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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.

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