The goals of my research program are to 1) Understand insulin signaling and insulin resistance using patients with rare disorders resulting in extreme insulin resistance; 2) Apply what I learn about pathophysiology to develop therapies for these rare and life-threatening diseases; and 3) Use what I learn from rare diseases to elucidate pathways that may serve as drug targets for more common disorders of insulin resistance, such as obesity and type 2 diabetes. My lab has utilized our rare patient populations with severe insulin resistance affecting only a subset of insulin signaling pathways (selective insulin resistance) versus all insulin signaling pathways (nonselective insulin resistance) to show mechanisms by which increased or decreased insulin signaling lead to metabolic and cardiovascular disease. These findings are applicable to the broader population with obesity associated selective insulin resistance. We have extensively studied the clinical benefits, risks, and mechanisms of action of the adipokine leptin in patient populations including generalized and partial lipodystrophy, and mutations of the insulin receptor. These studies not only have led to FDA approval of recombinant human leptin for patients with severe leptin deficiency due to generalized lipodystrophy, but have extended both clinical benefits and mechanistic understanding of pharmacologic doses of leptin in populations with leptin concentrations in the normal range. Our studies of the role of insulin and leptin in reproductive function using rare patient models provide insights applicable to patients with the common polycystic ovarian syndrome and hypothalamic amenorrhea.