Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia
| Autor: | E. J. P. de Koning, Frans M. A. Hofhuis, S. van Gaalen, Cornelis J.M. Lips, K. L. Van Hulst, John F. Morris, A Clark, Jwm Hoppener, W. H. L. Hackeng, M. J. H. Berends, Peter J.A. Capel, H. J. Visser-Vernooy, C. Oosterwijk, H.S. Jansz, J. S. Verbeek |
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| Rok vydání: | 1993 |
| Předmět: |
Male
Amyloid endocrine system medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment Restriction Mapping BACE1-AS Radioimmunoassay Amylin Mice Transgenic Islets of Langerhans Mice Insulin resistance Internal medicine mental disorders Internal Medicine medicine Amyloid precursor protein Animals Humans Microscopy Immunoelectron Pancreatic hormone geography geography.geographical_feature_category biology Insulin Exons medicine.disease Islet Islet Amyloid Polypeptide Rats Mice Inbred C57BL Endocrinology Mice Inbred CBA biology.protein Female Lysosomes Plasmids |
| Zdroj: | Diabetologia. 36:1258-1265 |
| ISSN: | 1432-0428 0012-186X |
| DOI: | 10.1007/bf00400803 |
| Popis: | Type 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: | OpenAIRE |
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