title: Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells.
abstract: Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters.
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.|Departments of Nutrition, Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montréal, Montreal, Québec H3C 3J7, Canada, and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Mugabo
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.|Departments of Medicine and Human Genetics, McGill University, Montreal, Québec H3A 1B1, Canada.
authors.forename: Shangang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Lamontagne
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.|Departments of Medicine and Human Genetics, McGill University, Montreal, Québec H3A 1B1, Canada.
authors.forename: Anfal
authors.initials: A
authors.lastname: Al-Mass
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Peyot
authors.affiliation: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Corkey
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.
authors.forename: Erik
authors.initials: E
authors.lastname: Joly
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.
authors.forename: S R Murthy
authors.initials: SRM
authors.lastname: Madiraju
authors.affiliation: From the Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada, marc.prentki@umontreal.ca.|Departments of Nutrition, Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montréal, Montreal, Québec H3C 3J7, Canada, and.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism; D004099:Dihydroxyacetone Phosphate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D005994:Glycerophosphates / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D005227:Fatty Acids; D005994:Glycerophosphates; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D004099:Dihydroxyacetone Phosphate; D000255:Adenosine Triphosphate; D006003:Glycogen; C029620:alpha-glycerophosphoric acid; D005947:Glucose
keywords: glucodetoxification; glucose metabolism; insulin secretion; lipid metabolism; metabolomics; mitochondrial metabolism; pancreatic β cells