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

Abstract

(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 ␤-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 Ͼ250 and Ͼ450 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 ␤-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 ␤-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; ␤-cell TYPE 2 DIABETES MELLITUS (T2DM) is a devastating metabolic disease presently affecting at least 16 million people in the United States alone (33, 49). The prevalence of T2DM is also increasing in children and adolescents (42). With the increasing incidence of T2DM, the identification of preventative measures has become crucial, necessitating the development of effective preclinical models for studying approaches for both diabetes prevention and treatment.The most commonly used rodent models of T2DM include the Zucker diabetic fatty (ZDF) rat, the Otsuka Long Evans Tokushima fatty (OLETF) rat, and the db/db mouse, all of which exhibit obesity-associated insulin resistance and impaired ␤-cell function, resulting in diabetes (5, 25, 38). While these animal models have contributed substantially to understanding the pathophysiology and treatment of T2DM and its complications, the basic mechanisms underlying the pathogenesis of diabetes in these models do not correspond with what occurs in most human patients with T2DM. These differences in etiology are likely to hinder effective translational research.Obesity and insulin resistance in most animal models of T2DM result from monogenic mutations that are rare in human and animal populations and present multiple problems in terms of applying these models to clinical T2DM. For example, mutat...

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

“…Intra-assay CVs for total cholesterol, FFAs, and TGs were 2.9, 2.2, and 3.5%, respectively. These assay procedures have been validated for rodents (22).…”

Laboratory animals as surrogate models of human obesity

“…Havel and co-workers [78] have developed a polygenic rat model with adult-onset obesity, insulin resistance and late onset type 2 diabetes that maintains leptin signaling without dietary intervention. The model originates from crossing obese, insulin-resistant SD rats with lean ZDF rats.…”

“…By the F7 generation, it appeared that all animals were homozygous for the β-cell defect [79] , and both sexes develop diabetes at 183±10 and 286±17 days of age, respectively (the incidence is 91.9% for males and 42.6% for females). The body weight and caloric intake are significantly higher for the UC Davis type 2 diabetes mellitus rat [UCD (University of California Davis)-T2DM] than the lean SD rat.…”

Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats

“…For example, genetic leptin deficiency results in not only marked hyperphagia and obesity (1) but also severe insulin resistance, which is reversed by administration of exogenous leptin (1,12,13). Furthermore, leptin deficiency has been observed in models of both untreated type 1 and type 2 diabetes (9,14,15), and low leptin levels have been shown to contribute to the development of hyperphagia (15) and insulin resistance (9).…”

“…Given that leptin receptor mutations are rare in human populations and that human obesity and type 2 diabetes are most often polygenic in origin, models such as the db/db mouse and ZDF rat are not representative of the pathogenesis of type 2 diabetes in humans. In the present study, the effects of leptin treatment of type 2 diabetes were investigated in the University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rat model, which develops adult-onset polygenic obesity, insulin resistance, and marked hyperglycemia without a defect in leptin signaling (14). Twice-daily s.c. administration of murine leptin normalized fasting plasma glucose concentrations in diabetic UCD-T2DM rats.…”