ARE ANIMAL-MODELS OF DIABETES RELEVANT TO THE STUDY OF THE GENETICS OF NON-INSULIN-DEPENDENT DIABETES IN HUMANS

Although it is well-recognized that non-insulin-dependent diabetes-mel litus (NIDDM) shows a strong genetic component the search for candidat e genes has been very difficult since NIDDM is a complex, heterogeneou s, multifactorial syndrome resulting from both genetic susceptibility and environmental risk factors. Therefore, the use of inbred animal mo dels is an essential component of genetic investigations in this field . As these lines are genetically homogeneous, it is possible to direct mating for optimal genetic crosses and control environmental factors. Strains with spontaneous NIDDM may be constituted from animals with o ne or several genetic mutation(s) transmitted generation to generation or selected from non-diabetic outbred animals by repeated breeding. T he ob/ob and db/db mice, which are rodent models of NIDDM and obesity, belong to the first category. Recent studies using the positional clo ning approach allowed the mapping of oh gene and identification of its product, leptin, which is a protein secreted by white adipose tissue and involved in the control of food intake. The db gene encodes the le ptin receptor. The search for genetic linkage was undertaken in polyge nic models, especially the Goto-Kakisaki (GK) rat which was obtained b y selective breeding of individuals with glucose intolerance from a no ndiabetic Wistar rat colony. Through precise definition of sub-phenoty pes of glucose tolerance and insulin secretion, the mapping of microsa tellite markers and QTL analysis, it has proved possible to identify m any independent loci containing genes regulating glucose homeostasis a nd insulin secretion. In another polygenic model, the OLETF rat, a loc us present on chromosome X was identified. Many complementary approach es in different strains may lead to the identification of candidate ge nes for NIDDM and help direct the search for candidate genes in humans who show synteny relationships with rodents.