Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers

Abstract

Glucagon-like peptide-1 (GLP-1, GLP-1_7-36amide) and its sister peptide glucagon-like peptide 2 (GLP-2) influence numerous intestinal functions and GLP-2 greatly increases intestinal blood flow. We hypothesized that GLP-1 also stimulates intestinal blood flow and that this would impact on the overall digestive and cardiovascular effects of the hormone. To investigate the influence of GLP-1 receptor agonism on mesenteric and renal blood flow and cardiovascular parameters, we carried out a double-blinded randomized clinical trial. A total of eight healthy volunteers received high physiological subcutaneous injections of GLP-1, GLP-1_{9-36 amide} (bioactive metabolite), exenatide (stable GLP-1 agonist), or saline on four separate days. Blood flow in mesenteric, celiac, and renal arteries was measured by Doppler ultrasound. Blood pressure, heart rate, cardiac output, and stroke volume were measured continuously using an integrated system. Plasma was analyzed for glucose, GLP-1 (intact and total), exenatide and Pancreatic polypeptide (PP), and serum for insulin and C-peptide. Neither GLP-1, GLP-1_{9-36 amide}, exenatide nor saline elicited any changes in blood flow parameters in the mesenteric or renal arteries. GLP-1 significantly increased heart rate (two-way ANOVA, injection [P = 0.0162], time [P = 0.0038], and injection × time [P = 0.082]; Tukey post hoc GLP-1 vs. saline and GLP-1_9-36amide [P < 0.011]), and tended to increase cardiac output and decrease stroke volume compared to GLP-1_{9-36 amide} and saline. Blood pressures were not affected. As expected, glucose levels fell and insulin secretion increased after infusion of both GLP-1 and exenatide.

Keywords: Exenatide; glucagon like‐peptide‐1; mesenteric blood flow.

Figure 1

Exendin‐4, GLP‐1, and GLP‐1_9–36amide. (A) Exendin‐4 levels (squares) on the exenatide day. (B) Total (filled triangles) and intact (open triangles) GLP‐1 levels on the GLP‐1 day. (C) Total GLP‐1 levels (inverted triangles) on the GLP‐1_9–36amide day. Data are means (SEM).

Figure 2

Glucose, insulin, C‐peptide, and pancreatic polypeptide (PP). Symbol legends for the four experimental days; exenatide (squares), GLP‐1 (triangles), GLP‐1_9–36amide (inverted triangles), and saline (circles). (A) Plasma glucose: Days were compared by a two‐way ANOVA (infusion (P = 0.0001), time (P = 0.0001), and infusion × time (P = 0.0001)). Post hoc test (Tukey) yielded significant differences; exenatide versus saline/GLP‐1 9–36NH ₂ ($), exenatide versus GLP‐1_7–36amide (*), GLP‐1 versus saline/GLP‐1_9–36amide (#). (B) Plasma PP: Days were compared by a two‐way ANOVA (infusion (P < 0.0001), time (P = 0.012), infusion × time (P = 0.56)). Post hoc test (Tukey) yielded significant differences; exenatide versus GLP‐1 (&), GLP‐1 versus saline (€). (C) Time courses for serum insulin. (D) Incremental AUCs (iAUCs) for insulin: iAUCs were compared by a one‐way ANOVA (P = 0.006), post hoc test (Tukey) yielded significant differences denoted by asterisk (*). (E) Time courses for serum C‐peptide. (F) Incremental AUCs for C‐peptide: iAUCs were compared by a one‐way ANOVA (P = 0.0001), post hoc test (Tukey) yielded significant differences denoted by asterix (*). Data are means (SEM). Two‐sided P < 0.05 were considered significant.

Figure 3

Blood pressures. Symbol legends for the four experimental days; exenatide (squares), GLP‐1 (triangles), GLP‐1_9–36amide (inverted triangles), Saline (circles). (A) Systolic blood pressure (Systolic BP): Days were compared by a two‐way ANOVA (infusion (P = 0.053), time (P < 0.0001), and infusion × time (P = 0.93)). (B) Diastolic blood pressure (Diastolic BP): Days were compared by a two‐way ANOVA (infusion (P = 0.075), time (P < 0.0001), and infusion × time (P = 0.99)). (C) Mean arterial blood pressure (MAP): Days were compared by a two‐way ANOVA (infusion (P = 0.057), time (P < 0.0001), and infusion × time (P = 0.92)). Data are means (SEM). Two‐sided P < 0.05 were considered significant.

Figure 4

Cardiac parameters. Symbol legends for the four experimental days; exenatide (squares), GLP‐1 (triangles), GLP‐1_9–36amide (inverted triangles), Saline (circles). (A) Heart rate: Days were compared by a two‐way ANOVA (injection (P = 0.0162), time (P = 0.0038), and injection × time (P = 0.082)). Post hoc testing (Tukey) yielded a significant difference, GLP‐1 versus saline & GLP‐1_9–36amide (*). (B) Stroke volume: Days were compared by a two‐way ANOVA (injection (P = 0.51), time (P = 0.0050), injection × time (P > 0.99)). (C) Cardiac output: Days were compared by a two‐way ANOVA (injection (P = 0.92), time (P = 0.66), and injection × time (P > 0.99)). Data are means (SEM). Two‐sided P < 0.05 were considered significant.

Figure 5

Resistive indices. Symbol legends for the four experimental days; exenatide (squares), GLP‐1 (triangles), GLP‐1_9–36amide (inverted triangles), Saline (circles). (A) resistive index (RI) (superior mesenteric artery, SMA): Days were compared by a two‐way ANOVA (infusion (P = 0.45), time (P = 0.85), and infusion × time (P > 0.99)). (B) RI (celiac trunk, TC): Days were compared by a two‐way ANOVA (infusion (P = 0.14), time (P = 0.95), and infusion × time (P > 0.99)). (C) RI (Renal artery, RA): Days were compared by a two‐way ANOVA (infusion (P = 0.0044), time (P = 0.17), and infusion × time (P > 0.99)). Post hoc testing (Tukey) did not yield any time points where curves differed significantly. Data are means (SEM). Two‐sided P < 0.05 were considered significant.

Figure 6

TAMV. Symbol legends for the four experimental days; exenatide (squares), GLP‐1 (triangles), GLP‐1_9–36amide (inverted triangles), saline (circles). (A) TAMV (superior mesenteric artery, SMA): Days were compared by a two‐way ANOVA (infusion (P = 0.07), time (P = 0.36), infusion × time (P = 0.97)). (B) TAMV (celiac trunk, TC): Days were compared by a two‐way ANOVA (infusion (P < 0.0001), time (P = 0.98), and infusion × time (P > 0.99)). (C) TAMV (Renal artery, RA): Days were compared by a two‐way ANOVA (infusion (P = 0.0003), time (P = 0.99), and infusion × time (P = 0.35)). Post hoc testing (Tukey) identified a significant difference between exenatide and GLP‐1 and GLP‐1_9–36amide (*). Data are means (SEM). Two‐sided P < 0.05 were considered significant. TAMV, Time averaged mean velocity.