A look inside the diabetic brain: Contributors to diabetes-induced brain aging

Abstract

Central nervous system (CNS) complications resulting from diabetes is a problem that is gaining more acceptance and attention. Recent evidence suggests morphological, electrophysiological and cognitive changes, often observed in the hippocampus, in diabetic individuals. Many of the CNS changes observed in diabetic patients and animal models of diabetes are reminiscent of the changes seen in normal aging. The central commonalities between diabetes-induced and age-related CNS changes have led to the theory of advanced brain aging in diabetic patients. This review summarizes the findings of the literature as they relate to the relationship between diabetes and dementia and discusses some of the potential contributors to diabetes-induced CNS impairments.

Fig. 1

Hyperphosphorylation of tau is increased in the hippocampus of Zucker type 2 diabetic rats. Representative photomicrographs demonstrate an absence of hyperphosphorylated tau immunoreactivity in the dentate gyrus (Panel A) and the CA3 region (Panel C) of lean control rats. Conversely, hyperphosphorylated tau immunoreactivity is significantly increased in the dentate gyrus (Panel B, arrow heads) and the CA3 region (Panel D, arrow heads) of fatty Zucker diabetic rats. This AD-like pathology may contribute to the development of behavioral deficits observed in this experimental model of type 2 diabetes.

Fig. 2

Potential mechanistic mediators of diabetes-induced brain aging. The complex pathophysiological features of diabetes may include decreases in insulin activity, impaired glucose homeostasis, dysregulation of hypothalamic–pituitary–adrenal (HPA) axis function, and hyperleptinemia, among others. The consequences of these pathophysiologies in the hippocampus include dendritic atrophy, changes in synapse formation, electrophysiological deficits, as well as the appearance of Alzheimer’s disease-like histopathology, such as hyperphosphorylated tau. Additional pathological consequences that contribute to cognitive decline in diabetic subjects may include changes in oxidative stress status and the development of insulin and/or leptin resistance in the hippocampus. These factors, in combination with other pathological features such as microvascular complications and mediators such as the pro-inflammatory cytokines, act in an additive or synergistic fashion to accelerate brain aging in diabetic subjects, thereby increasing patient vulnerability for the development of age-related disorders such as mild cognitive impairment and AD. See text for details.