Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline.
Much recent attention has focused on the GLP-1 receptor as a potential target for antidiabetic drugs. Enzyme resistant GLP-1 mimetics such as exenatide are now employed for the treatment of type 2 diabetes, but must be administered by injection. The present study has examined and compared the in vitro and in vivo metabolic actions of a small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB), with native GLP-1, exenatide and liraglutide. DMB significantly stimulated in vitro insulin secretion from BRIN-BD11 cells but with decreased molar potency compared to native GLP-1 or related mimetics. Administration of DMB in combination with glucose to mice significantly (P<0.05) decreased the overall glucose excursion compared to controls. Exenatide and liraglutide evoked similar (P<0.001) reductions of the overall glycaemic excursion, but were significantly (P<0.001 and P<0.05; respectively) more effective than DMB. These observations were associated with prominently (P<0.05) enhanced glucose-mediated insulin release by exenatide and liraglutide, but not by DMB. Combined injection of DMB with either liraglutide or exenatide did not substantially improve glucose-lowering or insulin-releasing responses. However, administration of DMB in combination with exendin(9-39) did not impair its glucoregulatory actions. These results provide evidence to support the development and potential use of low molecular weight GLP-1 receptor agonists for the treatment of type 2 diabetes.
Irwin
Nigel
N
SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences Research Institute, University of Ulster, Coleraine, United Kingdom. n.irwin@ulster.ac.uk
Flatt
Peter R
PR
Patterson
Steven
S
Green
Brian D
BD
D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D000069450:Liraglutide; D051379:Mice; D008970:Molecular Weight; D010455:Peptides / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology
C517397:3-(tert-butylamino)-6,7-dichloro-2-(methylsulfonyl)quinoxaline; D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D011810:Quinoxalines; D018027:Receptors, Glucagon; D013450:Sulfones; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide