Contribution of glycolytic and mitochondrial pathways in glucose-induced changes in islet respiration and insulin secretion.
The different roles of glycolytic and mitochondrial pathways in glucose-induced metabolic activation and insulin secretion were studied in islets of Langerhans. Single islets were perifused with 3 mM glucose together with agents affecting the production or consumption of ATP. Subsequently, glucose was raised to 11 mM and the effects of the agents on metabolic and secretory responses were evaluated. Metabolism was monitored continuously with an oxygen-sensitive microelectrode inserted into the islet. Insulin secretion was determined by assaying insulin in perifusate with ELISA. Inhibitors of mitochondrial ATP production reduced the metabolic and secretory response to glucose. When glycolytic ATP production was reduced, initial but not sustained glucose-stimulated insulin release was observed. Inhibition of mitochondrial pyruvate transport reduced the glucose-induced decline in pO(2). Although mitochondrial metabolism was eventually similar to normal, insulin release was only 20% of normal. Increased energy expenditure also changed the kinetics of the glucose-induced decline in pO(2) and decreased the insulin release by 50%. In conclusion, glucose-induced enhancement of insulin release was only seen when the rise of the sugar concentration triggered a rapid and sustained increase of mitochondrial metabolism. This activation of mitochondrial metabolism required a good metabolic state prior to the glucose challenge.
Department of Medical Cell Biology, Box 571, Uppsala University, SE-751 23 Uppsala, Sweden, Henrik.Ortsater@medcellbiol.uu.se
Henrik
H
Ortsäter
Per
P
Liss
Karl E O
KE
Akerman
Peter
P
Bergsten
D000818:Animals; D001149:Arsenates / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003373:Coumaric Acids / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006096:Gramicidin / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008839:Microelectrodes; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010100:Oxygen / Q000032:analysis*; D014475:Uncoupling Agents / Q000494:pharmacology
D001149:Arsenates; D002614:Chelating Agents; D003373:Coumaric Acids; D004791:Enzyme Inhibitors; D007328:Insulin; D009840:Oligomycins; D014475:Uncoupling Agents; D006096:Gramicidin; C007175:alpha-cyano-4-hydroxycinnamate; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D004533:Egtazic Acid; D010042:Ouabain; D005947:Glucose; C025657:arsenic acid; D010100:Oxygen