Autocrine Igf2 Programmes Beta-Cell Plasticity Under Conditions Of Increased Metabolic Demand

When exposed to nutrient excess and insulin resistance, pancreatic beta-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming beta-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic beta-cells (Igf2(beta KO)) in mice. We show that autocrine actions of IGF2 are not critical for beta-cell development, or for the early post-natal wave of beta-cell remodelling. Additionally, adult Igf2(beta KO) mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2(beta KO) females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2(beta KO) females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2(beta KO) females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of beta-cell IGF2 during early development determine their adaptive capacity in adult life.