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

Biochem J. 2003 Jan 15;369(Pt 2):287-99. doi: 10.1042/BJ20021288.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Cyclic AMP / pharmacology
  • Diazoxide / pharmacology
  • Egtazic Acid / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Glucose / metabolism
  • Homeostasis
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Macrocyclic Compounds
  • Mitochondria / metabolism*
  • Oxazoles / pharmacology
  • Peptide Fragments / pharmacology*
  • Protein Precursors / pharmacology*
  • Ryanodine / pharmacology
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Thionucleotides / pharmacology


  • Chelating Agents
  • Cholinergic Agonists
  • Enzyme Inhibitors
  • Insulin
  • Macrocyclic Compounds
  • Oxazoles
  • Peptide Fragments
  • Protein Precursors
  • Ryanodine Receptor Calcium Release Channel
  • Thionucleotides
  • xestospongin A
  • Ryanodine
  • Colforsin
  • adenosine-3',5'-cyclic phosphorothioate
  • Egtazic Acid
  • Glucagon-Like Peptide 1
  • Adenosine Triphosphate
  • Carbachol
  • Glucagon
  • Cyclic AMP
  • Glucose
  • Diazoxide
  • Calcium