ISLET AMYLOID POLYPEPTIDE - A REVIEW OF ITS BIOLOGY AND POTENTIAL ROLES IN THE PATHOGENESIS OF DIABETES-MELLITUS

Islet amyloidosis (IA) is the principal lesion in the endocrine pancre as of human beings with non-insulin-dependent diabetes mellitus (NIDDM ) and in the similar forms of diabetes mellitus in domestic cats and m acaques. As such, the delineation of the pathogenesis of this form of amyloidosis may be crucial to the understanding of the development and progression of NIDDM. Islet amyloid polypeptide (IAPP) is a recently discovered polypeptide that is the principal constituent of IA in huma n beings, cats, and macaques. IAPP is produced by the pancreatic beta- cells and is co-packaged with insulin in the beta-cell secretory vesic les. Immunohistochemical and physiologic evidence supports the notion that the beta-cells are heterogenous with respect to their relative co ntents of insulin and IAPP. Therefore, although IAPP is co-secreted wi th insulin in response to a variety of well-known insulin secretogogue s, the molar ratio of these two proteins that is released from the isl ets may vary, depending upon the glucose concentration and prevailing metabolic milieu. IAPP is highly conserved among mammalian species and has about 45% homology to another neuropeptide, calcitonin gene-relat ed peptide. IAPP is encoded by a single-copy gene located, in the huma n being, on chromosome 12. IAPP is expressed as a 93 (murine)-89 (huma n)-amino acid prepropolypeptide that is processed enzymatically, resul ting in the removal of amino- and carboxy-terminal propeptide segments . The 20-29 region of the IAPP molecule is most important in the abili ty of IAPP to form amyloid fibrils. The role of IAPP and IA in the pat hogenesis of human NIDDM and similar forms of diabetes mellitus in cat s and macaques may involve several possible mechanisms, including 1) d irect physical/chemical damage to beta-cells, resulting in necrosis an d loss of functional islet tissue, 2) biologic activities of IAPP that oppose those of insulin or abnormally suppress insulin secretion, and 3) interference by IA deposits of passage of insulin out of beta-cell s and/or entrance of glucose and other secretogogues into the islet. T he roles of each of these possible mechanisms have yet to be demonstra ted. In addition, the physiological significance of the apparent IAPP deficiency in both insulin-dependent diabetes mellitus and NIDDM is cu rrently unknown.