Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat

1 Department of Molecular Biosciences, School of Veterinary Medicine; 2 Department of Nutrition, University of California, Davis, California; 3 Research and Development Service, Department of Veterans Affairs Puget Sound Health Care System and Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition; 4 Department of Medicine, University of Washington, Seattle, Washington; and 5 Department of Internal Medicine, University of California, Davis, Sacramento, California Submitted 27 July 2008 ; accepted in final form 26 September 2008 The prevalence of type 2 diabetes (T2DM) is increasing, creating a need for T2DM animal models for the study of disease pathogenesis, prevention, and treatment. The purpose of this project was to develop a rat model of T2DM that more closely models the pathophysiology of T2DM in humans. The model was created by crossing obese Sprague-Dawley rats with insulin resistance resulting from polygenic adult-onset obesity with Zucker diabetic fatty-lean rats that have a defect in pancreatic β-cell function but normal leptin signaling. We have characterized the model with respect to diabetes incidence; age of onset; longitudinal measurements of glucose, insulin, and lipids; and glucose tolerance. Longitudinal fasting glucose and insulin data demonstrated progressive hyperglycemia (with fasting and fed glucose concentrations >250 and >450 mg/dl, respectively) after onset along with hyperinsulinemia resulting from insulin resistance at onset followed by a progressive decline in circulating insulin concentrations, indicative of β-cell decompensation. The incidence of diabetes in male and female rats was 92 and 43%, respectively, with an average age of onset of 6 mo in males and 9.5 mo in females. Results from intravenous glucose tolerance tests, pancreas immunohistochemistry, and islet insulin content further support a role for β-cell dysfunction in the pathophysiology of T2DM in this model. Diabetic animals also exhibit glycosuria, polyuria, and hyperphagia. Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM. diabetic rodent model; hyperglycemia; insulin; β-cell Address for reprint requests and other correspondence: P. J. Havel, Dept. of Molecular Biosciences, School of Veterinary Medicine, Univ. of California, Davis, One Shields Ave., Davis, CA 95616 (e-m