Synergistic effect of dimethyl sulfoxide on glucagon-like peptide 1 (GLP-1)-stimulated insulin secretion and gene transcription in INS-1 cells: characterization and implications.
Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is secreted from the enteroendocrine L-cells of the gut in response to nutrient ingestion. GLP-1 enhances both insulin secretion and insulin gene expression in a glucose-dependent manner via activation of its putative G-protein-coupled receptor on pancreatic beta-cells. In the presence of DMSO (0.5-2.5%), these functional responses were enhanced significantly (2- to 2.5-fold) in a concentration-dependent manner in the beta-cell line INS-1, although basal levels were not affected. Rat insulin 1 (rINS1) promoter activity appeared to be augmented in a cAMP-response element (CRE)-dependent manner as the effect of DMSO was abolished following a mutation in the CRE of the rINS1 promoter. Also, expression of a generic cAMP-driven reporter gene was enhanced by 1.5% DMSO in response to GLP-1 (3.5-fold), forskolin (2-fold), and 3-isobutyl-1-methylxanthine (2-fold). Analysis of intracellular signaling components revealed that DMSO did not elevate cAMP levels, protein kinase A activity, or phosphorylated levels of CRE-binding protein (CREB), CRE-modulator (CREM), and activating transcription factor-1 (ATF-1). These data suggest that GLP-1 induces insulin gene transcription in a CREB, CREM, and ATF-1-independent manner in beta-cells. The mechanism by which DMSO imparts this amplifying action is unclear but may involve redistribution of intracellular compartments or a direct molecular interaction with a downstream target of the GLP-1 receptor signaling pathway in the beta-cell. These effects of DMSO on incretin action may provide novel applications with respect to further characterizing GLP-1 receptor signaling, identifying incretin-like compounds in screening assays, and as a therapeutic treatment in type 2 diabetes.
Kemp
Daniel M
DM
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, 55 Fruit St., WEL320, Boston 02114, USA.
Habener
Joel F
JF
D051697:Activating Transcription Factor 1; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D012097:Repressor Proteins; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004121:Dimethyl Sulfoxide