Abstract
Type 2 diabetes mellitus (T2DM) has been clearlylinked to oxidative stress and amylin amyloidosis in pancreatic β-cells. Yet despite extensive investigation, the biological significance of this is not fully understood. Recently, we proposed that Alzheimer’s disease (AD)-relevant amyloidogenic proteins (APs), such as amyloid-β (Aβ) and tau, might be involved in evolvability against diverse stressors in the brain. Given the analogous cellular stress environments shared by both T2DM and AD, the objective of this study is to explore T2DM pathogenesis from the viewpoint of amyloidogenic evolvability. Similar to AD-related APs, protofibrillar amylin might confer resistance against the multiple stressors in β-cells and be transmitted to offspring to deliver stress information, in the absence of which, type 1 DM (T1DM) in offspring might develop. On the contrary, T2DM may be manifested through an antagonistic pleiotropy mechanism during parental aging. Such evolvability-associated processes might be affected by parental diabetic conditions, including T1DM and T2DM. Furthermore, the T2DM-mediated increase in AD risk during aging might be attributed to an interaction of amylin with AD-related APs through evolvability, in which amylin protofibrillar formation presumably caused by adiponectin (APN) resistance could increase protofibril formation of AD-related APs in evolvability and subsequently lead to T2DM promotion of AD through antagonistic pleiotropy in aging. This suggests that targeting APN combined with an anti-T2DM agent might be therapeutic against neurodegeneration. Collectively, T1DM and T2DM might be linked through amylin evolvability, and a better understanding of amyloidogenic evolvability might also reveal clues to therapeutic interventions for AD comorbid with T2DM.
Highlights
Accumulating evidence suggests that type 2 diabetes mellitus (T2DM) may drive the pathogenesis of various nervous system disorders, including ischemia, depression, and neurodegenerative conditions (Atlantis et al, 2014; Takamatsu et al, 2017)
Since T2DM is associated with increased biological stressors and formation of amyloid-like fibrils of amylin in pancreatic β cells, we propose that amylin evolvability might be involved in the pathogenesis of T2DM
It is generally believed that type 1 DM (T1DM) occurs during youth and may be etiologically distinct from T2DM, which emerges during later adulthood, we alternatively propose that the two types of DM might be closely linked through amyloidogenic evolvability
Summary
Accumulating evidence suggests that type 2 diabetes mellitus (T2DM) may drive the pathogenesis of various nervous system disorders, including ischemia, depression, and neurodegenerative conditions (Atlantis et al, 2014; Takamatsu et al, 2017). In view of the possible involvement of the APN paradox in linking neurodegeneration to metabolic disease, this may account for the pathological positioning of T2DM upstream of AD in aging, suggesting that therapeutic targeting of APN might be a viable strategy For this purpose, suppressing APN expression by various methods, such as antisense oligonucleotides against APN mRNA (Rinaldi and Wood, 2018) and immunotherapy against the APN protein (Lannfelt et al, 2014), might effectively decrease formation of APs protofibrils, leading to suppression of APN paradox and AD (Figure 2C). Since it is possible that Aβ evolvability might be promoted by amylin protofibrils and by other molecules, such as cholesterol and catecholamines, it follows that disease-modifying therapies targeted against other metabolic syndrome disorders in addition to T2DM, especially anti-hypertension agents, might increase overall treatment efficacy
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