Diabetes and cognitive decline: Challenges and future direction

Abstract

There is growing evidence that diabetes can induce cognitive decline and dementia. It is a slow, progressive cognitive decline that can occur in any age group, but is seen more frequently in older individuals. Symptoms related to cognitive decline are worsened by chronic metabolic syndrome. Animal models are frequently utilized to elucidate the mechanisms of cognitive decline in diabetes and to assess potential drugs for therapy and prevention. This review addresses the common factors and pathophysiology involved in diabetes-related cognitive decline and outlines the various animal models used to study this condition.

Keywords: Animal models; Cognitive decline; Diabetes mellitus; Insulin signaling; Macrovascular disease; Microvascular disease; Pathophysiology.

Figure 1

Multifactorial pathophysiology of diabetes-induced cognitive decline.

Figure 2

Insulin receptor signaling in the hippocampus (adapted from Biessels and Reagan[40], 2015). Cerebral insulin resistance causes downregulation of insulin transporters at the blood-brain barrier, limiting the amount of insulin that can enter the brain (step 1), decreasing the expression and/or activity of insulin receptors (step 2), modulating the phosphorylation state of insulin receptor substrates (step 3), phosphorylation of Akt (step 4), affecting several downstream components in the insulin signaling cascade (including glycogen synthase kinase 3β) (step 5), regulating the phosphorylation state of the microtubule protein tau and forkhead box O family of transcription factors (step 6), and impairing the trafficking of GLUT4 to the plasma membrane of the brain (step 7). GSK3β: Glycogen synthase kinase 3β; FOXO: Forkhead box O.