Control of pancreatic β cell regeneration by glucose metabolism.
Porat S., Weinberg-Corem N., Tornovsky-Babaey S., Schyr-Ben-Haroush R., Hija A., Stolovich-Rain M., Dadon D., Granot Z., Ben-Hur V., White P., Girard CA., Karni R., Kaestner KH., Ashcroft FM., Magnuson MA., Saada A., Grimsby J., Glaser B., Dor Y.
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.