Abstract
Diabetes affects hundreds of millions of patients worldwide. Despite the advances in understanding the disease and therapeutic options, it remains a leading cause of death and of comorbidities globally. Islet amyloid polypeptide (IAPP), or amylin, is a hormone produced by pancreatic β-cells. It contributes to the maintenance of glucose physiological levels namely by inhibiting insulin and glucagon secretion as well as controlling adiposity and satiation. IAPP is a highly amyloidogenic polypeptide forming intracellular aggregates and amyloid structures that are associated with β-cell death. Data also suggest the relevance of unprocessed IAPP forms as seeding for amyloid buildup. Besides the known consequences of hyperamylinemia in the pancreas, evidence has also pointed out that IAPP has a pathological role in cognitive function. More specifically, IAPP was shown to impair the blood–brain barrier; it was also seen to interact and co-deposit with amyloid beta peptide (Aß), and possibly with Tau, within the brain of Alzheimer's disease (AD) patients, thereby contributing to diabetes-associated dementia. In fact, it has been suggested that AD results from a metabolic dysfunction in the brain, leading to its proposed designation as type 3 diabetes. Here, we have first provided a brief perspective on the IAPP amyloidogenic process and its role in diabetes and AD. We have then discussed the potential interventions for modulating IAPP proteotoxicity that can be explored for therapeutics. Finally, we have proposed the concept of a “diabetes brain phenotype” hypothesis in AD, which may help design future IAPP-centered drug developmentstrategies against AD.
Highlights
Amyloidogenesis is a process by which peptides spontaneously self-assemble into higher order structures, namely oligomers, protofibrils, and mature amyloid fibrils (Martins et al, 2008; MaurerStroh et al, 2010; Hauser et al, 2014)
We have reviewed the mechanisms of islet amyloid polypeptide (IAPP) dysfunction in diabetes and dementia, in Alzheimer’s disease (AD), adding to the recent view of multi-factorial contributions to both diseases
The role of IAPP is undeniably relevant in both diabetes and AD
Summary
Amyloidogenesis is a process by which peptides spontaneously self-assemble into higher order structures, namely oligomers, protofibrils, and mature amyloid fibrils (Martins et al, 2008; MaurerStroh et al, 2010; Hauser et al, 2014). A transgenic mice model expressing human IAPP (hIAPP) spontaneously developed amyloidosis, showing impaired insulin production, β-cell loss, and fasting hyperglycemia (Janson et al, 1996).
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