Affiliation:
1. From the Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts
Abstract
Type 2 diabetes is a complex disease in which genetic and environmental factors interact to produce alterations in insulin action and insulin secretion, leading to hyperglycemia. To evaluate the influence of genetic background on development of diabetes in a genetically susceptible host, we generated mice that are double heterozygous (DH) for knockout of the insulin receptor and insulin receptor substrate-1 on three genetic backgrounds (C57BL/6 [B6], 129Sv, and DBA). Although DH mice on all backgrounds showed insulin resistance, their phenotypes were dramatically different. B6 DH mice exhibited marked hyperinsulinemia and massive islet hyperplasia and developed early hyperglycemia, with 85% overtly diabetic by 6 months. By contrast, 129Sv DH mice showed mild hyperinsulinemia and minimal islet hyperplasia, and < 2% developed diabetes. DBA mice had slower development of hyperglycemia, intermediate insulin levels, and evidence of islet degeneration, with 64% developing diabetes. Thus, mice carrying the same genetic defects on different backgrounds exhibited the full spectrum of abnormalities observed in humans with type 2 diabetes, which allowed for identification of potential loci that promote development of the diabetic phenotype.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference34 articles.
1. Kahn CR: Insulin action, diabetogenes, and the cause of type II diabetes (Banting Lecture). Diabetes 43:1066–1084,1994
2. Kahn CR, Vicent D, Doria A: Genetics of non-insulin-dependent (type II) diabetes mellitus. Annu Rev Med 47:509–531,1996
3. Froguel P, Velho G: Genetic determinants of type 2 diabetes. Recent Prog Horm Res 56:91–105,2001
4. Steiner DF, Tager HS, Nanjo K, Chan SJ, Rubenstein AH: Familial syndromes of hyperproinsulinemia and hyperinsulinemia with mild diabetes. In The Metabolic and Molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D, Eds. New York, McGraw-Hill,1995, p.897–904
5. Taylor SI: Diabetes mellitus. In The Metabolic and Molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D, Eds. New York, McGraw-Hill,1995, p.843–896
Cited by
100 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献