Insulin Resistance and Alzheimers Disease: Molecular Links & Clinical Implications

Abstract

Hyperinsulinemia as well as type II diabetes mellitus are among the risk factors for Alzheimer's disease (AD). However, the molecular and cellular basis that link insulin resistance disorders and diabetes with AD are far from clear. Here, we discuss the potential molecular mechanisms that may explain the participation of these metabolic disorders in the pathogenesis of AD. The human brain uses glucose as a primary fuel; insulin secreted by the pancreas cross the blood-brain barrier (BBB), reaching neurons and glial cells, and exerts a region-specific effect on glucose metabolism. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming full-blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Abeta) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3beta activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and a reduced insulin signaling in brain, altering all of insulin's actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition-enhancing effect in patient with AD. Some drugs utilized in type II diabetes mellitus reduce cognitive impairment associated with AD. The link between insulin resistance and neurodegeneration and AD, and the possible therapeutic targets in preventing the insulin-resistance disorders are analyzed.

Glucose metabolism and the risk of Alzheimer’s disease and dementia: a population-based 12 year follow-up study in 71-year-old men

“…Our results support the current information from neurobiological and neuropathological studies suggesting that insulin has important functions in the brain and may be involved in the pathogenesis of Alzheimer's disease [6]. Although acute intravenous insulin facilitated memory functions in an experimental study, chronic hyperinsulinaemia and insulin resistance had negative effects [27].…”

“…Hyperglycaemia is accompanied by accumulation of advanced glycation end-products, oxidative stress and microvascular changes, which might lead to cerebral ischaemia. Insulin resistance and chronic peripheral hyperinsulinaemia may also lead to reduced insulin action in the brain [6]. In experimental studies, defective insulin signalling has been linked to cerebral accumulation of β-amyloid, a key neuropathological feature in Alzheimer's disease [7].…”

Alzheimer's disease and type 2 diabetes: Two diseases, one common link?

“…We were interested in PPARγ(p) because six months of treatment with rosiglitazone, a typical T2DM treatment and a PPARγ agonist, preserved cognitive function for patients with AD and amnestic mild cognitive impairment compared with a placebo-treated group (Watson et al 2005). A number of studies have examined potential mechanisms by which PPARγ agonists may ameliorate AD pathogenesis and progression (Landreth 2007;Neumann et al 2008); PPARγ agonists improve insulin sensitivity by decreasing the level of circulating insulin, increasing insulin-mediated glucose uptake, and enhancing insulin action in the brain, resulting in cognitive improvement (Sato et al 2009). The phosphorylated isoform of PPARγ is the inactive variant of this protein (Fig.…”

Cognitive Impairment in Type 2 Diabetic Patients Treated with Metformin in Comparison with those Taking Glibenclamide

“…Abeta is a short peptide found predominantly in the brain affected by AD. When there is hyperinsulinemia, through this competition, Abeta may rise in the brain and cause AD [12,13].…”