Haploinsufficiency of Insm1 Impairs Postnatal Baseline β-Cell Mass.

Abstract

Baseline β-cell mass is established during the early postnatal period when β-cells expand. In this study, we show that heterozygous ablation of <i>Insm1</i> decreases baseline β-cell mass and subsequently impairs glucose tolerance. When exposed to a high-fat diet or on an <i>ob/ob</i> background, glucose intolerance was more severe in <i>Insm1^+/lacZ</i> mice compared with <i>Insm1^+/+</i> mice, although no further decrease in the β-cell mass was detected. In islets of early postnatal <i>Insm1^+/lacZ</i> mice, the cell cycle was prolonged in β-cells due to downregulation of the cell cycle gene <i>Ccnd1</i> Although Insm1 had a low affinity for the <i>Ccnd1</i> promoter compared with other binding sites, binding affinity was strongly dependent on Insm1 levels. We observed dramatically decreased binding of Insm1 to the <i>Ccnd1</i> promoter after downregulation of <i>Insm1</i> expression. Furthermore, downregulation of <i>Ccnd1</i> 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.