AIM:A hyperdynamic circulation in type 2 diabetes (T2D) has been proposed. We investigated this hypothesis in patients admitted to a tertiary care hospital in Denmark. METHODS:Cardiac index (CI) and systemic vascular resistance (SVR) were estimated noninvasively in 933 patients admitted to the medical division of the emergency department (ED) of Bispebjerg University Hospital, Copenhagen, Denmark, between May 2019 and January 2023. The population included 154 people with T2D. RESULTS:Among people with T2D, CI was 17% higher (p < 0.0001) and SVR was 24% lower (p < 0.0001) compared to people without T2D. In linear regression models adjusted for age, sex, smoking status, body mass index, comorbidities, and medication for hypertension, T2D was independently associated with increased CI and decreased SVR (p < 0.001). This association remained significant after propensity matching on age, sex, BMI, hypertension, ischemic heart disease, and congestive heart failure. People with T2D treated with insulin (n = 43) exhibited higher CI (p = 0.04) and lower SVR (p = 0.003) than non-insulin-treated people with T2D (n = 111). CONCLUSIONS:Our findings support the notion that hyperdynamic circulation is an intrinsic feature of T2D, but further studies should explore its relevance for prognosis, risk stratification, and targeted interventions.

Abstract Glucagon‐like peptide‐1 (GLP‐1) receptor agonists elicit cardiovascular and renal protection. In humans, GLP‐1 reduces plasma angiotensin II (ANGII) and increases renal perfusion, leading to increased natriuresis. The mechanisms underlying suppression of ANGII remain unclear but may involve ACE2 activation and/or a decrease in angiotensinogen. To address this hypothesis, we performed post‐hoc analyses on stored arterial plasma samples from a published study. The study used a randomized, placebo‐controlled cross‐over design in which eight healthy male adults ingested a sodium‐standardized diet for 4 days to reach steady state. Participants were examined during a 3‐h infusion of GLP‐1 (1.5 pmol/kg/min) or vehicle concurrent with an intravenous infusion of 0.9% NaCl (750 mL/h) to expand the extracellular volume. As previously published, GLP‐1 infusion significantly increased urinary sodium excretion, and plasma ANGII concentrations decreased significantly only during GLP‐1 infusion. The present analyses demonstrated that plasma angiotensinogen and ACE concentrations decreased similarly (parallel to renin concentrations) during GLP‐1 and vehicle. Plasma ACE2 and Ang‐(1–7) peptide concentrations remained unchanged during infusions of saline with and without GLP‐1. In conclusion, the acute ANGII‐lowering effect of GLP‐1 does not depend on changes in circulating concentrations of angiotensinogen, ACE, ACE2, or Ang‐(1–7). Changes in enzyme activities independent of concentrations cannot be excluded.

Context Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with potent vasoactive and metabolic effects in adipose tissue, but its effects on splanchnic blood flow (SBF) in humans remain unclear. Investigating potential regional differences is important for understanding the vascular actions of GIP in humans.Objective The aim of this study was to examine the effects of GIP on SBF, both independently and in combination with hyperglycemia and hyperinsulinemia.Methods In a randomized, controlled crossover study, 8 healthy, lean male participants underwent 4 separate experimental conditions. The interventions included intravenous infusions of either GIP at a rate of 1.5 pmol-1 kg-1 minute-1 or saline, administered alone or in combination with a hyperglycemic and hyperinsulinemic clamp, respectively. Splanchnic blood flow was measured by Fick's Principle after catheterization of a hepatic vein, using indocyanine green as indicator.Results Splanchnic blood flow remained comparable across all experimental conditions, including GIP and saline infusions, both with and without the hyperglycemic and hyperinsulinemic clamp (P = .42).Conclusion Under the applied conditions, GIP does not appear to play a substantial role in the acute regulation of net SBF, either alone or in combination with induced hyperglycemia and hyperinsulinemia.

Splanchnic vessel blood flow assessment can describe physiology or pathophysiology and also has clinical relevance for patients with altered abdominal blood flow, vascular neuropathy, or atherosclerotic conditions. Reliable and practicable methods for this assessment are needed. We assessed the reproducibility of non-invasive phase-contrast MRI (PC-MRI) for measuring splanchnic blood flow and its feasibility for detecting postprandial blood flow changes. We included measurements from two groups of healthy individuals (Group A: n = 10; C: n = 10) and a group of patients with type 2 diabetes (B: n = 10) from randomized, single-blind, placebo-controlled studies, and assessed blood flow with 2D PC sequences (3 Tesla Siemens Biograph MRI and 3 Tesla Philips Achieva). Blood flow was measured in the arteria mesenterica superior, truncus coeliacus, arteria hepatica (Group A only), and vena portae hepatis over multiple days, with repeated scans each day to assess variability and reproducibility. To confirm detection of postprandial changes, nine repeated measurements were acquired during ingestion of 75-g oral glucose tolerance test compared to water ingestion. Reproducibility was assessed by coefficient of variation (CoV) and limits of agreement with the mean (LoAM) using an extended Bland-Altman analysis. Blood flow in arteria mesenterica superior, truncus coeliacus, and vena portae hepatis demonstrated low intrasubject within session CoV (7%-22%) and intrasubject between session CoV (16%-26%). Blood flow in arteria hepatica had poorer CoV for both within sessions (12%) and between sessions (32%). Glucose ingestion induced a blood flow peak increase of 88% ± 52% in arteria mesenterica superior and 68% ± 36% in vena portae hepatis, both robustly detected, while no change was observed in the arteria hepatica or truncus coeliacus. In conclusion, PC-MRI is a reproducible and feasible technique for measuring blood flow in arteria mesenterica superior, truncus coeliacus, and vena portae hepatis with the ability to detect postprandial changes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05391581, NCT06426823, NCT06774807.

In healthy lean humans, endogenous glucose-dependent insulinotropic polypeptide (GIP) contributes significantly to the postprandial increase in arteria mesenterica superior blood flow. The vascular biology related to activation of the GIP receptor is markedly impaired in individuals with type 2 diabetes and is sometimes absent. In this population, we investigated the role of endogenous GIP on postprandial splanchnic blood flow by using the GIP receptor antagonist, GIP(3-30)NH2. The primary outcome of this study was the changes in blood flow in arteria mesenterica superior during oral glucose with or without GIP receptor antagonist infusion. Ten participants with type 2 diabetes (age 20–80 years, BMI 20–35 kg/m2, and HbA1c >48 mmol/mol and <75 mmol/mol) were investigated in a randomised, placebo-controlled, crossover study. On four separate occasions, participants received the following treatment: oral glucose + i.v. GIP(3-30)NH2; oral glucose + i.v. saline (154 mmol/l NaCl); oral water + i.v. GIP(3-30)NH2; oral water + i.v. saline. Participants were randomly assigned to intervention groups using (random.org). Participants were unaware of allocation, while investigators were aware. No additional allocation concealment procedures were used. During all four interventions, splanchnic blood flow was measured using phase-contrast MRI in the arteria mesenterica superior, truncus coeliacus and vena portae during oral glucose (75 g) or water ingestion. The study was conducted at Rigshospitalet, Copenhagen. Liver volume and oxygenation, as well as gallbladder volume, were assessed. Blood samples were collected and analysed for insulin, C-peptide, GIP, glucagon and glucose. Oral glucose alone increased mean blood flow in arteria mesenterica superior by 57

Gastrointestinal hormones are essential for nutrient handling and regulation of glucose metabolism and may affect postprandial blood redistribution. In a randomized cross-over design in 10 healthy men, the involvement of glucose-dependent insulinotropic polypeptide (GIP) in splanchnic blood flow regulation was investigated using an infusion of GIP receptor antagonist (GIPR-An) GIP(3-30)NH2 during ingestion of oral glucose (75 g). In five separate sessions, we investigated GIP(1-42), GIPR-An with and without oral glucose, oral glucose alone, and a control saline infusion. Blood flow was assessed by phase contrast MRI, hepatic oxygen consumption by T2*, and plasma glucose, insulin, C-peptide, glucagon, GIP, GIPR-An, glucagon-like peptide 2, and bone metabolism markers by frequent blood sampling during all sessions. We found GIP(1-42) to stimulate blood flow in the superior mesenteric artery by ∼10% in the fasting state. Oral glucose alone increased mean blood flow in the superior mesenteric artery by ∼70% and portal vein by ∼40% of baseline. During oral glucose ingestion with concurrent infusion of GIPR-An, blood flow in the superior mesenteric artery was ∼22% lower. The hormone infusions did not affect blood flow in the hepatic artery and the celiac artery. Infusion of GIPR-An during oral glucose ingestion resulted in lower insulin secretion and higher levels of carboxy-terminal collagen crosslinks (bone resorption biomarker) compared with saline infusion, whereas glucagon levels were unaffected by both the injection of GIP and the GIPR-An infusions. We conclude that endogenous GIP increases splanchnic blood flow and contributes to postprandial intestinal hyperemia in healthy men. ARTICLE HIGHLIGHTS:Administration of the gut hormone glucose-dependent insulinotropic polypeptide (GIP) increases splanchnic blood flow. We investigated the role of endogenous GIP in splanchnic blood flow regulation using a receptor antagonist in humans. Oral glucose ingestion increased blood flow in the superior mesenteric artery by ∼70%, and the increase was significantly lower during concurrent infusion of the GIP receptor antagonist. Thus, endogenous GIP contributed ∼22% of the postprandial increase in superior mesenteric artery blood flow. We have identified a novel physiological aspect of vascular biology related to the GIP receptor in humans. Treatments targeting the GIP receptors are likely to affect splanchnic blood flow.

Obesity is a major contributor to cardiovascular disease. Although altered central hemodynamics have been reported in obesity, studies are few, small, and limited to specific populations, leaving these changes underrecognized. This study investigates the association between body mass index (BMI) and central hemodynamics in a large cohort of adult patients admitted for medical reasons. We hypothesized that higher BMI is associated with increased cardiac index (CI) and reduced systemic vascular resistance (SVR), reflecting a hyperdynamic circulatory state. This is a cross-sectional study of adults admitted to the Emergency Department at a large tertiary care hospital in Copenhagen, Denmark during 2019–2023. Patients were evaluated by physical examination and laboratory testing. Hemodynamic measurements, including CI and SVR, were estimated within 24 hours of admission using the non-invasive and continuous pulse wave analysis by Finapres® NOVA. The relationship between BMI, CI, and SVR were investigated using linear regression models. Of 942 participants (mean age 64 years; 44

Chronic kidney disease (CKD) is a major population disease. In diabetes as well as hypertension, kidney disease is one of the most serious complications. Recent research has demonstrated that chronic hypoxia is a key actor in the pathogenesis of CKD. In this review, we focus on how functional magnetic resonance imaging (fMRI) techniques can shed light on pathogenetic mechanisms and monitor new treatments aimed at preventing or ameliorating the disease. Multiparametric MRI techniques can measure changes in renal artery flow, tissue perfusion, and oxygenation repetitively over short time periods, enabling high time resolution. Furthermore, renal fibrosis can be quantified noninvasively by MRI diffusion tensor imaging, and techniques are upcoming to measure renal oxygen consumption. These techniques are all radiation and contrast-free.We briefly present data, demonstrating that fMRI techniques can play a major role in future research in CKD, and possibly also in daily clinical practice.

Introduction: In humans, the natriuretic effect of GLP-1 depends on GLP-1 receptor interaction, is independent of changes in renal blood flow, renin, ANP, and aldosterone but is accompanied by suppression of angiotensin II (ANGII). The mechanism by which GLP-1 reduces ANGII independently of changes in renin is not clarified. Hypothesis: It was hypothesized that GLP-1 suppresses renin substrate, angiotensinogen, in plasma. Methods: To test this proposal, we measured arterial angiotensinogen concentration in biobanked plasma samples from healthy males during a 3-hour GLP-1 infusion that induced natriuresis (1). Samples were from a study with fixed sodium intake where eight 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). Arterial plasma angiotensinogen was measured in plasma by dilution (1:200) and addition of excess exogenous human renin (Inst. Of Biological Standards UK). After prolonged incubation, ANGI was quantified by radioimmunoassay. Intraassay variation was 9-12%. Results: Arterial plasma angiotensinogen and renin levels decreased similarly and modestly (~15 and ~30%, respectively) after NaCl infusion during both studies whereas ANGII levels decreased significantly (~25%) only during GLP-1 infusion. Conclusions: Suppression of plasma angiotensinogen is less likely to account for GLP-1-mediated ANGII suppression in healthy young males. In perspective, GLP-1 could enhance pathways of ANGII degradation rather than inhibit its formation. 1. Asmar A et al. Extracellular fluid volume expansion uncovers a natriuretic action of GLP-1: a functional GLP-1-renal axis in man. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519.

Incretin-based therapy is an antidiabetic and antiobesity approach mimicking glucagon-like peptide-1 (GLP-1) with additional end-organ protection. This review solely focuses on randomized, controlled mechanistic human studies, investigating the renal effects of GLP-1. There is no consensus about the localization of GLP-1 receptors (GLP-1Rs) in human kidneys. Rodent and primate data suggest GLP-1R distribution in smooth muscle cells in the preglomerular vasculature. Native GLP-1 and GLP-1R agonists elicit renal effects. Independently of renal plasma flow and glomerular filtration rate, GLP-1 has a natriuretic effect but only during volume expansion. This is associated with high renal extraction of GLP-1, suppression of angiotensin II, and increased medullary as well as cortical perfusion. These observations may potentially indicate that impaired GLP-1 sensing could establish a connection between salt sensitivity and insulin resistance. It is concluded that a functional GLP-1 kidney axis exists in humans, which may play a role in renoprotection.

CONTEXTGlucagon-like-peptide-1 receptor agonists (GLP-1 RAs) exert cardiovascular benefits by reducing plasma glucose, body weight and blood pressure. The blood pressure lowering effect may be mediated by angiotensin II suppression and consecutive natriuresis. However, the role of angiotensin II and other vasoactive hormones on GLP-1 RA treatment has not been clearly defined.OBJECTIVETo investigate the effect of a three-week treatment with the GLP-1 RA dulaglutide on vasoactive hormones, i.e., renin, angiotensin II, aldosterone, MP-proANP and natriuresis in euvolemic participants.DESIGNRandomized, double-blinded, placebo-controlled, cross-over trials.SETTINGUniversity Hospital Basel, Switzerland.PARTICIPANTS54 euvolemic participants, including 20 healthy participants and 34 patients with primary polydipsia.INTERVENTIONSubcutaneous injection of dulaglutide (Trulicity ®) 1.5 mg and placebo (0.9% sodium chloride) once weekly over a three-week treatment phase.RESULTSAfter a three-week treatment phase, dulaglutide showed no effect on plasma renin, plasma angiotensin II or plasma aldosterone levels in comparison to placebo. Natriuresis remained unchanged or decreased on dulaglutide depending on the measured parameter. Dulaglutide significantly decreased plasma MR-proANP levels [treatment effect: 10.60pmol/L; 95% CI -14.70 to -7.90; p < 0.001] and systolic blood pressure [median: 3 mmHg; 95% CI -5 to 0; p = 0.036], whereas heart rate increased [median: 5 bpm; 95% CI 3 to 11; p < 0.001].CONCLUSIONIn euvolemic participants, a three-week treatment of dulaglutide reduced systolic blood pressure independently of plasma renin, angiotensin II, or aldosterone levels and urinary sodium excretion. The reduction in MR-proANP might be secondary to reduced arterial pulse pressure.

Background GLP‐1 (glucagon‐like peptide‐1) receptor agonists exert beneficial long‐term effects on cardiovascular and renal outcomes. In humans, the natriuretic effect of GLP‐1 depends on GLP‐1 receptor interaction, is accompanied by suppression of angiotensin II, and is independent of changes in renal plasma flow. In rodents, angiotensin II constricts vasa recta and lowers medullary perfusion. The current randomized, controlled, crossover study was designed to test the hypothesis that GLP‐1 increases renal medullary perfusion in healthy humans. Methods and Results Healthy male participants (n=10, aged 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 per minute) or placebo together with infusion of 0.9% NaCl (750 mL/h). Interleaved measurements of renal arterial blood flow, oxygenation (R 2 *), and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging. GLP‐1 infusion increased medullary perfusion (32±7%, P <0.001) and cortical perfusion (13±4%, P <0.001) compared with placebo. Here, NaCl infusion decreased medullary perfusion (−5±2%, P =0.007), whereas cortical perfusion remained unchanged. R 2 * values increased by 3±2% ( P =0.025) in the medulla and 4±1% ( P =0.008) in the cortex during placebo, indicative of decreased oxygenation, but remained unchanged during GLP‐1. Blood flow in the renal artery was not altered significantly by either intervention. Conclusions GLP‐1 increases predominantly medullary but also cortical perfusion in the healthy human kidney and maintains renal oxygenation during NaCl loading. In perspective, suppression of angiotensin II by GLP‐1 may account for the increase in regional perfusion. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04337268.

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<0.001) and cortical perfusion (13 ± 4%, p<0.001) compared to placebo. Here, NaCl infusion decreased medullary perfusion (-5 ± 2%, p=0.007) while cortical perfusion remained unchanged. R2* values increased by 3 ± 2% (p=0.025) in the medulla and 4 ± 1% (p=0.008) in the cortex during placebo, indicative of decreased oxygenation but remained unchanged during GLP-1. Renal arterial blood flow was not altered significantly by either intervention. 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.

CONTEXT:Glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) exert cardiovascular benefits by reducing plasma glucose, body weight, and blood pressure. The blood pressure-lowering effect may be mediated by angiotensin II (ANG II) suppression and consecutive natriuresis. However, the role of ANG II and other vasoactive hormones on GLP-1 RA treatment has not been clearly defined. OBJECTIVE:This work aimed to investigate the effect of a 3-week treatment with the GLP-1 RA dulaglutide on vasoactive hormones, that is, renin, ANG II, aldosterone, mid-regional proatrial natriuretic peptide (MP-proANP), and natriuresis in euvolemic participants. METHODS:Randomized, double-blinded, placebo-controlled, crossover trials were conducted at University Hospital Basel, Switzerland. A total of 54 euvolemic participants, including 20 healthy individuals and 34 patients with primary polydipsia, received a subcutaneous injection of dulaglutide (Trulicity) 1.5 mg and placebo (0.9% sodium chloride) once weekly over a 3-week treatment phase. RESULTS:After a 3-week treatment phase, dulaglutide showed no effect on plasma renin, plasma ANG II, or plasma aldosterone levels in comparison to placebo. Natriuresis remained unchanged or decreased on dulaglutide depending on the measured parameter. Dulaglutide significantly decreased plasma MR-proANP levels (treatment effect: 10.60 pmol/L; 95% CI, -14.70 to -7.90; P < .001) and systolic blood pressure (median: 3 mm Hg; 95% CI, -5 to 0; P = .036), whereas heart rate increased (median: 5 bpm; 95% CI, 3-11; P < .001). CONCLUSION:In euvolemic participants, a 3-week treatment of dulaglutide reduced systolic blood pressure independently of plasma renin, ANG II, or aldosterone levels and urinary sodium excretion. The reduction in MR-proANP might be secondary to reduced arterial pulse pressure.

Abstract Rationale: This case report demonstrates the use of flourine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) to rule out Richter transformation (RT) as the cause of clinical deterioration in a patient with chronic lymphatic leukemia (CLL) and severe COVID-19. 18F-FDG PET/CT can be used to establish the diagnosis of RT in patients with CLL, but the use of 18F-FDG PET/CT to exclude RT as the cause of clinical deterioration in patients with CLL and severe COVID-19 has not previously been described. Patient concerns: A 61-year-old male with CLL and COVID-19 developed increased dyspnea, malaise and fever during hospitalization for treatment of severe and prolonged COVID-19. Diagnoses: 18F-FDG PET/CT ruled out RT and revealed progression of opacities in both lungs consistent with exacerbation of severe acute respiratory syndrome coronavirus 2 pneumonia. Interventions: 18F-FDG PET/CT imaging. Outcomes: The patient was discharged at day 52 without the need of supplemental oxygen, with normalized infection marks and continued care for CLL with venetoclax. Lessons: 18F-FDG PET/CT ruled out RT as the cause of deteriorations in a patient with CLL and severe COVID-19, enabling directed care of exacerbation of severe acute respiratory syndrome coronavirus 2 pneumonia.

Background: Efficacy of protein absorption and subsequent amino acid utilization may be reduced in the elderly. Higher protein intakes have been suggested to counteract this. Objectives: We aimed to elucidate how habituated amounts of protein intake affect the fasted state of, and the stimulatory effect of a protein-rich meal on, protein absorption, whole-body protein turnover, and splanchnic amino acid metabolism. Methods: Twelve men (65-70 y) were included in a double-blinded crossover intervention study, consisting of a 20-d habituation period to a protein intake at the RDA or a high amount [1.1 g . kg lean body mass (LBM)(-)(1) . d(-1) or >2.1 g . kg LBM-1 . d(-1), respectively], each followed by an experimental trial with a primed, constant infusion of D-8-phenylalanine and D-2-tyrosine. Arterial and hepatic venous blood samples were obtained after an overnight fast and repeatedly 4 h after a standardized meal including intrinsically labeled whey protein concentrate and calcium-caseinate proteins. Blood was analyzed for amino acid concentrations and phenylalanine and tyrosine tracer enrichments from which whole-body and splanchnic amino acid and protein kinetics were calculated. Results: High (compared with the recommended amount of) protein intake resulted in a higher fasting whole-body protein turnover with a resultant mean +/- SEM 0.03 +/- 0.01 mu mol . kg LBM-1 . min(-1) lower net balance (P < 0.05), which was not rescued by the intake of a protein-dense meal. The mean +/- SEM plasma protein fractional synthesis rate was 0.13 +/- 0.06%/h lower (P < 0.05) after habituation to high protein. Furthermore, higher fasting and postprandial amino acid removal were observed after habituation to high protein, yielding higher urea excretion and increased phenylalanine oxidation rates (P < 0.01). Conclusions: Three weeks of habituation to high protein intake (>2.1 g protein . kg LBM-1 . d(-1)) led to a significantly higher net protein loss in the fasted state. This was not compensated for in the 4-h postprandial period after intake of a meal high in protein.

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.

Purpose: The natriuretic effect of glucagon-like peptide-1 (GLP-1) in humans is independent of changes in renal plasma flow (RPF) and glomerular filtration rate (GFR) but may involve suppression of angiotensin II (ANG II) and a significant (similar to 45%) renal extraction of GLP-1. The current study was designed to investigate the consequences for the renal extraction and the natriuretic effect of blocking GLP-1 receptors with the specific GLP-1 receptor antagonist, Exendin 9-39 (Ex 9-39). Methods: Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study where GLP-1 or vehicle was infused (1). In the present new experiments, participants were examined during a 3-hour infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-hour infusion of Ex 9-39 (900 pmol/kg/min). Timed urine collections were conducted throughout the experiments. Renal extraction of GLP-1 as well as RPF and GFR were measured via Fick's principle after catheterization of a renal vein. Arterial plasma renin, ANG II, and aldosterone concentrations were measured. Results: Co-infusion of Ex 9-39 significantly reduced renal extraction of GLP-1 to similar to 25% compared with GLP-1 infusion alone (similar to 45%). Urinary sodium excretions remained at baseline levels during co-infusion of Ex 9-39 as well as vehicle. By contrast, GLP-1 infusion alone resulted in a 2-fold increase in natriuresis. Ex 9-39 abolished the GLP-1-induced decrease in arterial ANG II concentrations. RPF and GFR remained unchanged during all experiments. Conclusions: Renal extraction of GLP-1 and its effect on natriuresis are both dependent on GLP-1 receptor activation in healthy humans.