Islet amyloid polypeptide (IAPP), a putative polypeptide hormone, is a product of pancreatic (3-cells and the major constituent of the amyloid deposits seen mainly in islets of type 2 diabetic humans and diabetic cats. The connection between IAPP amyloid formation and diabetes is unknown, but a limited segment of the IAPP molecule, positions 20-29, seems responsible for the aggregation to fibrils. Differences in the amino acid sequence ofthis region probably determine whether or not islet amyloid can develop in a particular species. Amyloid fibril formation can be mimicked in vitro with the aid ofsynthetic peptides. With this technique we show that peptides corresponding to IAPP positions 20-29 of human and cat, species that develop IAPP-derived islet amyloid, form amyloidlike fibrils in vitro. The corresponding IAPP segment from three rodent species that do not develop IAPP-derived amyloid did not give rise to fibrils. Substitution of the human IAPP-(20-29) decapeptide with one or two amino acid residues from species without islet amyloid generally reduced the capacity to form fibrils. We conclude that the sequence Ala-Ile-LeuSer-Ser, corresponding to positions 25-29 of human IAPP, is strongly amyloidogenic and that a proline-for-serine substitution in position 28, as in several rodents, almost completely inhibits formation of amyloid fibrils.Human type 2 diabetes is characterized by peripheral insulin resistance and impaired insulin response to increased glucose levels (1). The primary islet abnormality in type 2 diabetes mellitus in humans is not known, but the most characteristic morphological alteration, seen in up to 95% of the patients, is the extracellular deposition of amyloid (2). Like other amyloids, islet amyloid consists mainly of a small protein aggregated into fine fibrils. The main constituent of islet amyloid is a polypeptide displaying amino acid sequence homology with calcitonin gene-related peptide (CGRP) and is called islet amyloid polypeptide (IAPP, also designated diabetes-associated peptide or amylin) (3-6). IAPP is normally expressed by the islet /3 cells, stored in cytoplasmic granules with insulin (7-9), and probably released together with this hormone. The normal function of IAPP is not known, but a depression of insulin-mediated glucose uptake by skeletal muscle cells in vitro has been reported (10). In agreement with this, impaired glucose tolerance was demonstrated in cats after intravenous injection of synthetic IAPP (11). Theoretically, an overproduction of IAPP from islet p cells could be of importance in the development of the peripheral insulin resistance. This hypothesis is supported by the finding of abnormally strong IAPP immunoreactivity in islets of nondiabetic cats with impaired glucose tolerance (12).It is not clear why IAPP forms amyloid fibrils in type 2 diabetes. However, it is known that the amyloid fibrils morphologically occur in close relationship to 13 cells and that the fibrils are present within deep invaginations of these cells (13,14). The cell membr...

Amyloid deposits localized to the islets of Langerhans are typical of non-insulin-dependent human diabetes mellitus and of diabetes mellitus in adult cats. Amyloid deposits also commonly occur in insulin-producing pancreatic tumors. We have purified a major protein-insulinoma or islet amyloid polypeptide (IAPP)-from human and cat islet amyloid and from amyloid of a human insulinoma. IAPP from human insulinoma contained 37 amino acid residues and had a theoretical molecular mass of 3850 Da. The amino acid sequence is unique but has >40% identity with the human calcitonin gelie-related peptide. A partial amino acid sequence of cat islet IAPP corresponding to positions 1-27 of human insulinoma IAPP was identical to the human IAPP except for substitutions in three positions. An antiserum raised to a synthetic human insulinoma IAPP-(7-17) undecapeptide showed specific immunohistochemical reactivity with human and cat islet amyloid and with islet B cells.

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Amyloid deposits in the islets of Langerhans occur in association with type 2 diabetes mellitus (DM) in humans and cats and consist of a 37-amino-acid polypeptide known as islet amyloid polypeptide (IAPP). In order to find an explanation for the situation that islet amyloid (IA) does not develop in common rodent species, we have deduced the amino acid sequence of the IAPP molecule in mouse, rat and hamster. We find that a specific region of the molecule diverges to a high degree. Synthetic peptides corresponding to this region of human and hamster IAPP were compared for their ability to form amyloid fibrils in vitro. Whereas the human peptide readily formed fibrils with amyloid character, the hamster peptide completely lacked this property. We suggest this to be a likely explanation for the differences in IA formation between humans and rodents and discuss our findings in relation to the type 2 DM syndrome.

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