Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide
| Autor: | Walter C. Soeller, Juliette Janson, Peter C. Butler, Robin T. Nelson, Anthony J. Torchia, Patrick C. Roche, David K. Kreutter |
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| Rok vydání: | 1996 |
| Předmět: |
Blood Glucose
Male Genetically modified mouse Aging Amyloid endocrine system medicine.medical_specialty endocrine system diseases medicine.medical_treatment Transgene Mice Transgenic Biology Glucagon Islets of Langerhans Mice Diabetes mellitus Internal medicine medicine Extracellular Animals Humans Insulin Promoter Regions Genetic Sex Characteristics geography Multidisciplinary geography.geographical_feature_category medicine.disease Islet Islet Amyloid Polypeptide Rats Microscopy Electron Endocrinology Diabetes Mellitus Type 2 Female Research Article |
| Zdroj: | Proceedings of the National Academy of Sciences. 93:7283-7288 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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