A useful list of spontaneously arising animal models of obesity and diabetes

Abstract

TO THE EDITOR: over the years, we have had the opportunity to edit books and compendia that characterize diverse animal models of obesity and diabetes. Most of those animal models have been either selected through inbreeding or characterized following spontaneously arising mutations. It is now timely to provide, in a summary manner, a concise list of such models as an update and reference for future research. The major defects are described in the references cited. In some cases, insulin resistance has been linked to impaired insulin signaling at various levels, including negative feedback at the level of the insulin receptor substrate (IRS)-1 (5, 15, 24). However, in most cases the mechanism of the diabetogenic changes has not been exhaustively investigated. We hope that this list will guide studies geared at elucidating specific defects in the signal flow and how these studies may explain the metabolic failures leading to the diabetic proneness of the models as well as the mechanism of the ensuing complications. These animal models should also enable the discovery of therapeutic modalities with relevance to human diabetes and should continue to be a useful tool along with specific target-generated transgenic and knockout animals so amply used to understand metabolism and energy balance. Obesity and diabetes in mice with mutations in leptin or leptin receptor genes. Since the discovery that ob is a mutation in the leptin structural gene and db is a mutation in the leptin receptor gene, the nomenclature for these mutations has been changed to reflect their molecular basis. The Lep ob mutation on chromosome 6 was discovered in the Jackson Laboratory, Bar Harbor, ME, and recognized by marked obesity and hyperphagia. This mutation was subsequently transferred to the B6 inbred strain background. On this genetic background, the mutation produces juvenile-onset obesity, hyperinsulinemia, and insulin resistance with mild hyperglycemia and a sustained hyperplasia of the pancreatic -cells. The Lepr db mutation is a recessive mutation on chromosome 4 that occurred spontaneously in the C57BLKS/J inbred strain. The obesity/diabetes syndrome is associated with progressively severe hyperglycemia and correlated with pancreatic cell necrosis and islet atrophy at the end stage. The ob mutation is predominantly obese and exhibits only mild hyperglycemia. The current genetic nomenclature for these mice is as follows: Lep obJ , common name “obese” gene product; leptin or leptin mRNA and Lepr db-IJ , common name “diabetic” gene product leptin receptor or leptin receptor mRNA. Detailed information on these strains can be found in Chua et al. (2). Zucker diabetic fatty rat with a leptin receptor defect. The Zucker diabetic fatty (ZDF) rat exhibits leptin receptor defects. This type of obesity, although associated with insulin resistance, is unlike common forms of human obesity. The ZDF rat was developed into a reproducible type 2 diabetic model at Indiana University (16) from a Zucker rat colony (lepr fa )i n which certain individuals exhibited a propensity to diabetes. The male rat is characterized by hyperinsulinemia and hyperglycemia at 6‐7 wk of age, with glucose reaching levels of 500 mg/dl and insulin levels dropping successively. The female rat requires a high-fat diet for the expression of diabetes. The ZDF rat carries a genetic defect in -cell transcription that is independent of the leptin receptor mutation, causing obesity and insulin resistance likely to be inherited in the -cell gene. Goto-Kakizaki rat with impaired -cell mass and function due to polygenic inheritance. The Goto-Kakizaki rat is a nonobese substrain of Wistar rat origin with inherited chronic hyperglycemia. It was selected through a group of eight generation-inbreeding Wistar rats displaying high glucose levels during a glucose tolerance test. They present “starfish-shaped” islet abnormalities and pancreatic hormone deficiencies, resembling the polygenic basis of human type 2 diabetes (14). New Zealand obese mouse. This is a model of obesity, glucose intolerance, and metabolic syndrome of polygenic nature. This animal exhibits hepatic and peripheral leptin insensitivity, insulin resistance, impaired insulin secretion, hypercholesteremia, and hypertension (6). It displays classic features of obesity, including excessive body weight hyperphagia and reduced energy expenditure. Such obesity is responsible for its impaired glucose metabolism. JCR:LA-cp rat: exhibiting metabolic syndrome with microand macrovascular disease. The prediabetic state in the JCR: LA-cp rat is characterized by abdominal obesity, hypertriglyceridemia and insulin resistance, and a marked damage to the vascular system, which is associated with atherosclerosis, vasculopathy, and ischemic end-stage disease (19). It is a unique model of the obesity/insulin resistance syndrome with cardiovascular implications of polygenic derivation. SHROB rat: a model of metabolic syndrome. The spontaneously obese SHROB (Koletzky) rat is an overtly nondiabetic rat with the primary and secondary characteristics associated with the human metabolic syndrome, including insulin resistance. It exhibits a single recessive trait, a nonsense mutation causing loss of hypothalamic leptin receptors designated as fa k (12), and its insulin-signaling defects were initially reported by