Cyclins D2 and D1 Are Essential for Postnatal Pancreatic β-Cell Growth

Abstract

Regulation of adult β-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G₁ phase of the cell cycle. Here we show that cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2^−/− or cyclin D1^{+/ −} D2^−/− mice. However, β-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2^−/− mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1^{+/ −} mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1^{− /+} D2^−/− mice as β-cell mass decreased after birth. Thus, cyclins D2 and D1 were essential for β-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in β cells could prevent or cure diabetes.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grants to M.F.W. (DK55326, DK43808, DK38712) and P.S. (CA83688) and HHMI funds to M.F.W. J.A.K. was supported by institutional (DK02024) and individual (DK064101) National Institutes of Health training grants, a Charles H. Hood Foundation Child Health Research grant, and a Lawson Wilkins Pediatric Endocrine Society Clinical Scholar Award. M.A.C. was supported by a Research Training Fellowship awarded by the International Agency for Research on Cancer and The Kosciuszko Foundation Fellowship.