Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 8; pp. 3492 - 3496
• Main Authors: Verchere, C. Bruce, D'Alessio, David A., Palmiter, Richard D., Weir, Gordon C., Bonner-Weir, Susan, Baskin, Denis G., Kahn, Steven E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 16.04.1996; National Acad Sciences; National Academy of Sciences
• Subjects: Amyloid - genetics; Amyloid - metabolism; Amyloid plaque; Amyloids; animal transgenique; animales transgenicos; Animals; Biochemistry; Blood plasma; diabete; Diabetes; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Female; Gene Expression; genero humano; genre humain; glicoproteinas; glycoproteine; glycoproteins; hiperglicemia; Humans; hyperglycaemia; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - metabolism; hyperglycemie; Insulin; Insulin - blood; insulina; insuline; Islet Amyloid Polypeptide; Islets of Langerhans - metabolism; Islets of Langerhans - ultrastructure; Male; mankind; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Microscopy, Immunoelectron; pancreas; peptide; peptides; peptidos; raton; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rodents; Solar fibrils; souris; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.8.3492

Pancreatic islet amyloid deposits are a characteristic pathologic feature of non-insulin-dependent diabetes mellitus and contain islet amyloid polypeptide (IAPP: amylin). We used transgenic mice that express human IAPP in pancreatic beta cells to explore the potential role of islet amyloid in the pathogenesis of non-insulin-dependent diabetes mellitus. Extensive amyloid deposits were observed in the pancreatic islets of approximately 80% of male transgenic mice > 13 months of age. Islet amyloid deposits were rarely observed in female transgenic mice (11%) and were never seen in nontransgenic animals. Ultrastructural analysis revealed that these deposits were composed of human IAPP-immunoreactive fibrils that accumulated between beta cells and islet capillaries. Strikingly, approximately half of the mice with islet amyloid deposits were hyperglycemic (plasma glucose > 11 mM). In younger (6-to 9-month-old) male transgenic mice, islet amyloid deposits were less commonly observed but were always associated with severe hyperglycemia (plasma glucose > 22 mM). These data indicate that expression of human IAPP in beta cells predisposes male mice to the development of islet amyloid and hyperglycemia. The frequent concordance of islet amyloid with hyperglycemia in these mice suggests an interdependence of these two conditions and supports the hypothesis that islet amyloid may play a role in the development of hyperglycemia.