4.8 Article

Control of Pancreatic β Cell Regeneration by Glucose Metabolism

Journal

CELL METABOLISM
Volume 13, Issue 4, Pages 440-449

Publisher

CELL PRESS
DOI: 10.1016/j.cmet.2011.02.012

Keywords

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Funding

  1. JDRF
  2. NIH (Beta-cell Biology Consortium)
  3. ICRF (Barbara Goodman PC-RCDA)
  4. EU [241883]
  5. Leona M. and Harry B. Helmsley Charitable Trust
  6. Dutch Friends of Hebrew University
  7. Wellcome Trust
  8. NIH [DK 19525]

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Recent studies revealed a surprising regenerative capacity of insulin-producing beta cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic beta cell regeneration under stressed conditions relies on accelerated proliferation of surviving beta cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that beta cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in beta cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory beta cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces beta 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 beta cell mass by metabolic demand.

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