspring, probably due to altered N-methyl-d-aspartate receptors/Wnt signaling and oxidative stress in the hippocampus.
Publication Date: 2017-05-24 00:00:00
Journal: Brain research


Exercise benefits on Alzheimer's disease: State-of-the-science.
Although there is no unanimity, growing evidence supports the value of regular physical exercise to prevent Alzheimer's disease as well as cognitive decline in affected patients. Together with an introductory summary on epidemiological evidence, the aim of this review is to summarize the current knowledge on the potential biological mechanisms underlying exercise benefits in this condition. Regular physical exercise has proven to be beneficial for traditional cardiovascular risk factors (e.g., reduced vascular flow, diabetes) involved in the pathogenesis of Alzheimer's disease. Exercise also promotes neurogenesis via increases in exercise induced metabolic factors (e.g., ketone bodies, lactate) and muscle-derived myokines (cathepsin-B, irisin), which in turn stimulate the production of neurotrophins such as brain-derived neurotrophic factor. Finally, regular exercise exerts anti-inflammatory effects and improves the brain redox status, thereby ameliorating the pathophysiological hallmarks of Alzheimer's disease (e.g., amyloid-β deposition). In summary, physical exercise might provide numerous benefits through different pathways that might, in turn, help prevent risk and progression of Alzheimer's disease. More evidence is needed, however, based on human studies.
Publication Date: 2020-06-21 00:00:00
Journal: Ageing research reviews


Iron deficiency in pregnancy.
Iron is essential for the function of all cells through its roles in oxygen delivery, electron transport, and enzymatic activity. Cells with high metabolic rates require more iron and are at greater risk for dysfunction during iron deficiency Iron requirements during pregnancy increase dramatically, as the mother's blood volume expands and the fetus grows and develops. Thus, pregnancy is a condition of impending or existing iron deficiency which may be difficult to diagnose because of limitations to commonly used biomarkers such as hemoglobin and ferritin concentrations. Iron deficiency is associated with adverse pregnancy outcomes, including increased maternal illness, low birthweight, prematurity, and intrauterine growth restriction. The rapidly developing fetal brain is at particular risk of iron deficiency which can occur because of maternal iron deficiency hypertension, smoking, or glucose intolerance. Low maternal gestational iron intake is associated with autism, schizophrenia, and abnormal brain structure in the offspring. Newborns with iron deficiency have compromised recognition memory, slower speed of processing, and poorer bonding that persist despite postnatal iron repletion. Preclinical models of fetal iron deficiency confirm that expected iron-dependent processes such as monoamine neurotransmission, neuronal growth and differentiation, myelination, and gene expression are all compromised acutely and long term into adulthood. This review outlines strategies to diagnose and prevent iron deficiency in pregnancy. It describes the neurocognitive and mental health consequences of fetal iron deficiency It emphasizes that fetal iron is a key nutrient that influences brain development and function across the lifespan.
Publication Date: 2020-03-19 00:00:00
Journal: American journal of obstetrics and gynecology