Extracellular Volume Expansion Uncovers a Natriuretic Action of Glucagon-Like Peptide-1

Abstract

We have previously demonstrated that the gut hormone glucagon-like peptide-1 (GLP-1) does not affect renal hemodynamics or function at baseline conditions in healthy individuals and in patients with type 2 diabetes mellitus. However, it is possible that GLP-1 promotes renal NaCl excretion under conditions with addition of salt and water to the extracellular fluid (mimicking a mixed meal/daily NaCl load). The present study was designed to investigate whether GLP-1 induces natriuresis in healthy, volume overloaded individuals. Under fixed sodium intake, 8 healthy men were examined twice in random order during a 3-hour infusion of either GLP-1(1.5 pmol kg-1 min-1) or vehicle together with an intravenous infusion of 0.9% NaCl (750 ml/hour) given throughout both experiments. Timed urine collections were conducted throughout the experiments at voluntary voiding, and subjects remained supine during the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and uptake/release of hormones and ions were measured using Fick’s Principle after catheterization of a renal vein and an artery. During GLP-1 infusion, urinary sodium excretion increased compared to vehicle infusion (193 ± 40 mmol/180 min vs. 89 00B110 mmol/180 min, p<0.05), whereas GLP-1 had no significant effect on urine flow rate (1666 ± 284 ml/180 min vs. 1189 ± 132 ml/180 min, p=0.184). Plasma renin levels decreased similarly on both days, whereas angiotensin II levels decreased significantly only during GLP-1 infusion. During GLP-1 infusion, GLP-1 was extracted by the kidneys by about 50%. RPF and GFR remained unchanged on both days. Plasma proANP, ANP, and BNP levels remained unchanged on both days. This study shows that physiologically relevant changes in GLP-1 induce significant natriuresis independent of measurable changes in RPF and GFR in volume overloaded subjects. The natriuresis is likely brought about via a tubular mechanism secondary to suppression angiotensin II. Disclosure A. Asmar: None. P.K. Cramon: Employee; Spouse/Partner; Novo Nordisk A/S. L. Simonsen: None. M. Asmar: None. C.M. Sorensen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Eli Lilly and Company. Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi-Aventis, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. C. Moro: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. B.L. Jensen: None. J. Bülow: None.