Genetically diabetic animals.

Several animal species, mostly rodents, were described to exhibit spontaneously diabetes mellitus on a hereditary basis. These findings were highly appreciated with the expectation to get more insight into the pathogenesis of diabetes in humans. During the last few years since the discovery of leptin (Zhang et al. 1994) and its downstream signal transduction cascade (Friedman and Halaas 1998), tremendous new insight of the genetics of diabetic and obese animal disease models was derived. Up to now, at least six genetically diabetic animal models exhibit defects in the leptin pathway: the ob mutation in the mouse resulted in leptin deficiency. The db mutation in the mouse and the cp and fa mutations in the rat are different mutations of the leptin receptor gene. The fat mutation in the mouse results in a biologically inactive carboxypeptidase E, which processes the prohormone conversion of POMC into α-MSH, which activates the hypothalamic MC4 receptor. Finally the Agouti yellow (y) mouse exhibit a ubiquitous expression of the Agouti protein which represents an antagonist of the hypothalamic MC4 receptor