Amyloid in the islets of Langerhans: Thoughts and some historical aspects

Per Westermark

doi:10.3109/03009734.2011.573884

Abstract

Deposition of amyloid, derived from the polypeptide hormone islet amyloid polypeptide (IAPP; ‘amylin’) is the single most typical islet alteration in type 2 diabetes. Islet amyloid was described as hyalinization already in 1901, but not until 1986 was it understood that it is a polymerization product of a novel β-cell regulatory product. The subject of this focused review deals with the pathogenesis and importance of the islet amyloid itself, not with the biological effect of the polypeptide. Similar to the situation in Alzheimer's disease, it has been argued that the amyloid may not be of importance since there is no strict correlation between the degree of islet amyloid infiltration and the disease. However, it is hardly discussable that the amyloid is important in subjects where islets have been destroyed by pronounced islet amyloid deposits. Even when there is less islet amyloid the deposits are widely spread, and β-cells show ultrastructural signs of cell membrane destruction. It is suggested that type 2 diabetes is heterogeneous and that in one major subtype aggregation of IAPP into amyloid fibrils is determining the progressive loss of β-cells. Interestingly, development of islet amyloid may be an important event in the loss of β-cell function after islet transplantation into type 1 diabetic subjects.

Highlights

It is 25 years since we elucidated the nature of the amyloid in the islets of Langerhans [1]
We have suggested that this first amyloid leads to apoptosis of the cell, leaving the amyloid, which is resistant to degradation, extracellularly where it seeds further amyloid formation from exocytosed islet amyloid polypeptide (IAPP) [46]
Is islet amyloid of any importance in type 2 diabetes?. This question can be rephrased as to whether aggregated IAPP in any form is pathogenically important since there is evidence that not fully developed amyloid fibrils but smaller, oligomeric assemblies exert toxic effects on b-cells and thereby kill them [60]

Summary

Introduction

It is 25 years since we elucidated the nature of the amyloid in the islets of Langerhans [1]. Direct amino acid sequence analysis of purified degu islet amyloid revealed surprisingly that the fibril protein in this species is derived from insulin [40]. This finding closed the circle, since insulin was, for natural reasons, believed to be the fibril protein in human islet amyloid [41] before IAPP was discovered.

Results

Conclusion