Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance
| Autor: | Shaoping Zhang, Hong Liu, Winifred P. S. Wong, Garth J. S. Cooper, Athena Ferreira, Yee Soon Choong, Etuate L. Saafi, Chia Lin Chuang, David Scott |
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| Rok vydání: | 2008 |
| Předmět: |
Blood Glucose
Genetically modified mouse Amyloid endocrine system medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment Glucose uptake Amylin Apoptosis Enzyme-Linked Immunosorbent Assay Mice Inbred Strains Mice Transgenic macromolecular substances Biology Islets of Langerhans Mice Insulin resistance Microscopy Electron Transmission Internal medicine Diabetes Mellitus Internal Medicine medicine Animals Humans Glucose tolerance test geography geography.geographical_feature_category medicine.diagnostic_test Insulin Glucose Tolerance Test Glucagon Islet medicine.disease Immunohistochemistry Islet Amyloid Polypeptide Glucose Endocrinology Islet Studies Insulin Resistance Somatostatin |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db06-1755 |
| Popis: | OBJECTIVES—We sought to 1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes. RESEARCH DESIGN AND METHODS—We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [25,28,29Pro]human amylin, in an FVB/n background. RESULTS—Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive β-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals. [25,28,29Pro]human amylin transgenic mice developed neither β-cell degeneration nor glucose intolerance. CONCLUSIONS—Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused β-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with β-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro. |
| Databáze: | OpenAIRE |
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