Type 2 diabetes and risk of cognitive impairment and dementia
Diabetes is a major public health burden. Even a modest effect of diabetes on cognitive function has significant public health implications. Several lines of mechanistic evidence implicate a role of insulin and glucose metabolism on risk of developing dementia, including Alzheimer's disease. Population-based studies have shown that those with type 2 diabetes mellitus have an increased risk of cognitive impairment, dementia, and neurodegeneration. There are many mechanisms through which diabetes could increase risk of dementia, including glycemia, insulin resistance, oxidative stress, advanced glycation endproducts, inflammatory cytokines, and microvascular and macrovascular disease. This paper presents a review of the evidence on diabetes and increased risk of dementia and cognitive impairment, a discussion of different possible mechanisms, and remaining gaps in our knowledge.
[Show abstract] [Hide abstract] ABSTRACT: Prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-β (Aβ) is neurotoxic, and we showed that intrahippocampal oligomeric Aβ produces cognitive and metabolic dysfunction similar to those seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aβ, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions.0Comments 0Citations
- "AMPAR and NMDARs are important for synaptic transmission and essential for learning-associated processes including synaptogenesis and CREB activation; these actions are dependent upon the receptors being adequately trafficked to the plasma membrane727374. However, these receptors are also responsible for mediating cell death and inhibiting synaptic growth, and are heavily implicated in AD pathology757677 . Our measures of PM receptor levels did not differentiate between synaptic versus extrasynaptic receptor location. "
[Show abstract] [Hide abstract] ABSTRACT: Objective To investigate associations between retinal microvascular changes and cognitive impairment in newly diagnosed type 2 diabetes mellitus. Design Case control study. Setting A primary care cohort with newly diagnosed type 2 diabetes mellitus. Methods For this analysis, we compared 69 cases with lowest decile scores (for the cohort) on the Modified Telephone Interview for Cognitive Status and 68 controls randomly selected from the remainder of the cohort. Retinal images were rated and the following measures compared between cases and controls: retinal vessel calibre, arterio-venous ratio, retinal fractal dimension, and simple and curvature retinal vessel tortuosity. Results Total and venular (but not arteriolar) simple retinal vessel tortuosity levels were significantly higher in cases than controls (t = 2.45, p = 0.015; t = 2.53, p = 0.013 respectively). The associations persisted after adjustment for demographic factors, retinopathy, neuropathy, obesity and blood pressure. There were no other significant differences between cases and controls in retinal measures. Conclusions A novel association was found between higher venular tortuosity and cognitive impairment in newly diagnosed type 2 diabetes mellitus. This might be accounted for by factors such as hypoxia, thrombus formation, increased vasoendothelial growth factor release and inflammation affecting both the visible retinal and the unobserved cerebral microvasculature.0Comments 0Citations
- "Both hypoxia and hyperglycemia are associated with increased vasoendothelial growth factor release, which stimulates vasculogenesis and angiogenesis in response to hypoxia ; these processes might initiate retinal changes in early diabetes, localized to the venules and capillaries of the superficial inner retinal vasculature , resulting in venular tortuosity , and may increase vascular permeability , leading to protein extravasation, chronic edema and tissue necrosis. Finally, increased high-sensitivity C-reactive protein has been found to be associated with increased retinal venular tortuosity  and the finding might thus reflect an underlying pro-inflammatory state implicated in T2DM , cognitive decline  and dementia , separate from hyperglycaemia. Our findings suggest at least a link, whether causal or not, between retinal microvascular change and cognitive impairment in T2DM. "
[Show abstract] [Hide abstract] ABSTRACT: Diabetes is a chronic illness which has an effect on multiple organ systems. Frailty is a state of increased vulnerability to stressors and a limited capacity to maintain homeostasis. It is a multidimensional concept and a dynamic condition that can improve or worsen over time. Frailty is either physical or psychological or a combination of these 2 components. Sarcopenia, which is the age-related loss of skeletal muscle mass and strength, is the main attributor to the physical form of frailty. Although the pathophysiology of diabetes is commonly focused on impaired insulin secretion, overload of gluconeogenesis and insulin resistance, newer insights broaden this etiologic horizon. Immunologic factors which create a chronic state of low-grade inflammation - 'inflammaging' - have an influence on both the ageing process and diabetes. Persons with diabetes mellitus already tend to have an accelerated aging process that places them at greater risk for developing frailty at an earlier age. The development of frailty - and sarcopenia - is multifactorial and includes nutritional, physical and hormonal elements; these elements are interlinked with those of diabetes. A lower muscle mass will lead to poorer glycemic control through lower muscle glucose uptake. This leads to higher insulin secretion and insulin resistance, which is the stepping stone for diabetes itself. This article is protected by copyright. All rights reserved.0Comments 2Citations
- "Also, a slower gait speed is seen in persons with diabetes [84,85]. There is an increased risk of neurocognitive decline in people with diabetes through many mechanisms, including hyperglycaemia, insulin resistance, oxidative stress, advanced glycosylation end products (AGEs), inflammatory cytokines and both microvascular and macrovascular disease . A review of multiple longitudinal studies concluded that individuals with diabetes had a 1.2-to 1.5-fold greater change over time in measures of cognitive function than those without diabetes . "