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Purpose: GLP-1 receptor agonism has shown beneficial cardiovascular effects which could include the kidneys. In the human kidney, the high GLP-1 extraction and its natriuretic effect depend on the GLP-1 receptor and is accompanied by suppression of angiotensin II, independent of changes in renal plasma flow. Preclinical data showed that angiotensin II constricts the vasa recta and lowers medullary perfusion. The current randomized, controlled study was designed to test the hypothesis that GLP-1 increases renal medullary perfusion in healthy humans. Methods: Healthy male participants (n=10, 27 ± 4 years) ingested a fixed sodium intake for 4 days and were examined twice during a 1-hour infusion of either GLP-1 (1.5 pmol/kg/min) or placebo together with infusion of 0.9% NaCl (750 mL/h) . Interleaved measurements of renal artery flow, oxygenation (R2*) , and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging. Results: GLP-1 infusion increased medullary perfusion (32 ± 7%, p Conclusions: GLP-1 increases predominantly medullary but also cortical perfusion in healthy human kidneys and maintains oxygenation during NaCl-loading. In perspective, GLP-1 may exert protective effects against renal hypoperfusion and ischemia. Disclosure B. Haddock: n/a. B. L. Jensen: None. A. Asmar: None.

We have recently demonstrated that renal extraction of GLP-1 is ∼45% and that extracellular fluid volume expansion in healthy participants uncovered a natriuretic action of GLP-1 probably via a tubular mechanism secondary to suppression of angiotensin II (ANG II) and independent of changes in renal hemodynamics. It is not known whether the high extraction is due to receptor binding. The present study was designed to test the hypotheses that the renal extraction and natriuretic effect of GLP-1 are mediated via GLP-1 receptor. Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study1 and examined during a 3-h infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-h infusion of the GLP-1 receptor antagonist, exendin 9-39 (Ex 9-39) (900 pmol/kg/min), initiated 30 minutes before start of GLP-1 infusion. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and renal extraction of GLP-1 were measured via Fick’s principle after catheterization of a renal vein. Renal extraction of GLP-1 was ∼45% during infusion of GLP-1 alone and decreased significantly to ∼25% during co-infusion of GLP-1 and Ex 9-39. Urinary sodium and osmolar excretions remained at baseline levels during co-infusion of GLP-1 and Ex 9-39 compared to a mean 2-fold natriuretic effect during GLP-1 infusion alone. Arterial plasma ANG II levels were unaffected during the co-infusions, whereas ANG II decreased significantly during GLP-1 alone. Arterial plasma renin levels decreased similarly on the two study days, and arterial aldosterone levels remained unchanged on both days. RPF and GFR remained unchanged on both days. In conclusion, renal extraction of GLP-1 is partially and natriuresis is fully dependent on GLP-1 receptor activation, probably via GLP-1-mediated ANG II suppression. 1Asmar A et al. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519. Disclosure A. Asmar: None. P.K. Cramon: None. M. Asmar: None. L. Simonsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C.M. Sorensen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. P. Hovind: None. B.L. Jensen: None. J. Bülow: None.

The aim of this study was to investigate the effect of glucose-dependent insulinotropic polypeptide (GIP) per se and in combination with hyperglycemia and hyperinsulinemia on splanchnic blood flow and further to investigate the role of GIP in splanchnic lipid metabolism in humans. Eight healthy lean males were examined in a randomized order on four different occasions. Splanchnic blood flow and lipid metabolism were measured by Fick’s Principle using indocyanine green as indicator during GIP (1.5 pmol/kg/min) or saline infused intravenously alone or in combination with a hyperglycemia and hyperinsulinemia (Hygluc-Hyinsu) clamp. During all four experiments, splanchnic blood flow increased similarly. Splanchnic triglyceride output decreased similarly during the Hygluc-Hyinsu clamp with and without GIP (8.6 ± 1.8 and 10.3 ± 2.6 µmol/min, respectively, P=NS). Likewise, during the clamp alone and with GIP, free fatty acids uptake decreased similarly (3.5 ± 3.8 and 6.7 ± 4.6 µmol/min, respectively, P=NS). GIP does not seem to play a key role in the acute regulation of splanchnic blood flow or lipid metabolism under these particular conditions in vivo. Disclosure A. Asmar: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M. Asmar: None.

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 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.