beta-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulatedinsulin secretion.

摘要

Glucose-stimulated insulin secretion (GSIS) by beta-cells requires the generation ofATP from oxidation of pyruvate as well as generation of coupling factorsinvolving three different pyruvate cycling shuttles. The roles of several keyenzymes involved in pyruvate cycling in beta-cells have been documented usingisolated islets and beta-cell clonal lines. To investigate the role of the pyruvate dehydrogenase (PDH) complex (PDC) in GSIS, a murine model of beta-cell-specific PDH deficiency (beta-PDHKO) was created. Pancreatic insulin content was decreased in1-day-old beta-PDHKO male pups and adult male mice. The plasma insulin levels weredecreased and blood glucose levels increased in beta-PDHKO male mice from neonatallife onward. GSIS was reduced in isolated islets from beta-PDHKO male mice withabout 50% reduction in PDC activity. Impairment in a glucose tolerance test andin vivo insulin secretion during hyperglycemic clamp was evident in beta-PDHKOadults. No change in the number or size of islets was found in pancreata from4-wk-old beta-PDHKO male mice. However, an increase in the mean size of individualbeta-cells in islets of these mice was observed. These findings show a key role ofPDC in GSIS by pyruvate oxidation. This beta-PDHKO mouse model represents the first mouse model in which a mitochondrial oxidative enzyme deletion by gene knockouthas been employed to demonstrate an altered GSIS by beta-cells.