Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus

THE 37-amino-acid polypeptide amylin is the principal constituent of the amyloid deposits that form in the islets of Langerhans in patients with type-2 diabetes mellitus1–5, but its role in the pathogenesis of this disease is unresolved6–8. In view of the fact that the β-amyloid protein that forms fibrils in Alzheimer's disease is toxic to neurons 9,10, we have investigated whether amylin fibrils could be toxic to pancreatic islet cells. We show here that human amylin is toxic to insulin-producing β-cells of the adult pancreas of rats and humans. This toxicity is mediated by the fibrillar form of the amylin peptide and requires direct contact of the fibrils with the cell surface. The mechanism of cell death involves RNA and protein synthesis and is characterized by plasma membrane blebbing, chromatin condensation and DNA fragmentation, indicating that amylin induces islet cell apoptosis. These findings indicate that amylin fibril formation in the pancreas may cause islet cell dysfunction and death in type-2 diabetes mellitus.

[1]  C. Newgard,et al.  Rat amylin: cloning and tissue-specific expression in pancreatic islets. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Greene,et al.  Aurintricarboxylic acid rescues PC12 cells and sympathetic neurons from cell death caused by nerve growth factor deprivation: correlation with suppression of endonuclease activity , 1991, The Journal of cell biology.

[3]  C. Parish,et al.  New fluorescent dyes for lymphocyte migration studies. Analysis by flow cytometry and fluorescence microscopy. , 1990, Journal of immunological methods.

[4]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[5]  C. Betsholtz,et al.  Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. W. Hayden,et al.  Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. W. Hayden,et al.  Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. , 1987, The American journal of pathology.

[8]  P. Westermark,et al.  Quantitative studies on amyloid in the islets of Langerhans. , 1972, Upsala journal of medical sciences.

[9]  D. Longnecker,et al.  The relation of islet amyloid to the clinical type of diabetes. , 1981, Human pathology.

[10]  E. Opie.  ON THE RELATION OF CHRONIC INTERSTITIAL PANCREATITIS TO THE ISLANDS OF LANGERHANS AND TO DIABETES MELUTUS , 1901, The Journal of experimental medicine.

[11]  R. Turner,et al.  Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Imahori,et al.  Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Mesulam,et al.  β-Amyloid and the pathogenesis of alzheimer's disease , 1991 .

[14]  L. Villa-komaroff,et al.  Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. , 1989, Science.

[15]  J. Rothbard,et al.  Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[16]  P. C. Butler,et al.  Islet Amyloid Polypeptide: A Review of Its Biology and Potential Roles in the Pathogenesis of Diabetes Mellitus , 1993, Veterinary pathology.

[17]  L. Magder,et al.  A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. , 1989, The New England journal of medicine.

[18]  C. Ricordi,et al.  Isolation of the elusive pig islet. , 1990, Surgery.

[19]  G. Forloni,et al.  Neurotoxicity of a prion protein fragment , 1993, Nature.

[20]  G. Cooper,et al.  Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro , 1988, Nature.

[21]  P. Fraser,et al.  pH-dependent structural transitions of Alzheimer amyloid peptides. , 1991, Biophysical journal.

[22]  G. Forloni,et al.  Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25-35. , 1993, Neuroreport.

[23]  Kenneth H. Johnson,et al.  Sequence divergence in a specific region of islet amyloid polypeptide (IAPP) explains differences in islet amyloid formation between species , 1989, FEBS letters.

[24]  C. Betsholtz,et al.  Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. , 1989, The New England journal of medicine.

[25]  M. Braunfeld,et al.  Identification of prion amyloid filaments in scrapie-infected brain , 1985, Cell.

[26]  A. Wyllie,et al.  Cell death: the significance of apoptosis. , 1980, International review of cytology.

[27]  D. Steiner,et al.  Conservation of the sequence of islet amyloid polypeptide in five mammals is consistent with its putative role as an islet hormone. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[28]  C. Cotman,et al.  Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  P. May,et al.  Neurotoxicity of Human Amylin in Rat Primary Hippocampal Cultures: Similarity to Alzheimer's Disease Amyloid‐β Neurotoxicity , 1993, Journal of neurochemistry.