The Role of the Pancreatic Amyloid in the Pathogenesis of Type 2 Diabetes

Aretaeus of Cappadocia in the second century A.D. made a short and vivid characterization of diabetes as a “mysterious disease”. With its multiple phenotypes and the main “thin diabetes” and the “fat diabetes”, Lancereaux indicated to us where the secret of type 2 diabetes must be found, namely in the adipose tissue. The pathogenic discordance between beta-cell mass (which progressively decreases) and adipocyte mass (which increases and thereafter remains increased) will be the subject of another paper. Here we attempt to clarify the significance of pancreatic amyloid described by Lancereaux and Paulesco in 1912 by renaming the pancreatic hyalinosis mentioned in 1901 by the American Opie and Viennese Weichselbaum. The interest in amyloid and diabetes was started by Westermark, who in 1986 discovered a second secretory line inside the beta-cells: pre-proamylin/proamylin/ amylin. However, despite the large amount of research on this topic, the amyloidogenic mechanism of amylin remains largely unknown. The importance of endoplasmic reticulum in post-translational molecular processing of proinsulin and proamylin could shed a light on the pathogenesis of type 2 diabetes. In our view, of the many other pathogenic factors (adipocytes, with their secretory function is one of them), an amyloidogenic mechanism could be related to the overload of pancreatic beta-cells, which, by trying to secrete more insulin, due to the processing defect, finally leads to the production of more proinsulin. This can have an adverse effect on beta-cell survival and by disequilibrium with amylin, can lead to the aggregation of monomers of amylin . Due to their toxic effects the insoluble amyloid aggregates could contribute to the progressive loss of the beta-cell mass, especially in the elderly.