title: Acute metabolic amplification of insulin secretion in mouse islets: Role of cytosolic acetyl-CoA.
abstract: Stimulation of the ß-cell metabolism by glucose and other fuels triggers insulin release by enhancing the mitochondrial ATP production and acutely amplifies the secretory response by increase in mitochondrial export of metabolites. We aimed to narrow down the uniform final reaction steps mediating fuel-induced acute amplification of insulin secretion.
  
  
  
  Insulin secretion and metabolic parameters were measured in isolated mouse islets exposed to the sulfonylurea glipizide in high concentration (closing all ATP-sensitive K(+) channels) during the entire experiment. Fuel-induced effects were examined after treating the islets for one hour with medium devoid of fuels. This experimental design prevented acute amplification, but only when glucose was the sole fuel.
  
  
  
  Strong amplification of insulin secretion by α-ketoisocaproate or glucose combined with α-ketoisovalerate (supplying mitochondrial oxaloacetate) was abolished within 14min after transition to medium devoid of fuels. After transition from medium containing glucose plus α-ketoisovalerate to medium containing solely glucose or α-ketoisovalerate, amplification (strong or weak, respectively) occurred until the end of the experiment. Glucose (alone or combined with α-ketoisovalerate) increased the total acetyl-CoA content as intensely as α-ketoisocaproate. Low concentrations of α-ketoisovalerate or α-ketoisocaproate were sufficient for saturation of acetyl-CoA increase, but caused no or only weak amplification, respectively. No acetyl-CoA increases occurred in the absence of glipizide.
  
  
  
  Glucose and other fuels regulate acute amplification of insulin secretion by controlling the supply of acetyl-CoA to the ß-cell cytosol. Cytosolic acetyl-CoA does not amplify by serving as substrate for syntheses of metabolic intermediates, but amplifies by acting as substrate for cytosolic protein acetylation.
authors: Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technical University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany. Electronic address: u.panten@tu-bs.de.
authors: Uwe
authors: U
authors: Panten
authors: Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technical University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany.
authors: Eike
authors: E
authors: Früh
authors: Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technical University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany.
authors: Kirstin
authors: K
authors: Reckers
authors: Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technical University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany.
authors: Ingo
authors: I
authors: Rustenbeck
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003470:Culture Media; D003600:Cytosol / Q000378:metabolism*; D005913:Glipizide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D054086:KATP Channels / Q000187:drug effects; D007651:Keto Acids / Q000494:pharmacology; D051379:Mice; D026902:Potassium Channel Blockers / Q000494:pharmacology
chemical_list: D003470:Culture Media; D007328:Insulin; D054086:KATP Channels; D007651:Keto Acids; D026902:Potassium Channel Blockers; D000244:Adenosine Diphosphate; D000105:Acetyl Coenzyme A; C013082:alpha-ketoisocaproic acid; D000255:Adenosine Triphosphate; D005947:Glucose; D005913:Glipizide
keywords: Acetyl-CoA; Beta cell; Glucose; Insulin secretion; α-ketoisocaproate