The Altered Cerebral Homeostasis with Aging in Diabetes Mellitus and Cognitive Decline

Overview-Diabetes and Cerebral Metabolism: Diabetes mellitus (DM) per se adversely alters cerebral metabolism, promotes cerebral atrophy and accelerate brain aging, and affects cognitive function. There is a consensus now that the cognitive decline should be listed as one of the major complications of diabetes. The insulin receptors are widely expressed in the brain and insulin as a pleiotropic peptide plays various roles in cerebral metabolism, neuronal growth, neuroplasticity and neuromodulation, and cognitive processes such as reward, motivation, cognition, attention, and memory formation. The insulin signaling mediates various alterations in neuronal integrity and functions in both the patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Contributors to Cognitive Decline in DM: There are various factors that contribute to the development of cognitive decline in patients with DM. Adults with diabetes have also been found to have structural changes, including atrophy and leukoariosis. The extremes in glycemia experienced by patients with T1DM and advanced T2DM have an impact on brain, and chronic exposure to recurrent hyperglycemias and hypoglycaemia leads to alterations in brain structure and function. During hyperglycemias in patients with both T1DM and T2DM, there is slowing of cognitive function, increased number of mental subtraction errors, loss of inhibition and focus, impaired speed of information processing, decreased attention, and impaired working memory. Higher glycated haemoglobin values are associated with moderate declines in motor speed and psychomotor efficiency.The hypoglycaemia also affects the cognitive functions adversely. The cortex, basal ganglia, and hippocampus are especially vulnerable to hypoglycaemia, and hypoglycaemia selectively damages neurons with sparing of astrocytes and oligodendrocytes. The impaired hypoglycaemia awareness adds to the cognitive function. Because the brain depends almost exclusively on glucose, recurrent hypoglycaemia may be a threat for cognitive dysfunction and cerebral damage, and the patients with DM are at increased risk for accelerated cognitive decline and dementia. The Role of Insulin Resistance: There is evidence that insulin resistance (IR), a factor contributing to the onset of T2DM, may play a role in the pathogenesis of MCI and AD, which are approximately 1.2-to1.7-fold higher in patients with T2DM compared with a control population. On the other hand, T2DM is also more common in patients with AD. The IR has been correlated to increased neuro-inflammation, inflammatory markers and vascular disease. It also causes disruption of the hypothalamic-pituitary adrenal axis and increased cortisol levels which may contribute to cognitive dysfunction. Finally, the IR contributes to cognitive dysfunction by affecting the metabolism of APP and β-amyloid leading to accumulation of β-amyloid and promoting the formation of senile plaques. The Impact of Longstanding DM: With aging in diabetic patients, the intrinsic brain tissue changes, vascular disease and alterations in cellular bioenergetics hamper the brain’s ability to cope up with metabolic stress. There occur cerebral structural and functional alterations like, cerebral atrophy and white matter lesions, micro-hemorrhages and lacunar infarcts, and neuronal dysfunction and network alterations. Patients with DM have a 2-to 6-fold increased risk of vascular disease. There occurs thickening of capillary basement membranes in cerebral vasculature, which is the hallmark of diabetic microangiopathy, and leads to decreased cerebral blood flow, which is akin to that encountered in AD. The decrease in cerebral blood flow, coupled with the stimulation of the thromboxane A2 receptor contributes to the inability of cerebral vessels to adequately vasodilate, and increases the likelihood of ischemia. The coexistence of ischemia and hyperglycemias may be particularly detrimental to the brain. Conclusion-Search for the Solutions: The cognitive decline affects ADL and QOL, it affects life expectancy also. The MCI is a stage before dementia, and when accompanied by DM, its progression to dementia is accelerated. There is preponderance of lifestyle-related diseases, such as adiposity, metabolic syndrome, IR, hypertension and dyslipidemia, in the middle aged, and risk factors for cardiovascular disease accumulate in diabetic patients. This leads to a subclinical inflammatory state which has been related to a higher risk of cognitive decline and dementia, including vascular dementia and late onset AD.