title: Metabolic amplification of insulin secretion is differentially desensitized by depolarization in the absence of exogenous fuels.
abstract: OBJECTIVE
  The metabolic amplification of insulin secretion is the sequence of events which enables the secretory response to a fuel secretagogue to exceed the secretory response to a purely depolarizing stimulus. The signals in this pathway are incompletely understood. Here, we have characterized an experimental procedure by which the amplifying response to glucose is reversibly desensitized, while the response to α-ketoisocaproic acid (KIC) is unchanged.
  
  
  METHODS
  Insulin secretion, NAD(P)H- and FAD-autofluorescence, Fura-2 fluorescence and oxygen consumption were measured in perifused NMRI mouse islets. The ATP- and ADP-contents were measured in statically incubated mouse islets. All islets were freshly isolated.
  
  
  RESULTS
  While the original observation on the dissociation between glucose- and KIC-amplification was obtained with islets that had been exposed to a high concentration of the sulfonylurea glipizide in the absence of glucose, we now show that in the absence of exogenous fuel a moderate depolarization, irrespective of its mechanism, progressively decreased the amplification in response to both glucose and KIC. However, the amplification in response to glucose declined faster, so a time window exists where glucose was already inefficient, whereas KIC was of unimpaired efficiency. Measurements of adenine nucleotides, NAD(P)H- and FAD-autofluorescence, and oxygen consumption point to a central role of the mitochondrial metabolism in this process. The desensitization could be quickly reversed by increasing oxidative deamination of glutamate and consequently anaplerosis of the citrate cycle.
  
  
  CONCLUSIONS
  Depolarization in the absence of exogenous fuel may be a useful model to identify those signals which are indispensable for the generation of metabolic amplification.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Schulze
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Mai
authors.initials: M
authors.lastname: Morsi
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Reckers
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Brüning
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Nele
authors.initials: N
authors.lastname: Seemann
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Panten
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany. Electronic address: i.rustenbeck@tu-bs.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005913:Glipizide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007651:Keto Acids / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption; D015398:Signal Transduction / Q000187:drug effects*; D064233:Sulfonylurea Receptors / Q000235:genetics
chemical_list: C577508:Abcc8 protein, mouse; D000227:Adenine Nucleotides; D007004:Hypoglycemic Agents; D007328:Insulin; D007651:Keto Acids; D064233:Sulfonylurea Receptors; D005182:Flavin-Adenine Dinucleotide; D009249:NADP; C013082:alpha-ketoisocaproic acid; D005947:Glucose; D005913:Glipizide
keywords: Cytosolic calcium concentration; Glucose; Glutamate; Insulin secretion; Metabolic amplification; Mitochondria