Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced -cell area in control offspring of LIRKO mothers shortly after birth. -Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller -cell mass/area and -cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development. maternal insulin resistance; intrauterine environment; offspring metabolism; endocrine pancreas development; hyperinsulinemia MATERNAL METABOLIC STATUS DURING PREGNANCY is important for fetal growth and development, since the fetus is completely dependent upon its mother for nutrition. Studies have reported that adverse experiences during fetal life can impair fetal development and cause permanent metabolic adaptations in the offspring that would influence their long-term health by increasing the risk for developing insulin resistance, type 2 diabetes, obesity, and/or cardiovascular disease in adulthood (8). To understand the role of intrauterine environment on fetal growth and development, investigators have used various animal models of maternal overnutrition [obesity (29), high-fat diet (15)] and maternal malnutrition (low-protein diet, lowenergy diet) (11) and have also investigated other conditions affecting mothers during pregnancy [e.g., gestational diabetes (34), hyperglycemia (16), hypoxia (46), anemia (24), and glucocorticoid exposure (23)] (2). However, the effects of insulin resistance on a background of transient hyperglycemia in the mother on alterations in metabolism and pancreas development in the offspring remain unclear.Insulin resistance contributes to a range of serious health p...