β-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion

Glucose-stimulated insulin secretion (GSIS) by beta-cells requires the generation of ATP from oxidation of pyruvate as well as generation of coupling factors involving three different pyruvate cycling shuttles. The roles of several key enzymes involved in pyruvate cycling in beta-cells have been documented using isolated 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 in 1-day-old beta-PDHKO male pups and adult male mice. The plasma insulin levels were decreased and blood glucose levels increased in beta-PDHKO male mice from neonatal life onward. GSIS was reduced in isolated islets from beta-PDHKO male mice with about 50% reduction in PDC activity. Impairment in a glucose tolerance test and in vivo insulin secretion during hyperglycemic clamp was evident in beta-PDHKO adults. No change in the number or size of islets was found in pancreata from 4-wk-old beta-PDHKO male mice. However, an increase in the mean size of individual beta-cells in islets of these mice was observed. These findings show a key role of PDC in GSIS by pyruvate oxidation. This beta-PDHKO mouse model represents the first mouse model in which a mitochondrial oxidative enzyme deletion by gene knockout has been employed to demonstrate an altered GSIS by beta-cells.