Importance of Aggregated Islet Amyloid Polypeptide for the Progressive Beta-Cell Failure in Type 2 Diabetes and in Transplanted Human Islets

The almost constantly appearing amyloid deposits in islets of Langerhans of individuals with type 2 diabetes was for long time regarded as more or less innocent bystanders. Even after that the amyloid was shown to be an aggre-gated form of a novel polypeptide hormone, islet amyloid polypeptide (IAPP or amylin), the deposits themselves attracted little interest. This can appear peculiar today and is in sharp contrast to another localized form of amyloid deposition occurring in the brain particularly in association with Alzheimer's disease. The protein forming the brain amyloid, Aβ-peptide, was discovered just two years (1984) before IAPP (1986), and aggregation of Aβ became immediately a central issue in the studies of the pathogenesis of Alzheimer's disease. So, why did almost the whole research field on senile and presenile dementia so rapidly focus on amyloid while most diabetologists, with a few exceptions, disregarded islet amyloid? A possible reason is that while Alzheimer researchers fumbled after a possible pathogenic mechanism for the brain pathology, the research field of type 2 diabetes was already established and in a high degree directed towards the development of insulin resistance. Many researchers regarded the obvious failure of beta-cells only as a secondary event due to some elusive mechanism of " glucose toxicity. " In addition, experimentalists in diabetes research most often used mice or rats as models, and in these species, islet amyloid cannot develop due to the amino acid sequence of their IAPP molecules. After the discovery of IAPP, there was a strong interest in the possible physiological role of the molecule and in the effect it may have on the development of type 2 diabetes. It was found early that the peptide induces insulin insensitivity in peripheral tissues. However, this effect was reached only after nonphysiological levels of IAPP. More established effects of the peptide include regulation of satiety, gastric emptying and para-or autocrine signalling of insulin, and glucagon secretion. All these effects seem to modulate the action of insulin, leading to a more even blood glucose level. Since IAPP is a beta-cell product and these cells are lost in type 1 diabetes, IAPP in a modified form has been introduced as supplement to insulin treatment. Today, however, we can note an increasing interest in the importance of the development of IAPP-derived islet amyloid on the beta-cell function. Earlier it was believed that islet amyloid could not be of any significance since even …