Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells

Takashi Tsuboi, Gabriela da Silva Xavier, George G Holz, Laurence S Jouaville, Andrew P Thomas, Guy A Rutter

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155 Citations (Scopus)


Glucagon-like peptide-1 (GLP-1) is a potent regulator of glucose-stimulated insulin secretion whose mechanisms of action are only partly understood. In the present paper, we show that at low (3 mM) glucose concentrations, GLP-1 increases the free intramitochondrial concentrations of both Ca(2+) ([Ca(2+)](m)), and ATP ([ATP](m)) in clonal MIN6 beta-cells. Suggesting that cAMP-mediated release of Ca(2+) from intracellular stores is responsible for these effects, increases in [ATP](m) that were induced by GLP-1 were completely blocked by the Rp isomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), or by chelation of intracellular Ca(2+). Furthermore, inhibition of Ins(1,4,5) P (3) (IP(3)) receptors with xestospongin C, or application of ryanodine, partially inhibited GLP-1-induced [ATP](m) increases, and the simultaneous blockade of both IP(3) and ryanodine receptors (RyR) completely eliminated the rise in [ATP](m). GLP-1 appeared to prompt Ca(2+)-induced Ca(2+) release through IP(3) receptors via a protein kinase A (PKA)-mediated phosphorylation event, since ryanodine-insensitive [ATP](m) increases were abrogated with the PKA inhibitor, H89. In contrast, the effects of GLP-1 on RyR-mediated [ATP](m) increases were apparently mediated by the cAMP-regulated guanine nucleotide exchange factor cAMP-GEFII, since xestospongin C-insensitive [ATP](m) increases were blocked by a dominant-negative form of cAMP-GEFII (G114E,G422D). Taken together, these results demonstrate that GLP-1 potentiates glucose-stimulated insulin release in part via the mobilization of intracellular Ca(2+), and the stimulation of mitochondrial ATP synthesis.

Original languageEnglish
Pages (from-to)287-99
Number of pages13
JournalBiochemical Journal
Issue numberPt 2
Publication statusPublished - 15 Jan 2003


  • Adenosine Triphosphate/biosynthesis
  • Animals
  • Calcium/metabolism
  • Calcium Signaling/physiology
  • Carbachol/pharmacology
  • Cell Line
  • Chelating Agents/metabolism
  • Cholinergic Agonists/pharmacology
  • Colforsin/pharmacology
  • Cyclic AMP/analogs & derivatives
  • Diazoxide/pharmacology
  • Egtazic Acid/pharmacology
  • Enzyme Inhibitors/pharmacology
  • Glucagon/pharmacology
  • Glucagon-Like Peptide 1
  • Glucose/metabolism
  • Homeostasis
  • Insulin/secretion
  • Islets of Langerhans/cytology
  • Macrocyclic Compounds
  • Mitochondria/metabolism
  • Oxazoles/pharmacology
  • Peptide Fragments/pharmacology
  • Protein Precursors/pharmacology
  • Ryanodine/pharmacology
  • Ryanodine Receptor Calcium Release Channel/metabolism
  • Thionucleotides/pharmacology


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