Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes

• Published in: American journal of physiology: endocrinology and metabolism 2007-07, Vol.293 (1), p.E327-E336
• Main Authors: Cho, You-Ree, Kim, Hyo-Jeong, Park, So-Young, Ko, Hwi Jin, Hong, Eun-Gyoung, Higashimori, Takamasa, Zhang, Zhiyou, Jung, Dae Young, Ola, M. Shamsul, LaNoue, Kathryn F, Leiter, Edward H, Kim, Jason. K
• Format: Article
• Language: English
• Subjects: Age of Onset; Animals; Diabetes Mellitus, Type 2 - pathology; Disease Models, Animal; Endocrinology; Glucose; Glucose - metabolism; Glucose Clamp Technique; Heart - drug effects; Hyperglycemia; Hyperglycemia - pathology; Insulin; Insulin - pharmacology; Insulin Resistance; Lipids; Liver - drug effects; Male; Metabolism; Mice; Mice, Inbred Strains; Mice, Obese; Muscle, Skeletal - drug effects; Obesity - pathology; Rodents
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00376.2006

1 Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut; 2 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and 3 The Jackson Laboratory, Bar Harbor, Maine Submitted 27 July 2006 ; accepted in final form 5 April 2007 As a new mouse model of obesity-induced diabetes generated by combining quantitative trait loci from New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/LtJ) mice, NONcNZO10/LtJ (RCS10) male mice developed type 2 diabetes characterized by maturity onset obesity, hyperglycemia, and insulin resistance. To metabolically profile the progression to diabetes in preobese and obese states, a 2-h hyperinsulinemic euglycemic clamp was performed and organ-specific changes in insulin action were assessed in awake RCS10 and NON/LtJ (control) males at 8 and 13 wk of age. Prior to development of obesity and attendant increases in hepatic lipid content, 8-wk-old RCS10 mice developed insulin resistance in liver and skeletal muscle due to significant decreases in insulin-stimulated glucose uptake and GLUT4 expression in muscle. Transition to an obese and hyperglycemic state by 13 wk of age exacerbated insulin resistance in skeletal muscle, liver, and heart associated with organ-specific increases in lipid content. Thus, this polygenic mouse model of type 2 diabetes, wherein plasma insulin is only modestly elevated and obesity develops with maturity yet insulin action and glucose metabolism in skeletal muscle and liver are reduced at an early prediabetic age, should provide new insights into the etiology of type 2 diabetes. glucose metabolism; skeletal muscle; liver; lipid; transgenic mouse Address for reprint requests and other correspondence: J. K. Kim, Dept. of Cellular and Molecular Physiology, Penn State Univ. College of Medicine, 500 University Dr. (H166), C4600D, Hershey, PA 17033 (e-mail: jason.kim{at}psu.edu )