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Diabetes. 2018 Dec;67(12):2615-2625. doi: 10.2337/db17-1330. Epub 2018 Sep 26.

Haploinsufficiency of Insm1 Impairs Postnatal Baseline β-Cell Mass.

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The First Affiliated Hospital, Jinan University, Guangzhou, China.
Developmental Biology/Signal Transduction Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Jinan University, Guangzhou, China.
Institute of Clinical Medicine, Jinan University, Guangzhou, China.
The First Affiliated Hospital, Jinan University, Guangzhou, China


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

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