Dominant negative mutations in human PPAR gamma associated with severe insulin resistance, diabetes mellitus and hypertension

Thiazolidinediones are a new class of antidiabetic agent that improve insul in sensitivity and reduce plasma glucose and blood pressure in subjects wit h type 2 diabetes(1). Although these agents can bind and activate an orphan nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR g amma), there is no direct evidence to conclusively implicate this receptor in the regulation of mammalian glucose homeostasis(2). Here we report two d ifferent heterozygous mutations in the ligand-binding domain of PPAR gamma in three subjects with severe insulin resistance. In the PPAR gamma crystal structure, the mutations destabilize helix 12 which mediates transactivati on. Consistent with this, both receptor mutants are markedly transcriptiona lly impaired and, moreover, are able to inhibit the action of coexpressed w ild-type PPAR gamma in a dominant negative manner. In addition to insulin r esistance, all three subjects developed type 2 diabetes mellitus and hypert ension at an unusually early age. Our findings represent the first germline loss-of-function mutations in PPAR gamma and provide compelling genetic ev idence that this receptor is important in the control of insulin sensitivit y, glucose homeostasis and blood pressure in man.