Glucose Metabolism and Insulin Action in Alzheimer’s Disease Pathogenesis

Abstract

Alzheimer’s disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. The pathological and histological hallmarks of AD include amyloid plaques, neurofibrillary tangles and amyloidal angiopathy, accompanied by diffuse loss of neurons and synapses [1]. Environmental and genetic factors interact in the development of disease. Type 2 diabetes mellitus (DM) appears to be a significant risk factor for vascular dementia and AD in several epidemiological studies [2, 3]. Recent longitudinal studies have shown that AD and disorder of glucose metabolism are related [4, 5]. One explanation could be that vascular complications of diabetes result in neurodegenerative disease [6]. On the other hand, in addition to its peripheral metabolic effects, insulin also appears have important outcome on brain functions. A recent commentary offers two models of the link between type-2 DM and AD, 1. “central insulin resistance” and 2. inflammation. Both mechanisms influence insulin sensitivity in the brain, finally leading to ┚-amyloid accumulation and, consequently, to AD [7]. Complex molecular mechanisms, referring to insulin and/or insulin like growth factor-1 (IGF-1) signaling could link DM and AD [8]. In fact, there is evidence that altered insulin and/or IGF-1 signaling to brain cells is probably responsible of amyloid accumulation in AD [9] and several independent effects of insulin on brain functions and cognitive performance have been described [10]. Insulin resistance with associated hyperinsulinemia are the mechanisms suggested to explain the increased AD risk in diabetes [11]. Subsequent investigations demonstrated reduced blood glucose levels and increased insulin levels in patients with late onset AD compared to aged controls or patients with vascular dementia. Although the authors concluded that these findings did not support an association between diabetes and AD [12], the same data were reinterpreted as an increased prevalence of insulin resistance in AD. The latter conclusion contradicts the finding that glucose administration could both increase plasma insulin levels and improve cognition in AD. Working under the assumption that increased insulin rather than glucose was responsible for the improvement in memory, further studies were used to demonstrate that the administration of insulin significantly improved memory performance in AD [8, 13]. Hyperinsulinemic euglycemic clamp studies in humans showed improvement