Control of Pancreatic β Cell Regeneration by Glucose Metabolism

SummaryRecent 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 KATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.

Graphical AbstractFigure optionsDownload high-quality image (130 K)Download as PowerPoint slideHighlights
► Pancreatic β cell regeneration is controlled systemically, primarily by glucose
► Glucose-induced replication is mediated by glycolysis and membrane depolarization
► Glucokinase is a potential drug target for impacting β cell replication and mass