Acute Effects of GLP-1 on Renal Hemodynamics (GLP1RRBF)

Acute Effects of GLP-1 on Renal Hemodynamics: Simultaneous Perfusion and Oxygenation Measurements in Cortex and Medulla Using Magnetic Resonance Imaging

This study investigates the hypothesis, that GLP-1's suppression of ANG II and natriuretic action increase medullary perfusion and decrease oxygen consumption, leading to higher tissue oxygenation.

Study Overview

• Status: Completed
• Conditions: The GLP-1-mediated Gut-kidney Axis
• Intervention / Treatment: Drug: Glucagon-Like Peptide 1; Drug: saline 0.9%

Detailed Description

Human studies have recently demonstrated a significant natriuretic effect of GLP-1 when the extracellular fluid volume (ECFV) is expanded by intravenous sodium-loading; in these studies, there was a suppression of ANG II with no change in net renal hemodynamics, pointing to a tubular mechanism for reduced NaCl reabsorption secondary to the ANG II suppression. In the current randomized and controlled study, investigators aim to test the hypothesis that GLP-1's suppression of ANG II and natriuretic action increase medullary perfusion and decrease oxygen consumption, leading to higher tissue oxygenation. Thus, contributing to the renoprotective action of GLP-1.

Under fixed sodium intake for 4 days before each study day, 10 healthy male participants will be investigated during a 1-hour infusion of GLP-1 (1.5 pmol/kg/min) or vehicle together with an intravenous infusion of 0.9% NaCl. Interleaved measurements of RAF, oxygenation (T2*) and perfusion by arterial spin labeling in the renal cortex and medulla at fixed time points will be conducted, using Magnetic Resonance Imaging (MRI).

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen
    • Glostrup, Copenhagen, Denmark, 2600
      • Rigshospitalet - Glostrup

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Normal health demonstrated by medical examination.
• Normal values for fasting plasma glucose, total cholesterol, triglyceride, HDL, LDL, creatinine, AST, ALT and electrolyte concentrations.

Exclusion Criteria:

• Immunosuppressive treatment for the previous 12 months.
• Alcohol abuse.
• Medical treatment with oral glucocorticoids, dipeptidyl peptidase-4 (DPP-4) inhibitors, or GLP-1 receptor agonists that, in the opinion of the investigator, may interfere with glucose metabolism.
• Use of lithium.
• Medical treatment that affects insulin secretion or cardiovascular efficacy goals.
• Liver disease (ALT> 2 x normal value).
• Renal impairment (creatinine> 130 µM and / or albuminuria).
• Severe claustrophobia.
• MRI incompatible foreign bodies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: human glucagon-like peptide-1; Intervention: Drug: human glucagon-like peptide-1 Other names: GLP-1	Drug: Glucagon-Like Peptide 1; Intravenous infusion (1.5 pmol/kg/min) for 60 min.; Other Names: GLP-1
Placebo Comparator: Placebo; Intervention: Drug: Placebo (saline) Other names: Placebo for human glucagon-like peptide-1	Drug: saline 0.9%; Intravenous infusion for 60 min.; Other Names: Placebo for GLP-1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
T2* signal	Changes in T2* signal in renal cortex and medulla	1 hour
Arterial Spin Labeled (ASL)	Changes in Arterial Spin Labeled (ASL) MRI Perfusion Imaging in renal cortex and medulla	1 hour
Renal Artery Flow Phase (RAF)	Changes in Renal Artery Flow Phase (RAF)-Contrast Magnetic Resonance	1 hour

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Department of Cardiovascular and Renal Research, University of Southern Denmark
• Investigators: Principal Investigator: Ali Asmar, MD, PhD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006.
• Korner M, Stockli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med. 2007 May;48(5):736-43. doi: 10.2967/jnumed.106.038679.
• Pyke C, Heller RS, Kirk RK, Orskov C, Reedtz-Runge S, Kaastrup P, Hvelplund A, Bardram L, Calatayud D, Knudsen LB. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014 Apr;155(4):1280-90. doi: 10.1210/en.2013-1934. Epub 2014 Jan 27.
• Asmar A, Simonsen L, Asmar M, Madsbad S, Holst JJ, Frandsen E, Moro C, Jonassen T, Bulow J. Renal extraction and acute effects of glucagon-like peptide-1 on central and renal hemodynamics in healthy men. Am J Physiol Endocrinol Metab. 2015 Apr 15;308(8):E641-9. doi: 10.1152/ajpendo.00429.2014. Epub 2015 Feb 10.
• Asmar A, Simonsen L, Asmar M, Madsbad S, Holst JJ, Frandsen E, Moro C, Sorensen CM, Jonassen T, Bulow J. Glucagon-like peptide-1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy. Am J Physiol Endocrinol Metab. 2016 May 1;310(9):E744-53. doi: 10.1152/ajpendo.00518.2015. Epub 2016 Mar 8.
• Asmar A, Asmar M, Simonsen L, Madsbad S, Holst JJ, Hartmann B, Sorensen CM, Bulow J. Glucagon-like peptide-1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men. Physiol Rep. 2017 Feb;5(3):e13073. doi: 10.14814/phy2.13073.
• Skov J, Dejgaard A, Frokiaer J, Holst JJ, Jonassen T, Rittig S, Christiansen JS. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J Clin Endocrinol Metab. 2013 Apr;98(4):E664-71. doi: 10.1210/jc.2012-3855. Epub 2013 Mar 5.
• Asmar A, Cramon PK, Simonsen L, Asmar M, Sorensen CM, Madsbad S, Moro C, Hartmann B, Jensen BL, Holst JJ, Bulow J. 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. doi: 10.1210/jc.2019-00004.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Actual): March 1, 2020
• Study Completion (Actual): March 1, 2020

Study Registration Dates

• First Submitted: March 29, 2020
• First Submitted That Met QC Criteria: April 3, 2020
• First Posted (Actual): April 7, 2020

Study Record Updates

• Last Update Posted (Actual): April 7, 2020
• Last Update Submitted That Met QC Criteria: April 3, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: kidney; glucagon-like peptide-1; renal blood flow; renal hemodynamics
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Glucagon; Glucagon-Like Peptide 1
• Other Study ID Numbers: H-18050603

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No