Insulin secretion from pancreatic beta cells is stimulated by glucose 
metabolism. However, the relative importance of metabolizing glucose via 
mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion 
remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, 
negatively regulates hypoxia-inducible factor HIF1alpha, a transcription factor 
implicated in promoting a glycolytic form of metabolism. Here we report a 
central role for the pVHL-HIF1alpha pathway in the control of beta-cell glucose 
utilization, insulin secretion, and glucose homeostasis. Conditional 
inactivation of Vhlh in beta cells promoted a diversion of glucose away from 
mitochondria into lactate production, causing cells to produce high levels of 
glycolytically derived ATP and to secrete elevated levels of insulin at low 
glucose concentrations. Vhlh-deficient mice exhibited diminished 
glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical 
activity, and insulin secretion, which culminate in impaired systemic glucose 
tolerance. Importantly, combined deletion of Vhlh and Hif1alpha rescued these 
phenotypes, implying that they are the result of HIF1alpha activation. Together, 
these results identify pVHL and HIF1alpha as key regulators of insulin secretion 
from pancreatic beta cells. They further suggest that changes in the metabolic 
strategy of glucose metabolism in beta cells have profound effects on whole-body 
glucose homeostasis.