Chronic high glucose lowers pyruvate dehydrogenase activity in islets through enhanced production of long chain acyl-CoA: prevention of impaired glucose oxidation by enhanced pyruvate recycling through the malate-pyruvate shuttle.
In islet beta-cells, the high expression of pyruvate carboxylase and the functional importance of the downstream anaplerosis pathways result in a unique characteristic whereby high glucose and fatty acids both increase production of a key fatty acid metabolite, long chain acyl-CoA, for signaling and enzyme regulation in beta-cells. We showed previously in islets that pyruvate dehydrogenase (PDH) activity is lowered by excess fatty acids (the so-called Randle effect). We have now investigated PDH activity and pyruvate metabolism in islets after 48-h culture at 16.7 mmol/liter glucose. Active PDH V(max) was lowered 65% by 48 h of high glucose, and this effect was markedly attenuated by co-culture with triacsin C, which inhibits acyl-CoA synthase. Despite the large reduction in PDH activity, glucose oxidation was twice normal. The reason was continued metabolism of pyruvate through pyruvate carboxylase (V(max), 83% of control) and diversion of flux through the pyruvate-malate shuttle. The result was a 3-fold increase of the pyruvate concentration that overcame the lowered PDH activity by mass action as shown by glucose oxidation measured with [6-(14)C]glucose being twice normal. In addition, glucose-induced insulin secretion was 3-fold increased after 48 h of high glucose, and this effect was totally blocked by co-culture with triacsin C. These results show that a unique feature of islet beta-cells is not only fatty acids but also excess glucose that impairs PDH activity. Also, a specialized trait of beta-cells is a long chain acyl-CoA-mediated defense mechanism that prevents a reduction in glucose oxidation and consequently in insulin secretion.
Liu
Ye Qi
YQ
Division of Endocrinology, Diabetes, and Metabolism, University of Vermont, Burlington, Vermont 05405.
Moibi
Jacob A
JA
Leahy
Jack L
JL
D000214:Acyl Coenzyme A / Q000096:biosynthesis*; D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D005947:Glucose / Q000008:administration & dosage* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014226:Triazenes / Q000494:pharmacology
D000214:Acyl Coenzyme A; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D014226:Triazenes; C034613:triacsin C; D019289:Pyruvic Acid; D003066:Coenzyme A Ligases; D005947:Glucose