ß-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion.
Glucose-stimulated insulin secretion (GSIS) by β-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 β-cells have been documented using isolated islets and β-cell clonal lines. To investigate the role of the pyruvate dehydrogenase (PDH) complex (PDC) in GSIS, a murine model of β-cell-specific PDH deficiency (β-PDHKO) was created. Pancreatic insulin content was decreased in 1-day-old β-PDHKO male pups and adult male mice. The plasma insulin levels were decreased and blood glucose levels increased in β-PDHKO male mice from neonatal life onward. GSIS was reduced in isolated islets from β-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 β-PDHKO adults. No change in the number or size of islets was found in pancreata from 4-wk-old β-PDHKO male mice. However, an increase in the mean size of individual β-cells in islets of these mice was observed. These findings show a key role of PDC in GSIS by pyruvate oxidation. This β-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 β-cells.
Srinivasan
Malathi
M
Dept. of Biochemistry, Univ. at Buffalo, Buffalo, NY 14214, USA.
Choi
Cheol S
CS
Ghoshal
Pushpankur
P
Pliss
Lioudmila
L
Pandya
Jignesh D
JD
Hill
David
D
Cline
Gary
G
Patel
Mulchand S
MS
D000367:Age Factors; D000818:Animals; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*
D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D005947:Glucose