Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incretins such as glucagon-like peptide-1 and gastric inhibitory polypeptide/glucose-dependent insulinotropic peptide are known to potentiate insulin secretion mainly through a cAMP/protein kinase A (PKA) signaling pathway in pancreatic beta-cells, but the mechanism is not clear. We recently found that the cAMP-binding protein cAMP-GEFII (or Epac 2), interacting with Rim2, a target of the small G protein Rab3, mediates cAMP-dependent, PKA-independent exocytosis in a reconstituted system. In the present study, we investigated the role of the cAMP-GEFII--Rim2 pathway in incretin-potentiated insulin secretion in native pancreatic beta-cells. Treatment of pancreatic islets with antisense oligodeoxynucleotides (ODNs) against cAMP-GEFII alone or with the PKA inhibitor H-89 alone inhibited incretin-potentiated insulin secretion approximately 50%, while a combination of antisense ODNs and H-89 inhibited the secretion approximately 80-90%. The effect of cAMP-GEFII on insulin secretion is mediated by Rim2 and depends on intracellular calcium as well as on cAMP. Treatment of the islets with antisense ODNs attenuated both the first and second phases of insulin secretion potentiated by the cAMP analog 8-bromo-cAMP. These results indicate that the PKA-independent mechanism involving the cAMP-GEFII--Rim2 pathway is critical in the potentiation of insulin secretion by incretins.
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PMID:Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion. 1159 34

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.
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PMID:Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells. 1241 Jun 38

Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone currently under investigation for use as a novel therapeutic agent in the treatment of type 2 diabetes. One of several important effects of GLP-1 is on nutrient-induced pancreatic hormone release and is mediated by binding to a specific G-protein coupled receptor resulting in the activation of adenylate cyclase and an increase in cAMP generation. In the beta-cell, cAMP binds and modulates activities of both protein kinase A and cAMP-regulated guanine nucleotide exchange factor II, thereby enhancing glucose-dependent insulin secretion. The stimulatory action of GLP-1 on insulin secretion involves interaction with a plethora of signal transduction processes including ion channel activity, intracellular Ca(2+) handling and exocytosis of the insulin-containing granules. In this review we focus principally on recent advances in our understanding on the cellular mechanisms proposed to underlie GLP-1's insulinotropic effect and attempt to incorporate this knowledge into a working model for the control of insulin secretion. Lastly, this review discusses the applicability of GLP-1 as a therapeutic agent for the treatment of type 2 diabetes.
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PMID:Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential. 1556 68

Synaptosomal protein of 25 kDa (SNAP-25) is important for Ca(2+)-dependent fusion of large dense core vesicles (LDCVs) in insulin-secreting cells. Exocytosis is further enhanced by cAMP-increasing agents such as glucagon-like peptide-1 (GLP-1), and this augmentation includes interaction with both PKA and cAMP-GEFII. To investigate the coupling between SNAP-25- and cAMP-dependent stimulation of insulin exocytosis, we have used capacitance measurements, protein-binding assays, and Western blot analysis. In insulin-secreting INS-1 cells overexpressing wild-type SNAP-25 (SNAP-25(WT)), rapid exocytosis was stimulated more than threefold by cAMP, similar to the situation in nontransfected cells. However, cAMP failed to potentiate rapid exocytosis in INS-1 cells overexpressing a truncated form of SNAP-25 (SNAP-25(1-197)) or Botulinum neurotoxin A (BoNT/A). Close dissection of the exocytotic response revealed that the inability of cAMP to stimulate exocytosis in the presence of a truncated SNAP-25 was confined to the release of primed LDCVs within the readily releasable pool, especially from the immediately releasable pool, whereas cAMP enhanced mobilization of granules from the reserve pool in both SNAP-25(1-197) (P < 0.01) and SNAP-25(WT) (P < 0.05) cells. This was supported by hormone release measurements. Augmentation of the immediately releasable pool by cAMP has been suggested to act through the cAMP-GEFII-dependent, PKA-independent pathway. Indeed, we were able to verify an interaction between SNAP-25 with both cAMP-GEFII and RIM2, two proteins involved in the PKA-independent pathway. Thus we hypothesize that SNAP-25 is a necessary partner in the complex mediating cAMP-enhanced rapid exocytosis in insulin-secreting cells.
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PMID:Truncation of SNAP-25 reduces the stimulatory action of cAMP on rapid exocytosis in insulin-secreting cells. 1950 85