Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.

The islet in non-insulin-dependent diabetes mellitus (NIDDM) is characterized by loss of beta cells and large local deposits of amyloid derived from the 37-amino acid protein, islet amyloid polypeptide (IAPP). We have hypothesized that IAPP amyloid forms intracellularly causing beta-cell destruction under conditions of high rates of expression. To test this we developed a homozygous transgenic mouse model with high rates of expression of human IAPP. Male transgenic mice spontaneously developed diabetes mellitus by 8 weeks of age, which was associated with selective beta-cell death and impaired insulin secretion. Small intra- and extracellular amorphous IAPP aggregates were present in islets of transgenic mice during the development of diabetes mellitus. However, IAPP derived amyloid deposits were found in only a minority of islets at approximately 20 weeks of age, notably after development of diabetes mellitus in male transgenic mice. Approximately 20% of female transgenic mice spontaneously developed diabetes mellitus at 30+ weeks of age, when beta-cell degeneration and both amorphous and amyloid deposits of IAPP were present. We conclude that overexpression of human IAPP causes beta-cell death, impaired insulin secretion, and diabetes mellitus. Large deposits of IAPP derived amyloid do not appear to be important in this cytotoxicity, but early, small amorphous intra- and extracellular aggregates of human IAPP were consistently present at the time of beta-cell death and therefore may be the most cytotoxic form of IAPP.

[1]  M. Couce,et al.  Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis. , 1996, The Journal of clinical endocrinology and metabolism.

[2]  W. V. Van Nostrand,et al.  Amyloid β-Protein Aggregation Nullifies Its Pathologic Properties in Cultured Cerebrovascular Smooth Muscle Cells (*) , 1995, The Journal of Biological Chemistry.

[3]  N. Eberhardt,et al.  Human islet amyloid polypeptide expression in COS-1 cells. A model of intracellular amyloidogenesis. , 1995, The American journal of pathology.

[4]  J. Miyazaki,et al.  Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. , 1995, European journal of endocrinology.

[5]  C. Behl,et al.  Amyloid peptides are toxic via a common oxidative mechanism. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. G. Powell,et al.  Dexamethasone-Induced Hyperglycemia in Obese Avy/a (Viable Yellow) Female Mice Entails Preferential Induction of a Hepatic Estrogen Sulfotransferase , 1994, Diabetes.

[7]  E. D. de Koning,et al.  Human Islet Amyloid Polypeptide Accumulates at Similar Sites in Islets of Transgenic Mice and Humans , 1994, Diabetes.

[8]  Bruce A. Yankner,et al.  Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus , 1994, Nature.

[9]  Kenneth H. Johnson,et al.  Islet Amyloid Polypeptide in Human Insulinomas: Evidence for Intracellular Amyloidogenesis , 1994, Diabetes.

[10]  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.

[11]  W. Soeller,et al.  Germline manipulation of glucose homeostasis via alteration of glucose transporter levels in skeletal muscle. , 1993, The Journal of biological chemistry.

[12]  D. Steiner,et al.  Human islet amyloid polypeptide transgenic mice as a model of non‐insulin‐dependent diabetes mellitus (NIDDM) , 1993, FEBS letters.

[13]  C. Betsholtz,et al.  Islet amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus. , 1992, Laboratory investigation; a journal of technical methods and pathology.

[14]  J. Culvenor,et al.  Overexpression of beta 2-microglobulin in transgenic mouse islet beta cells results in defective insulin secretion. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[15]  R. Rizza,et al.  Effects of Meal Ingestion on Plasma Amylin Concentration in NIDDM and Nondiabetic Humans , 1990, Diabetes.

[16]  D. Hanahan,et al.  Diabetes induced in male transgenic mice by expression of human H-ras oncoprotein in pancreatic beta cells , 1990, Molecular and cellular biology.

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

[18]  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.