Islet amyloid toxicity: From genesis to counteracting mechanisms

Abstract

Islet amyloid polypeptide (IAPP or amylin) is a hormone co-secreted with insulin by pancreatic β-cells and is the major component of islet amyloid. Islet amyloid is found in the pancreas of patients with type 2 diabetes (T2D) and may be involved in β-cell dysfunction and death, observed in this disease. Thus, investigating the aspects related to amyloid formation is relevant to the development of strategies towards β-cell protection. In this sense, IAPP misprocessing, IAPP overproduction, and disturbances in intra-and extracellular environments seem to be decisive for IAPP to form islet amyloid. Islet amyloid toxicity in β-cells may be triggered in intra-and/or extracellular sites by membrane damage, endoplasmic reticulum stress, autophagy disruption, mitochondrial dysfunction, inflammation, and apoptosis. Importantly, different approaches have been suggested to prevent islet amyloid cytotoxicity, from inhibition of IAPP aggregation to attenuation of cell death mechanisms. Such approaches have improved β-cell function and prevented the development of hyperglycemia in animals. Therefore, counteracting islet amyloid may be a promising therapy for T2D treatment.

Is islet amyloid polypeptide indeed expressed in the human brain?

“…The polyclonal IAPP Ab used by us and in the previous studies on this topic (T4149, Peninsula Laboratories) recognises the full length of the IAPP protein, thus including the sequence recognised in CGRP leading to labelling that is interpreted, by us, as non-specific [43]. Of note, the monoclonal IAPP Ab used by us (clone R10/99) recognises an 11-amino acid sequence (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) of the IAPP protein.…”

“…Islet amyloid polypeptide (IAPP), also called amylin, is a hormone synthesised and secreted by pancreatic β-cells [8,9]. IAPP is involved in insulin and glucagon homeostasis, regulation of bone mass, and blood pressure as well as satiety and gastric emptying.…”

“…In pathological conditions, IAPP is the main component of islet amyloid, contributing to β‐cell loss and finally T2DM. This is due to the molecular structure of IAPP and its ability to form β‐sheets that aggregate into amyloid fibrils [8–10]. These features are also common to other amyloid‐forming proteins in humans [10].…”