Document Detail

Low, but physiological, concentration of GLP-1 stimulates insulin secretion independent of the cAMP-dependent protein kinase pathway.
MedLine Citation:
PMID:  18987435     Owner:  NLM     Status:  MEDLINE    
Glucagon-like peptide-1 (GLP-1) induces pancreatic insulin secretion via the cAMP-dependent protein kinase (PKA) pathway. However, the GLP-1 concentration used in the previous in vitro experiments was far from the in vivo concentrations. Alteration of plasma GLP-1 concentration at pM order lowers blood glucose concentration. In this study, we examined the GLP-1 action mechanism at a physiological concentration on insulin secretion. A high concentration of GLP-1 (10 nM) stimulated intracellular cAMP accumulation and insulin secretion was significantly inhibited by KT5720, a selective inhibitor of PKA. Low GLP-1 concentrations (1 pM) also increased insulin secretion without significant accumulation of intracellular cAMP, and KT5720 did not affect insulin secretion. Insulin secretion stimulated by 1 pM GLP-1 was reduced by inhibitors of calcium action, including verapamil, dantrolene, and BAPTA. Thus, we concluded that relatively low GLP-1 concentrations-comparable to in vivo blood concentrations-promoted insulin secretion independent of the cAMP-PKA pathway. This effect was dependent on intracellular Ca2+ concentration. The results of the present study may further the understanding of the dose-dependent response of GLP-1 signal transducing pathways and the complicated mechanism of insulin secretion. Studies of GLP-1 at physiologic concentrations may lead to new developments in studies of pancreatic beta-cell function.
Makoto Shigeto; Masashi Katsura; Masafumi Matsuda; Seitaro Ohkuma; Kohei Kaku
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-06
Journal Detail:
Title:  Journal of pharmacological sciences     Volume:  108     ISSN:  1347-8613     ISO Abbreviation:  J. Pharmacol. Sci.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-21     Completed Date:  2009-01-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101167001     Medline TA:  J Pharmacol Sci     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  274-9     Citation Subset:  IM    
Division of Diabetes and Endocrinology, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan.
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MeSH Terms
Calcium / metabolism
Calcium Channel Blockers / pharmacology
Cell Line
Chelating Agents / pharmacology
Cyclic AMP / metabolism
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors,  metabolism
Glucagon-Like Peptide 1 / metabolism*
Insulin / metabolism*
Insulin-Secreting Cells / drug effects,  enzymology,  metabolism*
Protein Kinase Inhibitors / pharmacology
Signal Transduction* / drug effects
Time Factors
Reg. No./Substance:
0/Calcium Channel Blockers; 0/Chelating Agents; 0/Protein Kinase Inhibitors; 11061-68-0/Insulin; 60-92-4/Cyclic AMP; 7440-70-2/Calcium; 89750-14-1/Glucagon-Like Peptide 1; EC AMP-Dependent Protein Kinases

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