We investigate the molecular basis of insulin signal transduction to understand the pathophysiology of diabetes and related disorders, including obesity, infertility, and cardiovascular and retinal disease. Much of our work on signaling pathways that mediate the insulin response was fueled by our discovery of the insulin receptor substrate (IRS) protein family. Since diabetes is a complicated, multisystem disease, we use mice to integrate our molecular studies with physiology. Transgenic mice lacking the genes for Irs1 or Irs2 reveal a surprisingly close relation between the molecular regulation of insulin secretion and that of insulin action. We now understand that the IRS2-branch of the insulin/IGF signaling pathways controls pancreatic β-cell growth, function and survival.