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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.

Original publication

DOI

10.1016/j.cmet.2011.02.012

Type

Journal article

Journal

Cell Metab

Publication Date

06/04/2011

Volume

13

Pages

440 - 449

Keywords

Animals, Blood Glucose, Cell Membrane, Cell Proliferation, Glucokinase, Glycolysis, Insulin-Secreting Cells, KATP Channels, Mice, Regeneration