Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity

Rapamycin, a specific inhibitor for mTOR complex 1, is an FDA-approved immunosuppressant for organ transplant. Recent developments have raised the prospect of using rapamycin to treat cancer or diabetes and to delay aging. It is therefore important to assess how rapamycin treatment affects glucose homeostasis. Here, we show that the same rapamycin treatment reported to extend mouse life span significantly impaired glucose homeostasis of aged mice. Moreover, rapamycin treatment of lean C57B/L6 mice reduced glucose-stimulated insulin secretion in vivo and ex vivo as well as the insulin content and beta cell mass of pancreatic islets. Confounding the diminished capacity for insulin release, rapamycin decreased insulin sensitivity. The multitude of rapamycin effects thus all lead to glucose intolerance. As our findings reveal that chronic rapamycin treatment could be diabetogenic, monitoring glucose homeostasis is crucial when using rapamycin as a therapeutic as well as experimental reagent

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