title: Beta-cell hypersensitivity to glucose following 24-h exposure of rat islets to fatty acids.
abstract: Prolonged exposure of islets to fatty acids results in a lowered glucose set-point for insulin secretion. We examined the mechanism in islets cultured for 24 h with 0.25 mmol/l palmitate. As expected, insulin secretion at 2.8 and 8.3 mmol/l glucose was increased in the palmitate-treated islets as opposed to no change at 27.7 mmol/l glucose. Co-culturing with 0.05 microgram/ml Triacsin C, an inhibitor of long chain acyl-CoA synthetase, blocked this effect. Glucose utilization and oxidation showed the same pattern as insulin secretion, with the step-up for both measurements being fully manifest at 2.8 mmol/l glucose. Glucokinase Km and Vmax measured in islet extracts were unaffected by the palmitate. In contrast, hexokinase Vmax was increased by 25-35% in both the cytoplasmic and mitochondrial-bound pools. Our data suggest prolonged exposure to fatty acids increased beta-cell hexokinase activity, thereby modifying the kinetics of glucose entry into the metabolic pathway and glucose-induced insulin secretion. The cellular mediator is likely an increased level of long chain fatty acyl-CoA esters.
authors.affiliation: Division of Endocrinology, Diabetes Mellitus, and Molecular Medicine, New England Medical Center, Boston, Massachusetts, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hosokawa
authors.forename: B E
authors.initials: BE
authors.lastname: Corkey
authors.forename: J L
authors.initials: JL
authors.lastname: Leahy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014226:Triazenes / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D014226:Triazenes; D019308:Palmitic Acid; C034613:triacsin C; D006593:Hexokinase; D005941:Glucokinase; D003066:Coenzyme A Ligases; D005947:Glucose