Glucagon-Like Peptide 1 Induces Natriuresis in Healthy Subjects and in Insulin-Resistant Obese Men

Abstract

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is involved in satiety control and glucose homeostasis. Animal studies suggest a physiological role for GLP-1 in water and salt homeostasis. This study's aim was to define the effects of GLP-1 on water and sodium excretion in both healthy and obese men. Fifteen healthy subjects and 16 obese men (mean body mass index, 36 kg/m2) were examined in a double-blind, placebo-controlled, crossover study to demonstrate the effects of a 3-h infusion of GLP-1 on urinary sodium excretion, urinary output, and the glomerular filtration rate after an i.v. 9.9-g salt load. Infusion of GLP-1 evoked a dose-dependent increase in urinary sodium excretion in healthy subjects (from 74 +/- 8 to 143 +/- 18 mmol/180 min, P = 0.0013). In obese men, there was a significant increase in urinary sodium excretion (from 59 to 96 mmol/180 min, P = 0.015), a decrease in urinary H+ secretion (from 1.1 to 0.3 pmol/180 min, P = 0.013), and a 6% decrease in the glomerular filtration rate (from 151 +/- 8 to 142 +/- 8 ml/min, P = 0.022). Intravenous infusions of GLP-1 enhance sodium excretion, reduce H+ secretion, and reduce glomerular hyperfiltration in obese men. These findings suggest an action at the proximal renal tubule and a potential renoprotective effect.

Effects of exogenous glucagon-like peptide-1 on blood pressure, heart rate, gastric emptying, mesenteric blood flow and glycaemic responses to oral glucose in older individuals with normal glucose tolerance or type 2 diabetes

“…It was suggested that the increase in cardiac output may be a compensatory response to vasodilatation elsewhere. The effectiveness of GLP-1R agonists in reducing BP in clinical trials of type 2 diabetes and obesity is most evident in individuals with higher baseline BP [1,5,6] and may be attributable to reductions in tubular sodium reabsorption [32] or central sympathetic output [33] as well as peripheral vasodilatory effects [34]. In contrast to findings in rodents [35], GLP-1 and GLP-1R agonists do not appear to promote the secretion of atrial natriuretic peptide in humans [30,31].…”

Liraglutide Promotes Natriuresis but Does Not Increase Circulating Levels of Atrial Natriuretic Peptide in Hypertensive Subjects With Type 2 Diabetes

“…Interestingly, natriuresis is induced by both SGLT2 inhibitors and GLP-1R agonists through different mechanisms; notably, the pathways and mechanisms linking GLP-1R signaling to renal sodium excretion are controversial and less well understood (7). Although short-term infusion (3 h) of GLP-1 7-36amide increases natriuresis in healthy volunteers (8,9) and in insulin-resistant obese males (8), whether these actions are sustained with chronic GLP-1R activation is unclear. Furthermore, the majority of studies examining how GLP-1R agonists increase sodium excretion are often 3-72 h in duration (7)(8)(9)(10)(11).…”

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

“…Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6,30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in urinary Na ϩ excretion without changing GFR (20,21). Studies in intact rat and porcine renal proximal tubules indicated that GLP-1 decreases Na ϩ /H ϩ exchanger (NHE3)-mediated bicarbonate reabsorption (6,34).…”

“…Studies in humans demonstrate that obese men responded to GLP-1 infusion with a natriuresis, but, in contrast to healthy subjects, this natriuresis was associated with a decrease in GFR (21), indicating that factors related to body mass may affect the renal response to EX4 and/or DPP-4 inhibition. Therefore, we also compared the effect of EX4 and ALG on renal function in obese type 2 diabetic db/db mice.…”