Recent Insights in Islet Amyloid Polypeptide‐Induced Membrane Disruption and Its Role in β‐Cell Death in Type 2 Diabetes Mellitus

Abstract

The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet β-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-induced β-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of β-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer's disease, Parkinson's disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to β-cell death in DM2.

Islet amyloid polypeptide acts on glucose‐ stimulated beta cells to reduce voltage‐gated calcium channel activation, intracellular Ca2+ concentration, and insulin secretion

“…The ability of L-type calcium channel blockers to inhibit glucose-stimulated insulin secretion is consistent with the possibility that L-type calcium channels may play an important role in calcium influx and insulin exocytosis [17,18]. Under physiological conditions, the insulin synthesized by β cells is stored in the cytoplasm.…”

Islet amyloid polypeptide toxicity and membrane interactions

“…We do not wish to imply that loss of membrane integrity is unimportant in vivo; it may be one mechanism contributing to cytotoxicity along with a range of other cellular events. IAPP amyloid has been shown to cluster at or near membranes, and exogenously added IAPP can perturb cell membranes (21,26,42,43), but it can be difficult to extrapolate from in vitro studies with model membranes to the situation in vivo. The fact that differences in the ability to induce leakage are observed for the 48 h incubation in the presence of the 25% anionic vesicle might suggest that there is some correlation with in vitro leakage and toxicity.…”

Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure

“…On the other hand, two recent works investigating the inflammatory properties of islet amyloid polypeptide (IAPP), whose fibrillar deposits are found in the pancreas of patients with type II diabetes, pointed oligomers as the immunologically active species [9,14]. However, since aggregation of IAPP is extremely rapid [47,48] and the presence of lipidic bilayers or cell membranes further accelerates this process [47,49,50], it is very difficult to identify precisely the entities responsible for cellular activation, and to know whether they contain cross-β structures. In contrast, the different species used in our work are stable.…”