Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.
Bibliographical noteFunding Information:
Y.D. was supported by grants from JDRF, NIH (Beta-cell Biology Consortium), ICRF (Barbara Goodman PC-RCDA), EU (ERC and the Seventh Framework Programme under grant agreement n°241883), the Leona M. and Harry B. Helmsley Charitable Trust, and the Dutch Friends of Hebrew University. B.G. was supported by a grant from JDRF. F.M.A. was supported by the Wellcome Trust. This work was supported in part through core services provided by the DERC at the University of Pennsylvania from a grant sponsored by NIH DK 19525. J.G. is an employee and shareholder of Hoffmann-La Roche. We thank Chris Wright for the generous gift of pdx1 antisera; Antonello Pileggi and Camillo Ricordi for advice on islet transplantation; and Dick Insel, Avigail Dreazen, and Oded Meyuhas for discussions.