Clinical trial NCT04337268: Acute Effects of GLP-1 on Renal Hemodynamics
Official title: Acute Effects of GLP-1 on Renal Hemodynamics: Simultaneous Perfusion and Oxygenation Measurements in Cortex and Medulla Using Magnetic Resonance Imaging
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: The GLP-1-mediated Gut-kidney Axis
Keywords: glucagon-like peptide-1
kidney
renal hemodynamics
renal blood flow
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Department of Cardiovascular and Renal Research, University of Southern Denmark
First posted: 2020-04-07
Enrollment: 10
Sex: MALE
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: T2* signal
timeFrame: 1 hour
measure: Arterial Spin Labeled (ASL)
timeFrame: 1 hour
measure: Renal Artery Flow Phase (RAF)
timeFrame: 1 hour
Secondary outcomes:
Other outcomes:
Locations:
city: Glostrup
country: Denmark
facility: Rigshospitalet - Glostrup
state: Copenhagen
Study officials:
affiliation: Rigshospitalet, Denmark
name: Ali Asmar, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.