In population studies, chronic use of metformin have been associated to increased risk of dementia, but a causal relationship between both could not be established. Both positive results (metformin may counteract structural changes in tau protein in nerve cells from mice) 11 and negative results (the drug may increase β-amyloid production through dysregulation of β-secretase) 12 have been reported. Thus, conflicting results have been reported for metformin. There is currently no agreement on the drug class to be used for diabetes control in order to achieve potential prevention of AD or to slow cognitive loss when this already exists, but use of drugs not causing hypoglycemia appears logical.
2 However, the results of the ACCORD-MIND substudy do not support intensive treatment as a strategy to improve cognition. By contrast, higher glycosylated hemoglobin levels are associated to poorer cognitive performance and greater difficulty for executive functions. With regard to DM control, a moderate improvement in learning memory and a less marked improvement in complex motor skills have been reported three weeks after achievement of good glycemic control. Thus, while recurrent hypoglycemia appears to promote cognitive impairment, people who already have cognitive impairment have greater difficulty to achieve stable diabetes control and therefore experience more hypoglycemic episodes. 2,9Īs regards the potential leading role of hypoglycemia in cognitive impairment, it should be noted that this is a controversial and usually two-directional issue.
β-Amyloid would accumulate due to its decreased degradation by IDE, among other mechanisms. 2 Thus, possible diabetes 3 would be defined as the condition occurring when hyperinsulinemia in response to insulin resistance leads to a decrease in cerebral insulin and poor regulation of IDE.
7,8 Insulin activates IDEs and, when effective insulin levels are low, IDE activation may be lower, and a greater harmful accumulation of β-amyloid may therefore occur. This is important because, among other effects in the brain, insulin promotes learning and long-term memory, stimulates acecylcholinesterase expression responsible for acetylcholine, and decreases phosphorylation of tau proteins. If chronic peripheral hyperinsulinemia exists, insulin transport across the blood-brain barrier will decrease. 1–3 Under normal conditions, excess β-amyloid may be removed through the lipoprotein receptor-related protein 1 (which decreases if insulin resistance exists) or by a degradation process in which insulin-degrading enzyme (IDE) is involved. 2Ī very interesting theory considers hyperinsulinemia and insulin resistance as a potential risk factor for AD, because they may cause neuron apoptosis and promote formation of extracellular β-amyloid deposits. 1–3 Chronic hyperglycemia may also involve increased oxidative stress, mitochondrial dysfunction, and production of advanced glycation end-products. Various hypotheses have been proposed to explain the relationship between DM and dementia, from the effect of acute hyperglycemia itself (which may affect working memory and attention) to the effect of chronic hyperglycemia, which may cause and aggravate macrovascular disease, more related to vascular dementia, and microvascular disease. 5 It should be noted that current epidemiological studies were not especially designed to assess the relationship between diabetes and dementia, and have therefore some limitations which are expected to be solved with future evidence from the Edinburgh Type 2 Diabetes Study. Impact is lower in older groups, but diabetes continues to be a risk factor even in people aged 85 years. A greater impact of diabetes on dementia has been reported in people who also have a genetic predisposition, and also when diabetes is diagnosed earlier in life. 1–3 According to a recent complete meta-analysis, patients with DM have a relative risk of 1.46 4 of suffering AD. Significant epidemiological evidence relating DM and dementia has accumulated in the past decade. The term type 3 diabetes has therefore been proposed to try and provide a view integrating the potential pathogenetic mechanisms shared by DM and Alzheimer disease (AD). Type 2 diabetes mellitus (DM) and dementia are two conditions highly prevalent today and probably interrelated.
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