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 patho-physiology 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.

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

“…Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are two of the most prominent diseases plaguing the aging population (Alzheimer’s Association, 2016; Baglietto-Vargas et al, 2016; Zilliox et al, 2016). Epidemiological, clinical, and preclinical, evidence compellingly suggests that T2D and AD bear interrelated disease risks and mechanisms (Haan, 2006; Heneka et al, 2015; Janson et al, 2004; Kandimalla et al, 2016; Steen et al, 2005).…”

“…Compelling evidence suggests that insulin resistance and T2D worsen AD pathology and cognitive deficits (Haan, 2006; Ramos-Rodriguez et al, 2016; Saedi et al, 2016; Sena et al, 2015; Sheen and Sheu, 2016; Zilliox et al, 2016). To this end, central insulin signaling dysregulation has been demonstrated in post-mortem hippocampal and cortical samples from subjects with both mild cognitive impairment (MCI) and early AD (Talbot et al, 2012a; Watson and Craft, 2004).…”

Metformin intake associates with better cognitive function in patients with Huntington's disease

“…Unfortunately, this comparison was not feasible with the Enroll-HD database since both groups were not comparable as metformin users were all diabetic and diabetes is known to negatively affect cognitive test results (reviewed by Zilliox and coworkers [18]). A doubled blind placebo controlled clinical trial using metformin, in non-diabetic HD patients, would be required compare HD patients taking metformin vs not taking.…”

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

“…Compelling evidence suggests that insulin resistance results in cognitive deficits and worsens AD pathology [81-85]. Dysregulations in insulin signaling have been reported in postmortem hippocampal and cortical samples from subjects with AD [86].…”