Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride.
Sulfonylureas (SU) with glucagon-like peptide-1 (GLP-1)-based therapy are an emerging therapeutic combination for type 2 diabetes. Prior human studies have hinted at endothelial effects of GLP-1 and SU. To study the endothelial effects of GLP-1 per se and to evaluate the modulatory effects, if any, of SU agents on GLP-1-induced changes in endothelial function, healthy, nondiabetic, normotensive, nonsmokers, age 18-50 yr with no family history of diabetes, were studied. Subjects were randomized to either placebo (n = 10), 10 mg of glyburide (n = 11), or 4 mg of glimepiride (n = 8) orally. Euglycemic somatostatin pancreatic clamp with replacement basal insulin, glucagon, and growth hormone was performed for 240 min. Forearm blood flow (FBF) was measured by venous occlusion plethysmography with graded brachial artery infusions of acetylcholine (Ach) and nitroprusside (NTP) before and after intravenous infusion of GLP-1. GLP-1 (preinfusion 3.4 +/- 0.2, postinfusion 25.5 +/- 2.8 pM) enhanced (P < 0.03) Ach-mediated vasodilatation (Delta+6.5 +/- 1.1 vs. Delta+9.1 +/- 1.2 ml.100 ml(-1).min(-1), change from baseline FBF) in those on placebo. However, in contrast, glyburide abolished GLP-1-induced Ach-mediated vasodilatation (Delta+11.7 +/- 2.0 vs. Delta+11.7 +/- 2.5 ml.100 ml(-1).min(-1)). On the other hand, glimepiride did not alter the ability of GLP-1 to enhance Ach-mediated vasodilatation (Delta+7.9 +/- 0.5 vs. Delta+10.2 +/- 1.3 ml.100 ml(-1).min(-1), P < 0.04). Neither GLP-1 nor SU altered NTP-induced vasodilatation. These data demonstrate that GLP-1 per se has direct beneficial effects on endothelium-dependent vasodilatation in humans that are differentially modulated by SU.
Basu
Ananda
A
Division of Endocrinology & Metabolism, 5-193 Joseph, Saint Mary's Hospital, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. basu.ananda@mayo.edu
Charkoudian
Nisha
N
Schrage
William
W
Rizza
Robert A
RA
Basu
Rita
R
Joyner
Michael J
MJ
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005542:Forearm / Q000098:blood supply; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054795:Incretins / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D013453:Sulfonylurea Compounds; D014665:Vasodilator Agents; D009599:Nitroprusside; C057619:glimepiride; D052216:Glucagon-Like Peptide 1; D002097:C-Reactive Protein; D000109:Acetylcholine; D005905:Glyburide