Abstract
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 language | English |
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Pages (from-to) | 287-99 |
Number of pages | 13 |
Journal | Biochemical Journal |
Volume | 369 |
Issue number | Pt 2 |
DOIs | |
Publication status | Published - 15 Jan 2003 |
Keywords
- 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