Diabetes and Cognitive Impairment: A Role for Glucotoxicity and Dopaminergic Dysfunction

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA’s role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been observed in animal models of experimental diabetes and in diabetic patients, too. Evidence is accumulating that advanced glycation end products (AGEs) and their precursor methylglyoxal (MGO) are associated with cognitive impairment and alterations of the dopaminergic system. Further research is needed to clarify the molecular mechanisms linking DM-associated dopaminergic dysfunction and cognitive impairment and to assess the deleterious impact of glucotoxicity.

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Physical activity and cognitive function in older persons

Swiss Sports & Exercise Medicine ◽

10.34045/ssem/2016/8 ◽

2016 ◽

Vol 64 (2) ◽

Keyword(s):

Physical Activity ◽

Cognitive Impairment ◽

Cognitive Function ◽

Executive Functions ◽

Cognitive Aging ◽

Clinical Studies ◽

Older Persons ◽

Positive Effects ◽

Critical Challenge

Strategies to improve cognitive aging are highly needed. Among those, promotion of exercise and physical activity appears as one of the most attractive and beneficial intervention. Indeed, results from basic and clinical studies suggest that exercise and physical activity have positive effects on cognition in older persons without cognitive impairment, as well as in those with dementia. Despite inconsistent results, aerobic exercise appears to have the strongest potential to enhance cognition. However, even limited periods of walking (45 minutes, three times a week, over a 6-month period) have also been shown to enhance cognition, particularly executive functions. Changing long-term lifestyle habits in these older persons remains a critical challenge and attractive programs susceptible to gain adherence are needed to succeed in achieving improved cognitive aging.

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α-Oxoaldehyde metabolism and diabetic complications

Biochemical Society Transactions ◽

10.1042/bst0311358 ◽

2003 ◽

Vol 31 (6) ◽

pp. 1358-1363 ◽

Cited By ~ 80

Author(s):

P.J. Beisswenger ◽

S.K. Howell ◽

R.G. Nelson ◽

M. Mauer ◽

B.S. Szwergold

Keyword(s):

Diabetic Complications ◽

Complex Mixture ◽

Therapeutic Interventions ◽

Diabetic Patients ◽

Human Populations ◽

Control Mechanisms ◽

Protective Mechanisms ◽

Glycation End Products ◽

End Products

The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including α-oxoaldehydes, which are inherently toxic as well as serving as presursors for advanced glycation end-products. Protective mechanisms exist to control this unavoidable glycation, and these are determined by genetic or environmental factors that can regulate the concentrations of the reactive sugars or end-products. In diabetes these protective mechanisms become more important, since glycation stress increases, and less efficient defence systems against this stress could lead to diabetic complications. Some of these enzymatic control mechanisms, including those that regulate α-oxoaldehydes, have been identified. We have observed significant increases in production of the α-oxoaldehydes methylglyoxal and 3-deoxyglucosone in three human populations with biopsy-proven progression of nephropathy. The increase in methylglyoxal could be secondary to defects in downstream glycolytic enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) that regulate its production, or in detoxification mechanisms such as glyoxalase. Other mechanisms, however, appear to be responsible for the observed increase in 3-deoxyglucosone levels. We present results of our studies on the mechanisms responsible for variable production of α-oxoaldehydes by measuring the activity and characteristics of these enzymes in cells from complication-prone and -resistant diabetic patients. New therapeutic interventions designed to control these endogenous mechanisms could potentially enhance protection against excessive glycation and prevent or reverse complications of long-term diabetes.

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The Association Between Diabetes and Cognitive Function in Later Life

Current Aging Science ◽

10.2174/1874609812666190614104328 ◽

2019 ◽

Vol 12 (1) ◽

pp. 62-66

Author(s):

Yadollah A. Momtaz ◽

Tengku A. Hamid ◽

Mohamad F. Bagat ◽

Maryam Hazrati

Keyword(s):

Cognitive Impairment ◽

Cognitive Function ◽

Cognitive Decline ◽

Linear Regression Analysis ◽

Later Life ◽

Multiple Linear Regression Analysis ◽

Population Based ◽

Term Treatment ◽

Diabetic Patients ◽

Long Term Treatment

Introduction: Although diabetes through several possible mechanisms such as increased microvascular pathology and inefficiency of glucose utilization during cognitive tasks can be associated with cognitive impairment, there is inconclusive evidence that shows elderly diabetic patients under therapy have higher cognitive function compared to their non-diabetics counterparts. The present study was conducted to elucidate the association between diabetes and cognitive function in later life. Methods: Data for this study, consisting of 2202 older adults aged 60 years and above, were taken from a population-based survey entitled “Identifying Psychosocial and Identifying Economic Risk Factor of Cognitive Impairment among Elderly. Data analysis was conducted using the IBM SPSS Version 23.0. Results: The mean of MMSE was found to be 22.67 (SD = 4.93). The overall prevalence of selfreported diabetes was found to be 23.6% (CI95%: 21.8% - 25.4%). The result of independent t-test showed diabetic subjects had a higher mean score of MMSE (M = 23.05, SD =4 .55) than their counterparts without diabetes (M = 22.55, SD = 5.04) (t = -2.13 p<.05). The results of multiple linear regression analysis showed that diabetes was not significantly associated with cognitive function, after controlling the possible confounding factors. Conclusions: The findings from the current study revealed that diabetes is not associated with cognitive decline. This study supports the findings that long-term treatment of diabetes may reduce the risk of cognitive decline. This finding may provide new opportunities for the prevention and management of cognitive decline.

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Dementia associated with alcohol and other drug use

International Psychogeriatrics ◽

10.1017/s1041610205001985 ◽

2005 ◽

Vol 17 (s1) ◽

pp. S109-S127 ◽

Cited By ~ 50

Author(s):

Gary K. Hulse ◽

Nicola T. Lautenschlager ◽

Robert J. Tait ◽

Osvaldo P. Almeida

Keyword(s):

Cognitive Impairment ◽

Cognitive Function ◽

Drug Use ◽

Negative Impact ◽

Diagnostic Category ◽

Later Life ◽

Increased Risk ◽

Causal Pathway ◽

Chronic Use

The acute use of alcohol and several other licit and illicit drugs can affect mental state and cognitive function. The chronic use of certain drugs may also increase the risk of cognitive impairment and perhaps dementia in later life. This paper focuses on the long-term cognitive consequences of using alcohol, benzodiazepines, tobacco and cannabis. Currently available evidence indicates that mild to moderate alcohol consumption is not associated with increased risk of cognitive decline and may in fact have a protective effect against dementia, although heavy, long-term consumption is likely to have a negative impact on cognitive function. The degree that alcohol-related cognitive impairment must reach to be classified as dementia is currently obscure. Longer-term smoking is associated with increased risk of cognitive impairment and possibly dementia. The chronic use of benzodiazepines has been associated with increased risk of cognitive impairment but information relating to dementia remains inconclusive. The chronic use of cannabis may impair intellectual abilities but data on this topic remain sparse and difficult to interpret. In conclusion, there is evidence that some drugs contribute to the causal pathway that leads to the development of cognitive impairment but currently available data do not support the introduction of a separate diagnostic category of drug-induced dementia (such as alcohol-related dementia). Health promotion programs designed to decrease tobacco smoking and “harmful” alcohol use (and possibly other drug use) may decrease the burden of cognitive impairment and perhaps dementia in later life.

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Cognitive Function in Older Diabetic Subjects with a History of Alcohol Abuse

Psychological Reports ◽

10.2466/pr0.101.4.1125-1132 ◽

2007 ◽

Vol 101 (3_suppl) ◽

pp. 1125-1132 ◽

Cited By ~ 7

Author(s):

Judith A. Hudetz ◽

David C. Warltier

Keyword(s):

Cognitive Impairment ◽

Cognitive Function ◽

Alcohol Abuse ◽

Verbal Memory ◽

Cognitive Test ◽

Diabetic Patients ◽

Delayed Recall ◽

Immediate Recall ◽

Increased Risk ◽

History Of

Either diabetes or alcohol abuse can impair cognitive function, especially at older ages. Whether a history of alcohol abuse increases the risk for cognitive impairment in diabetic patients has not been examined. Cognitive function of type 2 diabetic subjects with a history of alcohol abuse was expected to be more impaired than that of subjects with either diabetes or alcohol abuse alone. Men, >55 years of age, were categorized as 15 alcoholic-diabetic; 15 alcoholic-nondiabetic; 15 nonalcoholic-diabetic; 15 nonalcoholic-nondiabetic, and matched on age, sex, and education. Participants' verbal memory, visuospatial memory, and executive functions were assessed using a neurocognitive test battery. Significant interactions of diabetes and alcoholism for Visual Delayed Recall, Story Immediate Recall, and Story Delayed Recall implied that diabetes and alcohol abuse enhanced each other's effect in lowering cognitive test scores. Alcohol abuse history in older diabetic subjects presents an increased risk for cognitive impairment.

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Long-term cognitive function following chemotherapy in patients with testicular cancer

Journal of the International Neuropsychological Society ◽

10.1017/s1355617709090316 ◽

2009 ◽

Vol 15 (2) ◽

pp. 296-301 ◽

Cited By ~ 44

Author(s):

ANDERS DEGN PEDERSEN ◽

PHILIP ROSSEN ◽

MIMI YUNG MEHLSEN ◽

CHRISTINA GUNDGAARD PEDERSEN ◽

ROBERT ZACHARIAE ◽

...

Keyword(s):

Breast Cancer ◽

Cognitive Impairment ◽

Cognitive Function ◽

Testicular Cancer ◽

Neuropsychological Tests ◽

Multiple Comparisons ◽

Cognitively Impaired ◽

Cognitive Tests ◽

Chemotherapy Patients

AbstractCancer patients frequently report cognitive complaints following chemotherapy, but the results from the available studies, mainly of women with breast cancer, are inconsistent. Our aim was to compare cognitive function of men with testicular cancer (TC) who had orchiectomy and chemotherapy (bleomycin, etoposide, cisplatin) with men who had orchiectomy only or orchiectomy and radiotherapy. Thirty-six chemotherapy patients and 36 nonchemotherapy patients were tested 2–7 years after treatment for TC with standardized neuropsychological tests. Chemotherapy and nonchemotherapy patients displayed similar performances on cognitive tests (p values adjusted for multiple comparisons: .63–1.00). Moreover, there was no difference in the proportion of cognitively impaired patients in the chemotherapy group (5.6%) compared to the nonchemotherapy group (8.3%) (χ2 = 0.22, p = .64). Our results are discordant with previous findings indicating cognitive impairment following chemotherapy and suggest that TC patients do not need to fear long-term cognitive consequences following chemotherapy. (JINS, 2009, 15, 296–301.)

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Sex differences in chronic social stress models in mice

10.1101/605527 ◽

2019 ◽

Author(s):

Orit Furman ◽

Michael Tsoory ◽

Alon Chen

Keyword(s):

Sex Differences ◽

Animal Models ◽

Mouse Model ◽

Treatment Response ◽

Chronic Stress ◽

Social Stress ◽

Molecular Mechanisms ◽

Body Weight Loss ◽

Chronic Social Stress

AbstractChronic stress creates an allostatic overload that may lead to mood disorders such as anxiety and depression. Modern causes of chronic stress in humans are mostly social in nature, relating to work and relationship stress. Research into neural and molecular mechanisms of vulnerability and resilience following chronic social stress (CSS) is ongoing and uses animal models to discover efficient prevention strategies and treatments. To date, most CSS studies have neglected the female sex and used male-focused aggression-based animal models such as chronic social defeat stress (CSDS). Accumulating evidence on sex differences suggests differences in the stress response, the prevalence of stress-related illness and the treatment response, indicating that researchers should expand CSS investigation to include female-focused protocols alongside the popular CSDS protocols. Here, we describe a novel female mouse model of CSS and a parallel modified male mouse model of CSDS in C57BL/6 mice. These new models enable the investigation of vulnerability, coping and downstream effectors mediating long-term consequences of CSS in both sexes. Our data demonstrate sex differences during CSS and for many weeks following CSS. Female mice are more prone to body weight loss during CSS and hyperactive anxious behavior following CSS. Both sexes show disturbances in social interaction, but only stressed male mice show long-term changes in neuroendocrine function and memory performance after fear conditioning. We discuss future avenues of research using these models to investigate mechanisms pertaining to sensitivity to CSS as well as treatment response profiles, in a sex-suitable manner.

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Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.750382 ◽

2021 ◽

Vol 9 ◽

Author(s):

Haoxiao Zheng ◽

Hailan Zhu ◽

Xinyue Liu ◽

Xiaohui Huang ◽

Anqing Huang ◽

...

Keyword(s):

Quality Control ◽

Diabetic Cardiomyopathy ◽

Molecular Mechanisms ◽

Myocardial Damage ◽

Diabetic Heart ◽

Substantial Contribution ◽

Diabetic Patients ◽

Mitochondrial Quality Control ◽

Comprehensive Overview ◽

Myocardial Insulin Resistance

Cardiovascular disease is the leading complication of diabetes mellitus (DM), and diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients. Multiple pathophysiologic mechanisms, including myocardial insulin resistance, oxidative stress and inflammation, are involved in the development of DCM. Recent studies have shown that mitochondrial dysfunction makes a substantial contribution to the development of DCM. Mitophagy is a type of autophagy that takes place in dysfunctional mitochondria, and it plays a key role in mitochondrial quality control. Although the precise molecular mechanisms of mitophagy in DCM have yet to be fully clarified, recent findings imply that mitophagy improves cardiac function in the diabetic heart. However, excessive mitophagy may exacerbate myocardial damage in patients with DCM. In this review, we aim to provide a comprehensive overview of mitochondrial quality control and the dual roles of mitophagy in DCM. We also propose that a balance between mitochondrial biogenesis and mitophagy is essential for the maintenance of cellular metabolism in the diabetic heart.

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Vascular Cognitive Impairment: Information from Animal Models on the Pathogenic Mechanisms of Cognitive Deficits

International Journal of Molecular Sciences ◽

10.3390/ijms20102405 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2405 ◽

Cited By ~ 3

Author(s):

Jakub Hort ◽

Martin Vališ ◽

Kamil Kuča ◽

Francesco Angelucci

Keyword(s):

Cognitive Impairment ◽

Animal Models ◽

Cognitive Deficits ◽

Molecular Mechanisms ◽

Target Population ◽

Vascular Cognitive Impairment ◽

Toxic Waste ◽

Waste Products ◽

Cascade Effects ◽

Vascular Clearance

Vascular cognitive impairment (VCI) is the second most common cause of cognitive deficit after Alzheimer’s disease. Since VCI patients represent an important target population for prevention, an ongoing effort has been made to elucidate the pathogenesis of this disorder. In this review, we summarize the information from animal models on the molecular changes that occur in the brain during a cerebral vascular insult and ultimately lead to cognitive deficits in VCI. Animal models cannot effectively represent the complex clinical picture of VCI in humans. Nonetheless, they allow some understanding of the important molecular mechanisms leading to cognitive deficits. VCI may be caused by various mechanisms and metabolic pathways. The pathological mechanisms, in terms of cognitive deficits, may span from oxidative stress to vascular clearance of toxic waste products (such as amyloid beta) and from neuroinflammation to impaired function of microglia, astrocytes, pericytes, and endothelial cells. Impaired production of elements of the immune response, such as cytokines, and vascular factors, such as insulin-like growth factor 1 (IGF-1), may also affect cognitive functions. No single event could be seen as being the unique cause of cognitive deficits in VCI. These events are interconnected, and may produce cascade effects resulting in cognitive impairment.

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The Association between Cognitive Impairment and Diabetic Foot Care: Role of Neuropathy and Glycated Hemoglobin

Pathophysiology ◽

10.3390/pathophysiology27010003 ◽

2020 ◽

Vol 27 (1) ◽

pp. 14-27

Author(s):

Lorenzo Brognara ◽

Iacopo Volta ◽

Vito Michele Cassano ◽

Emmanuel Navarro-Flores ◽

Omar Cauli

Keyword(s):

Diabetes Mellitus ◽

Cognitive Impairment ◽

Cognitive Function ◽

Glycemic Control ◽

Cognitive Dysfunction ◽

Cognitive Functions ◽

Diabetic Foot ◽

Glycated Hemoglobin ◽

Diabetic Patients ◽

Adherence To Treatment

Diabetes mellitus is associated with impairment in cognitive functions which can complicate adherence to self-care behaviors. We evaluated the incidence of cognitive impairment in patients with diabetes mellitus to determine the strength of the association between diabetic foot (a complication that occurs in about 10% of diabetic patients), adherence to the clinician’s recommendations, glycemic control, and cognitive function. A prospective study was carried out in a probabilistic sample of older patients with diabetic foot living in three nursing homes. Cognitive functions were evaluated by the MMSE (Mini-Mental State Examination), the Trail Making test (TMT), and the Michigan neuropathy screening instrument (MNSI). There were no significant associations between cognitive function and neuropathy or foot alterations, although glycated hemoglobin (HB1Ac > 7%) significantly (p < 0.05) associated with MMSE and adherence to treatment in the 1 month follow-up visit. Receiver operating characteristic curve analysis showed that both HB1Ac and the MNSI score significantly (p < 0.05) discriminate subsequent adherence to treatment for foot complication, with a sensitivity of 80.0–73.3% and specificity 70.6–64.7%, respectively. Proper control of foot complications in diabetic patients involves appropriate glycemic control and less severe neuropathy, and seems to be unrelated to cognitive dysfunction, and warrants further studies in order to tailor appropriate treatments to central and peripheral nervous system disorders. Poor glycemic control (Hb1Ac level > 7%) and a neuropathy score of 5.5 in the MNSI are the best-cut off points to discriminate poor adherence to the clinician’s recommendations for self-care behaviors in people with diabetic foot complication. In this study, we observed that foot disorders were associated with impaired global cognitive function in elderly patients (aged ≥ 65). Podiatrists and physicians should consider cognitive dysfunction as an important chronic complication in the management of diabetic foot.

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