Transgenic knockouts reveal a critical requirement for pancreatic β cell glucokinase in maintaining glucose homeostasis

Abstract The secretion of insulin is controlled by the rate of glucose metabolism in the pancreatic β cells. As phosphorylation by glucokinase (GLK) appears to be the rate-limiting step for glucose catabolism in β cells, this enzyme may be the glucose sensor. To test this possibility and to resolve the relative roles of liver and β cell GLK in maintaining glucose levels, we have generated mice completely deficient in GLK and transgenic mice in which GLK is expressed only in β cells. In mice with only one GLK allele, blood glucose levels are elevated and insulin secretion is reduced. GLK-deficient mice die perinatally with severe hyperglycemia. Expression of GLK in β cells in the absence of expression in the liver is sufficient for survival. These mice demonstrate the critical need for β cell GLK in maintaining normal glucose levels and provide a novel model for one form of noninsulin-dependent diabetes.