The discovery of insulin in 1922 is one of the miracles of modern medicine, and it turned a once deadly disease—insulin-deficient (autoimmune) type 1 diabetes mellitus (T1DM)—into a manageable one. It is now clear that insulin is a key metabolic regulator that is vital to glucose and lipid homeostasis and affects many aspects of growth and development. Insulin’s fundamental importance in biology is underscored by the conservation of insulin-like hormones and their receptors from flies and worms to humans. In PNAS, Wang et al. (1) extend previous findings (2–4) to suggest that another hormone, leptin, may substitute for or be used in combination with insulin to treat T1DM more effectively. Leptin, a prototypic fat-secreted hormone, is also a master metabolic regulator. It is critical for control of appetite, body weight, energy homeostasis, and reproduction (5). Deficiency of leptin or its receptor in rodents and humans causes severe hyperphagia, obesity, insulin resistance, and neuroendocrine and reproductive dysfunction (6). Based on its ability to normalize body weight in massively obese ob/ob mice (which lack leptin) and reduce food intake in normal rodents, it was anticipated that leptin would curb the obesity pandemic. Unfortunately, common obesity is a state of leptin resistance rather than leptin deficiency, and leptin therapy alone is generally unsuccessful in clinical trials for obesity (7), although a small study suggests potential efficacy for leptin in combination with amylin (8). To date, efficacy of leptin monotherapy in humans is primarily limited to leptin-deficient states such as congenital leptin deficiency, lipoatrophy, hypothalamic amenorrhea with reduced adipose mass, and HIV lipodystrophy (9). With insulin therapy, T1DM is no longer a life-threatening disease, and the burden of diabetic complications including nephropathy, retinopathy, neuropathy, cardiovascular disease, and lower limb amputation has also been reduced. However, modern treatment of T1DM falls far … 1To whom correspondence should be addressed: bkahn{at}bidmc.harvard.edu.