Glucokinase-Mediated Glucose Metabolism Regulates Beta Cell Regeneration

Increased glucose metabolism mediated by glucokinase can stimulate the regeneration of pancreatic beta cells and prevent the onset of diabetes by raising the level of insulin.

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver, pancreas, gut, and brain of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

Investigators at the Hebrew University of Jerusalem (Israel) worked with a genetically engineered mouse diabetes model in which more than 80% of the insulin-producing pancreatic beta cells had been destroyed.

They reported in the April 6, 2011, issue of the journal Cell Metabolism that the diabetic mice with their elevated blood glucose levels had regenerated a greater number of new beta cells than control mice without diabetes, suggesting that glucose was a key player in beta cell regeneration. Furthermore, increase in beta cell mass was 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, were the main positive regulator of beta cell proliferation in vivo. At the intracellular level genetic and pharmacologic manipulations revealed that glucose induced beta cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of potassium ATP channels and membrane depolarization.

“Our work shows that as the glucose level is increased in the blood, it tells the beta cells to regenerate,” said senior author Dr. Yuval Dor, professor of developmental biology and cancer research at the Hebrew University of Jerusalem. “It is not blood glucose per se that is the signal, but the glucose-sensing capacity of the beta cell that is the key for regeneration.”

These findings may help drug developers, since the understanding that regeneration depends on glucokinase levels may pave the way for developing a new kind of drug to modulate glucokinase or other steps in the glucose-sensing pathway to direct beta cells down the path of regeneration and replication.

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Hebrew University of Jerusalem