Suppression of beta cell energy metabolism and insulin release by PGC-1alpha.
beta cell dysfunction is an important component of type 2 diabetes, but the molecular basis for this defect is poorly understood. The transcriptional coactivator PGC-1alpha mRNA and protein levels are significantly elevated in islets from multiple animal models of diabetes; adenovirus-mediated expression of PGC-1alpha to levels similar to those present in diabetic rodents produces a marked inhibition of glucose-stimulated insulin secretion from islets in culture and in live mice. This inhibition coincides with changes in metabolic gene expression associated with impaired beta cell function, including the induction of glucose-6-phosphatase and suppression of GLUT2, glucokinase, and glycerol-3-phosphate dehydrogenase. These changes result in blunting of the glucose-induced rise in cellular ATP levels and membrane electrical activity responsible for Ca(2+) influx and insulin exocytosis. These results strongly suggest that PGC-1alpha plays a key functional role in the beta cell and is involved in the pathogenesis of the diabetic phenotype.
Yoon
J Cliff
JC
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Xu
Gang
G
Deeney
Jude T
JT
Yang
Shao-Nian
SN
Rhee
James
J
Puigserver
Pere
P
Levens
Adah R
AR
Yang
Ruojing
R
Zhang
Chen-Yu
CY
Lowell
Bradford B
BB
Berggren
Per-Olof
PO
Newgard
Christopher B
CB
Bonner-Weir
Susan
S
Weir
Gordon
G
Spiegelman
Bruce M
BM
D016475:3T3 Cells; D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D005941:Glucokinase / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D051381:Rats; D011922:Rats, Mutant Strains; D011924:Rats, Zucker; D014157:Transcription Factors / Q000494:pharmacology*; D014162:Transfection
D007328:Insulin; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D000255:Adenosine Triphosphate; D005941:Glucokinase; D005952:Glucose-6-Phosphatase