Activation of Stimulus-Secretion Coupling in Pancreatic -Cells by Specific Products of Glucose Metabolism

• Published in: The Journal of biological chemistry Vol. 271; no. 9; p. 4838
• Main Authors: Robert J. Mertz, Jennings F. Worley III, Ben Spencer, John H. Johnson, Iain D. Dukes
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 01-03-1996
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.271.9.4838

The energy requirements of most cells supplied with glucose are fulfilled by glycolytic and oxidative metabolism, yielding
ATP. In pancreatic β-cells, a rise in cytosolic ATP is also a critical signaling event, coupling closure of ATP-sensitive
K channels ( K ) to insulin secretion via depolarization-driven increases in intracellular Ca ([Ca ] ). We report that glycolytic but not Krebs cycle metabolism of glucose is critically involved in this signaling process. While
inhibitors of glycolysis suppressed glucose-stimulated insulin secretion, blockers of pyruvate transport or Krebs cycle enzymes
were without effect. While pyruvate was metabolized in islets to the same extent as glucose, it produced no stimulation of
insulin secretion and did not block K . A membrane-permeant analog, methyl pyruvate, however, produced a block of K , a sustained rise in [Ca ] , and an increase in insulin secretion 6-fold the magnitude of that induced by glucose. These results indicate that ATP derived
from mitochondrial pyruvate metabolism does not substantially contribute to the regulation of K responses to a glucose challenge, supporting the notion of subcompartmentation of ATP within the β-cell. Supranormal stimulation
of the Krebs cycle by methyl pyruvate can, however, overwhelm intracellular partitioning of ATP and thereby drive insulin
secretion.