Background: Fasting insulin secretion is increased in obesity and type 2 diabetes. Results: Culture of -cells in excess nutrients resulted in increased lipid stores and a left-shifted dose-response curve of glucose-stimulated insulin secretion due to an enhanced sensitivity of exocytosis to Ca 2ϩ . Conclusion: Intracellular lipid modulates the dose response of glucose-stimulated insulin secretion. Significance: A shift in -cell glucose sensitivity may contribute to hyperinsulinemia.