Altered glycemia and brain—update and potential relevance to the aging brain (original) (raw)
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Diabetes Mellitus And The Brain: Special Emphasis To Cognitive Function
Diabetes mellitus (DM) is a major public health problem. Cognitive deficits are common with DM which range from subclinical or subtle to severe deficits as dementia. Both hypoglycemia and hyperglycemia are causes of cognitive impairment with DM. In patients with DM, not only severe hypoglycemia but also recurrent mild or moderate hypoglycemia have deleterious effect on the brain. Recurrent mild/moderate hypoglycemia is associated with intellectual decline, reduced attention, impaired mental abilities and memory deficits. Hypoglycemia may result in abnormalities of neuronal plasticity, synaptic weakening and scattered neuronal death in the cerebral cortex and the hippocampus. Chronic hyperglycemia in type 1 and type 2 DM is associated with low IQ (verbal, performance and total) and abnormalities in testing for different domains of cognitive function as verbal relations, comprehension, visual reasoning, pattern analysis, quantitation, memory, learning, mental control, psychomotor efficiency, mental and motor processing speed and executive function. The suggested mechanisms incriminated in the pathogenesis of hyperglycemia related cognitive dysfunction include, macro- and micro-vascular disease or vasculopathy, hyperlipidemia, hypertension, insulin resistance and hyperinsulinemia, stress response, direct toxic effect of chronic hyperglycemia on the brain, advanced glycation end products, inflammatory cytokines and oxidative stress. Hyperglycemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, accumulation of β-amyloid and tau phosphorylation, neuroinflammation, mitochondrial pathology, apoptosis and neuronal degeneration in the cortex and hippocampus. Depression has been identified as a risk for accelerated cognitive decline with DM. The knowledge that diagnosis at early age, frequency of hypoglycemia, poor glycemic control and presence of risk factors which negatively affect cognitive functions in DM, will have important implications for treatment and for research purposes. Key Words: Diabetes Mellitus; Hypoglycemia; Insulin Resistance; Cognition; Vascular Disease
Hyperglycaemia as a determinant of cognitive decline in patients with type 1 diabetes
European Journal of Pharmacology, 2008
Individuals with type 1 diabetes show mild performance deficits in a range of neuropsychological tests compared to healthy controls, but the mechanisms underlying this cognitive deterioration are still poorly understood. Basically, two diabetes-related mechanisms can be postulated: recurrent severe hypoglycaemia and/or chronic hyperglycaemia. Intensive insulin therapy in type 1 diabetes, resulting in a durable improvement of glycaemic control, has been shown to lower the risk of long-term microvascular and macrovascular complications. The down side of striving for strict glycaemic control is the considerably elevated risk of severe hypoglycaemia, sometimes leading to seizure or coma. While retrospective studies in adult patients with type 1 diabetes have suggested an association between a history of recurrent severe hypoglycaemia and a modest or even severe degree of cognitive impairment, large prospective studies have failed to confirm this association. Only fairly recently, better appreciation of the possible deleterious effects of chronic hyperglycaemia on brain function and structure is emerging. In addition, it can be hypothesized that hyperglycaemia associated microvascular changes in the brain are responsible for the cognitive decline in patients with type 1 diabetes. This review presents various pathophysiological considerations concerning the cognitive decline in patients with type 1 diabetes.
(Pre)diabetes, brain aging, and cognition
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2009
We are glad to have our review pre-accepted for publication at BBAmolecular Basis of Disease. We have answered the points raised by the reviewers and we did the modifications suggested by them. We hope the revised paper is now in a proper form to publication at BBA -Molecular Basis of Disease. We look forward receiving your final decision. Yours sincerely, Matheus Roriz-Cruz (and coworkers) ABSTRACT Cognitive dysfunction and dementia have recently been proven to be common (and underrecognized) complications of Diabetes Mellitus (DM). In fact, several studies have evidenced that phenotypes associated with obesity and/or alterations on insulin homeostasis are at increased risk for developing cognitive decline and dementia, including not only vascular dementia, but also Alzheimer's Disease (AD). These phenotypes include prediabetes, diabetes, and the metabolic syndrome. Both types 1 and 2 Diabetes are also important risk factors for decreased performance in several neuropsychological functions. Chronic Hyperglycemia and hyperinsulinemia primarily stimulates the formation of Advanced Glucose Endproducts (AGEs), which leads to an overproduction of Reactive Oxygen Species (ROS). Protein glycation and increased oxidative stress are the two main mechanisms involved in biological aging, both being also probably related to the etiopathogeny of AD. AD patients were found to have lower than normal cerebrospinal fluid levels of insulin. Besides its traditional glucoregulatory
EC Neurology, 2020
Diabetes mellitus (DM) is a chronic metabolic disease, characterized mainly by elevated levels of blood glucose, associated with other important metabolic disturbances. Prevalence of DM is dramatically increasing worldwide, but especially in western countries, due to several factors as like diet, lifestyle and population aging. Recent studies demonstrate that some diabetic patients have an increased risk of developing cognitive decline and dementia compared with healthy individuals. Although this may reflect brain changes as a consequence of diabetes, the coexistence of diabetes and cognitive dysfunction suggest common risk factors and causative mechanisms. Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognized as an important comorbidity and complication of diabetes that affects patient's health and diabetes management with several public health implications. The aim of our work is to give an overview of cognitive dysfunction in people with diabetes, describing its clinical features and their biochemical basis and future perspectives.
Journal of Clinical Investigation, 1988
To establish the glycemic threshold for onset of neuroglycopenia (impaired cognitive function, measured by the latency of the P300 wave), activation of hormonal counterregulation and hypoglycemic symptoms, 12 normal subjects were studied either under conditions of insulin-induced, glucose-controlled plasma glucose decrements, or during maintenance of euglycemia. A decrement in plasma glucose concentration from 88±3 to 80±1 mg/dl for 150 min did not result in changes in the latency of the P300 wave nor in an activation of counterregulatory hormonal response. In contrast, a greater decrement in plasma glucose concentration from 87±3 to 72±1 mg/dl for 120 min caused an increase in the latency of the P300 wave (from 301±12 to 348±20 ms, P < 0.01), a subsequent increase in all counterregulatory hormones but no hypoglycemic symptoms. Finally, when plasma glucose concentration was decreased in a stepwise manner from 88±2 to 50±1 mg/dl within 75 min, the increase in the latency of the P300 wave was correlated with the corresponding plasma glucose concentration (r = -0.76, P < 0.001). The glycentic threshold for hypoglycemic symptoms was 49±2 mg/dl. Thus, in normal man the glycemic threshold for neuroglycopenia (72±1 mg/dl) is greater than currently thought; the hormonal counterregulation follows the onset of neuroglycopenia; the hypoglycemic symptoms are a late indicator of advanced neuroglycopenia. the circulation to the central nervous system is essential for normal brain function and whole body survival (1). Indeed,
Consequences of recurrent hypoglycaemia on brain function in diabetes
Diabetologia
The discovery of insulin and its subsequent mass manufacture transformed the lives of people with type 1 and 2 diabetes. Insulin, however, was a drug with a ‘dark side’. It brought with it the risk of iatrogenic hypoglycaemia. In this short review, the cellular consequences of recurrent hypoglycaemia, with a particular focus on the brain, are discussed. Using the ventromedial hypothalamus as an exemplar, this review highlights how recurrent hypoglycaemia has an impact on the specialised cells in the brain that are critical to the regulation of glucose homeostasis and the counterregulatory response to hypoglycaemia. In these cells, recurrent hypoglycaemia initiates a series of adaptations that ensure that they are more resilient to subsequent hypoglycaemia, but this leads to impaired hypoglycaemia awareness and a paradoxical increased risk of severe hypoglycaemia. This review also highlights how hypoglycaemia, as an oxidative stressor, may also exacerbate chronic hyperglycaemia-induc...
Diabetes and the Brain—An Overview of Existing Knowledge and Discussions and Future Implications
US Endocrinology, 2010
Diabetes affects many organ systems including the brain. Both type 1 and type 2 diabetes have been associated with reduced performance on multiple domains of cognitive function, including memory, psychomotor efficiency and executive function. In addition, structural abnormalities in the brain have been noted in subjects with both type 1 and type 2 diabetes using a variety of imaging techniques. The underlying pathophysiological mechanisms causing these changes in cognition and structure are not well understood but hyperglycemia, insulin resistance and vascular disease are likely to have key roles. Future research is needed to better understand of the natural history of the cerebral complications of diabetes and to identify the underlying mechanisms that lead to changes in brain function and structure.
Metabolic Alterations Associated to Brain Dysfunction in Diabetes
Aging and Disease, 2015
From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer's disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as well as recurrent hypoglycaemia are the factors that most likely affect brain function and structure. While difficult to study in patients, the mechanisms by which diabetes leads to brain dysfunction have been investigated in experimental models that display phenotypes of the disease. The present article reviews the impact of diabetes and AD on brain structure and function, and discusses recent findings from translational studies in animal models that link insulin resistance to metabolic alterations that underlie brain dysfunction. Such modifications of brain metabolism are likely to occur at early stages of neurodegeneration and impact regional neurochemical profiles and constitute non-invasive biomarkers detectable by magnetic resonance spectroscopy (MRS).