Fasting and decreased B cell sensitivity: important role for fatty acid-induced inhibition of PDH activity.
Fasting inhibits glucose-induced insulin secretion. We investigated the role of a glucose fatty acid cycle for such inhibition and its molecular basis in pancreatic islets from 48-h fasted rats. The fasting-impaired insulin response to 27 mM glucose was restored by 41% with a carnitine palmitoyltransferase I inhibitor, etomoxir. Etomoxir also restored (by 50%) impaired glucose oxidation in islets from fasted rats and increased the ratio of oxidation to glycolytic flux from 33 to 43%. Fasting decreased total pyruvate dehydrogenase (PDH) activity (active, unphosphorylated plus inactive, phosphorylated form) by 29%, as well as the percentage of active form (54 +/- 5 vs. 79 +/- 2% in fed rats, P < 0.001). Fasting increased islet PDH kinase activity as follows: PDH-bound activity by 36% and free (not PDH bound) PDH kinase by 70%. Fasting failed to affect PDH kinase content when assayed by an enzyme-linked immunoabsorbent assay with antibodies raised against 45 kDa PDH kinase alpha-chain. We conclude that fasting impairs B cell function to a major extent through the operation of a glucose fatty acid cycle and that decreased PDH activity resulting from increased specific activity of PDH kinase constitutes an important molecular mechanism.
Zhou
Y P
YP
Department of Molecular Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Priestman
D A
DA
Randle
P J
PJ
Grill
V E
VE
D000818:Animals; D046508:Culture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005215:Fasting; D005227:Fatty Acids / Q000502:physiology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D007328:Insulin; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D013386:Succinates; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; C054207:etomoxir; C041105:monomethyl succinate