Haploinsufficiency of Insm1 Impairs Postnatal Baseline β-Cell Mass.

Baseline β-cell mass is established during the early postnatal period when β-cells expand. In this study, we show that heterozygous ablation of decreases baseline β-cell mass and subsequently impairs glucose tolerance. When exposed to a high-fat diet or on an background, glucose intolerance was more severe in mice compared with mice, although no further decrease in the β-cell mass was detected. In islets of early postnatal mice, the cell cycle was prolonged in β-cells due to downregulation of the cell cycle gene Although Insm1 had a low affinity for the promoter compared with other binding sites, binding affinity was strongly dependent on Insm1 levels. We observed dramatically decreased binding of Insm1 to the promoter after downregulation of expression. Furthermore, downregulation of resulted in a prolonged cell cycle, and overexpression of Ccnd1 rescued cell cycle abnormalities observed in Insm1-deficient β-cells. We conclude that decreases in Insm1 interfere with β-cell specification during the early postnatal period and impair glucose homeostasis during metabolic stress in adults. Insm1 levels are therefore a factor that can influence the development of diabetes.