Abstract
Glucagon‐like peptide‐1 (GLP‐1, GLP‐17–36amide) 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‐19–36 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‐19–36 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‐19–36amide [P < 0.011]), and tended to increase cardiac output and decrease stroke volume compared to GLP‐19–36 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.
Highlights
The hormone glucagon-like peptide-1 (GLP-1, GLP-17–36amide) is best known for its actions on the endocrine pancreas, where it potentiates glucose-induced insulin secretion via activation of specific GLP-1 receptors and inhibits glucagon secretion (Holst 2007)
GLP-1 has other activities, which are important both physiologically and therapeutically. It inhibits appetite, and thereby food intake (Flint et al 1998), which is expedient considering the association between obesity and type 2 diabetes, and a GLP-1 receptor agonist has recently been approved for the therapy of obesity (Pi-Sunyer et al 2015)
Cardiovascular actions of GLP-1 and the GLP-1 renal artery (RA) have attracted considerable attention (Sivertsen et al 2012) because the agonists: (1) may improve myocardial performance; (2) may reduce myocardial damage after ischemia; (3) may improve endothelial dysfunction in diabetes; and (4) clearly improve cardiovascular risk factors, including improved blood pressure, lowered body weight, improved blood lipids, and beneficial changes in high-sensitivity C-reactive protein, plasminogen activator inhibitor-1 (PAI-1), andbrain natriuretic peptide ((pro)BNP) (Tate et al 2015). The mechanisms behind these actions are unclear; some may be related to the general metabolic improvement obtained during GLP-1 therapy; others may be related to interaction with GLP-1 receptors in the involved organs systems (Sivertsen et al 2012)
Summary
The hormone glucagon-like peptide-1 (GLP-1, GLP-17–36amide) is best known for its actions on the endocrine pancreas, where it potentiates glucose-induced insulin secretion via activation of specific GLP-1 receptors and inhibits glucagon secretion (Holst 2007). Cardiovascular actions of GLP-1 and the GLP-1 RA have attracted considerable attention (Sivertsen et al 2012) because the agonists: (1) may improve myocardial performance; (2) may reduce myocardial damage after ischemia; (3) may improve endothelial dysfunction in diabetes; and (4) clearly improve cardiovascular risk factors, including improved blood pressure, lowered body weight, improved blood lipids, and beneficial changes in high-sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1), and (pro)brain natriuretic peptide ((pro)BNP) (Tate et al 2015) The mechanisms behind these actions are unclear; some may be related to the general metabolic improvement obtained during GLP-1 therapy (weight loss, improved glycemic control); others may be related to interaction with GLP-1 receptors in the involved organs systems (Sivertsen et al 2012). Perhaps associated with its growth effects and metabolic actions on the gastrointestinal tract (Bremholm et al 2011), GLP-2 markedly stimulates intestinal blood flow in both experimental animals and humans (Bremholm et al 2009)
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