Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Abstract

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of ‘brain insulin resistance’ and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

Review: Relationship of type 2 diabetes to human brain pathology

“…However, IR, both peripherally and in the brain, may be a mechanistic link, as supported by emerging data showing that markers of both types of IR appear to be associated with ADNC. More data is needed to explore this area . In addition to CVD, ADNC, and IR, other mechanisms linking to T2D to dementia might be involved.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Clinically, there is a higher density of insulin receptors in the brain of patients with AD compared to control subjects, possibly reflecting upregulation of the receptor in an attempt to compensate for the decreased functionality of insulin (Frolich et al, 1998). By contrast, some studies reported decreased insulin receptor binding in individuals with AD in comparison with age‐matched control (Arnold et al, 2018; Rivera et al, 2005; Steen et al, 2005). For example, reduced insulin, insulin receptor, IGF1 and IGF2, reduced total IRS1 mRNA expression, and reduced protein indicators of downstream insulin signaling activity (including p85‐associated IRS1, phosphorylated AKT) have been reported in postmortem AD brain (Steen et al, 2005).…”

“…For example, reduced insulin, insulin receptor, IGF1 and IGF2, reduced total IRS1 mRNA expression, and reduced protein indicators of downstream insulin signaling activity (including p85‐associated IRS1, phosphorylated AKT) have been reported in postmortem AD brain (Steen et al, 2005). Although there are some controversial results about insulin receptor concentration, insulin resistance in AD has been demonstrated a novel ex vivo insulin signaling stimulation experiment (Arnold et al, 2018; Talbot et al, 2012). Insulin may affect Aβ degradation via an insulin‐degrading metalloprotease.…”

Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease

“…9–14 Insidious, progressive dementia is the clinical manifestation of these processes whose cumulative effects evolve over years before and after onset of clinical symptoms. 15 The complexity of AD’s biology and protean clinical features present many challenges, but also many entry points for affecting the disease and its symptoms.…”