OBJECTIVE To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth. RESEARCH DESIGN AND METHODS Using a validated and standardized MRI protocol, we measured pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members. Insulin secretory capacity was determined by measuring postprandial urinary C-peptide. RESULTS Family members with this form of monogenic diabetes had a markedly smaller pancreas and a severely impaired postprandial C-peptide level than family members without diabetes. CONCLUSIONS These results suggest that severe insulin deficiency, rather than islet-directed autoimmunity, leads to reduced pancreas size in type 1 diabetes and that insulin is a major trophic factor for the exocrine pancreas.