Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

When exposed to nutrient excess and insulin resistance, pancreatic β-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 β-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 β-cells (Igf2^βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2^βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2^βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2^βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2^βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.