Diabetes and Cognitive Impairment

Abstract

Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structural and functional brain magnetic resonance imaging (MRI). Cognitive deficits may occur at the very earliest stages of diabetes and are further exacerbated by the metabolic syndrome. The duration of diabetes and glycemic control may have an impact on the type and severity of cognitive impairment, but as yet we cannot predict who is at greatest risk of developing cognitive impairment. The pathophysiology of cognitive impairment is multifactorial, although dysfunction in each interconnecting pathway ultimately leads to discordance in metabolic signaling. The pathophysiology includes defects in insulin signaling, autonomic function, neuroinflammatory pathways, mitochondrial (Mt) metabolism, the sirtuin-peroxisome proliferator-activated receptor-gamma co-activator 1α (SIRT-PGC-1α) axis, and Tau signaling. Several promising therapies have been identified in pre-clinical studies, but remain to be validated in clinical trials.

Keywords: Brain; Dementia; Diabetes; Encephalopathy; MRI; Mitochondria; Neuropathy; Treatment.

Fig. 1

Neuronal insulin signaling in synaptic plasticity and memory in normal and diabetic brain. Schematic outline of neuronal insulin signaling in the normal brain (a) and in the diabetic brain (b). In physiological conditions, insulin binding to its receptor at the synapse triggers phosphorylation of insulin receptor substrate-1(IRS-1). This results in phosphoinositide 3-kinase (PI3K) activation, Akt phosphorylation, phosphorylation of GluA1, and increased presence of GluN2B at synapses. These events favor synapse formation and memory function. In the diabetic brain, insulin resistance decreases levels of insulin receptors and reduces insulin signaling. This leads to decreased levels of GluN2B and GluA1 phosphorylation at synapses, ultimately leading to impaired synaptic plasticity and memory. The reduction in brain insulin signaling increases GSK-3b activity which increases abnormal tau phosphorylation

Fig. 2

Mechanistic association of insulin signaling with mitochondrial function in normal and diabetic brain. Schematic outline of neuronal insulin signaling in the normal brain (a) and in the diabetic brain (b). In physiological conditions, insulin binding to its receptor at the synapse triggers phosphorylation of IRSs, PI3K activation, Akt phosphorylation, inhibits the transcriptional factor FOXO1, and promotes the AMPK-SIRT1-PGC-1α mediated Mt metabolic pathway. In the diabetic brain, insulin resistance and impaired insulin signaling reduces signaling in these pathways and decreases the stability of Mt electron transport proteins thereby increasing oxidative stress. Insulin resistance impairs the electron transport chain, reducing ATP and NAD⁺ generation, and inhibits activation of the NAD⁺-dependent deacetylase SIRT1. Inactivation of SIRT1 further reduces Mt function and repair. As in Fig. 1, the reduction in brain insulin signaling also increases GSK-3b activity that increases abnormal tau phosphorylation