Control of pancreatic ß cell regeneration by glucose metabolism.

ABSTRACT

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