Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer’s subjects?

Abstract

Background Type 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. Methods In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. Results In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. Conclusions In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

“…Therefore, insulin resistance may not only be a risk factor for the development of AD but also may serve as a feature that aggravates its pathology [38,49]. A recent study revealed that in non-diabetic AD patients, peripheral insulin resistance was independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, confirming the hypothesis of insulin resistance impact on AD pathology [56]. Moreover, neuroimaging studies of the brain reported significant correlations between the presence of T2DM, obesity, and/or peripheral insulin resistance with decreased hippocampal volume [67,68].…”

“…Interestingly, obesity, diabetes, and cognitive impairment/Alzheimer's disease share in common a core feature that is target-organ insulin resistance [55]. Insulin resistance is defined as reduced tissue responsiveness to the physiological action of insulin [56]. Similarly, brain insulin resistance is an impairment of brain cells to respond to insulin input [57].…”

“…Similarly, brain insulin resistance is an impairment of brain cells to respond to insulin input [57]. Furthermore, peripheral insulin resistance is associated with impaired brain insulin action [56]. Some obesity/T2DM-associated factors and mechanisms, related to inflammatory pathways, could modulate peripheral insulin signaling.…”

Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer’s Disease and Diabetes

“…It appears that the neuroprotective effects of insulin are due to the regulation of phosphorylated tau levels. An increased level of insulin resistance is also associated with high levels of proinflammatory cytokines which are linked to Aβ depositions in the brains [64]. In diabetes, insulin resistance causes mitochondrial dysfunction, triggering inflammatory response with increased levels of cytokines such as interleukin (Il)-1β, Il-6, Il-8, tumor necrosis factor-alpha (TNF-α), alpha-1-antichymotrypsin (ACT) and C-reactive protein (CRP), the same mechanism being triggered in AD [65].…”

“…Insulin signaling involves the brain to take up glucose and synthesize the insulin-degrading enzyme and is also involved in the degradation of β amyloid. In diabetes, due to the change in insulin signaling, a low synthesis of the enzyme involved in its degradation takes place, thus reducing the process of degradation of β-amyloid with abnormal accumulation in the brain [46,64,104,105]. Insulin and insulin-like growth factor (IGF) are hormones that regulate cell metabolism.…”