The Role of the Kidneys and Liver in the Elimination of Glucagon (MCR_EndCir)

The Role of the Kidneys and Liver in the Elimination of Glucagon An Evaluation of the Metabolic Clearance Rate of Glucagon in Patients With End-stage Renal Disease and Patients With Liver Cirrhosis

The study aims to evaluate the kinetics and effect of glucagon in patients with chronic kidney disease and liver cirrhosis and matched healthy subjects, respectively.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis; Chronic Kidney Diseases; Hyperglucagonemia
• Intervention / Treatment: Biological: Glucagon infusion; Biological: Primed tracer infusion

Detailed Description

In the present project the investigators wish to identify whether the effect, elimination and degradation of glucagon differ between healthy control subjects and patients with Chronic Kidney Disease (CKD) and liver cirrhosis, respectively. By performing glucagon infusions on healthy control subjects and matched subjects with either limited renal and hepatic function, the contribution of both organs to the metabolic clearance rate (MCR) of glucagon can be tested. A primed infusion of stable isotopic labelled tracers will allow the researchers to investigate the effects of the glucagon infusion on the glucose, lipid and amino acid metabolism.

The quantification of the MCR of glucagon will be accompanied by a range of pharmacodynamic measures in order to substantiate whether a potentially altered glucagon MCR inflicts pharmacodynamic changes of glucagon, which could contribute to the pathophysiology of CKD and liver cirrhosis.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Magnus FG Grøndahl, MD; Phone Number: 29362445; Email: magnus.frederik.gluud.groendahl@regionh.dk
• Study Contact Backup: Name: Filip K Knop, MD, PhD

Study Locations

• Denmark
  • Copenhagen
    • Hellerup, Copenhagen, Denmark, 2900
      • Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

The CKD group

• Men/women between 18 and 75 years of age
• CKD stage 4 or 5
• Normal liver function (alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), albumin and coagulation factor II, VII and X (INR) within normal range,
• Informed consent

The cirrhosis group

• Men/women between 18 and 75 years of age
• Verified diagnosis of cirrhosis - Child-Pugh Score of 5-12
• Normal kidney function (estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73m2 and absence of proteinuria)
• Informed consent

The control group

• Men/women between 18 and 75 years of age
• Normal kidney function (estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73m2 and absence of proteinuria)(plasma creatinine ≤105 micromol/L (µM) for men and ≤90 µM for women)
• Normal liver function (alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), albumin and coagulation factor II, VII and X (INR) within normal range
• Informed consent

Exclusion Criteria:

All groups

• Diagnosis of diabetes and/or HbA1c ≥43 mmol/mol and/or fasting plasma glucose ≥6 mmol/l.
• Previous kidney transplantation with remaining kidney graft
• Present treatment with oral glucocorticoids
• Polycystic kidney disease
• Pregnancy or breastfeeding
• Inflammatory bowel disease
• Surgical procedure within the last 3 months
• Haemoglobin < 6 mmol/l (women) or < 7 mmol/l (men)
• First-degree relatives with diabetes
• Any condition that the investigators feel would interfere with trial participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy control subjects; Healthy control subjects, matched for age, sex and BMI	Biological: Glucagon infusion; One hour glucagon-clamp followed by one hour of blood sampling; Biological: Primed tracer infusion; Infusion of primed isotopically labelled glucose, amino acids and lipids. From 2 hours prior to glucagon infusion and throughout the test day,
Experimental: Patients with End-stage Renal Disease; Patients with hemodialysis-treated ESRD.	Biological: Glucagon infusion; One hour glucagon-clamp followed by one hour of blood sampling; Biological: Primed tracer infusion; Infusion of primed isotopically labelled glucose, amino acids and lipids. From 2 hours prior to glucagon infusion and throughout the test day,
Experimental: Patients with liver cirrhosis; Patients with Child-Pugh A or B Cirrhosis	Biological: Glucagon infusion; One hour glucagon-clamp followed by one hour of blood sampling; Biological: Primed tracer infusion; Infusion of primed isotopically labelled glucose, amino acids and lipids. From 2 hours prior to glucagon infusion and throughout the test day,

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolic clearance rate of glucagon	Glucagon plasma concentration steady state glucagon concentrations	t = 50 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucagon pharmacokinetic 1	Elimination half-life	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Glucagon pharmacokinetic 2	volume of distribution of Glucagon	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Glucagon pharmacodynamic - amino acids	Effect of glucagon on amino acid plasma levels before, during and after infusion	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Glucagon pharmacodynamic - glucose	Effect of glucagon on plasma glucose levels before, during and after infusion	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Tracers	Tracer-to-tracee ratio of labelled isotopes	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120
Insulin	Excursions of plasma concentrations of insulin	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Glucagon-like peptide 1	Excursions of plasma concentrations of GLP-1	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Lipid metabolism	Effect of glucagon on lipid metabolism, through lipidomics	-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Vital parameter 1	Systolic blood pressure	-120, -30, 0, 60, 120 minutes
Vital parameter 2	Diastolic blood pressure	-120, -30, 0, 60, 120 minutes
Vital parameter 3	Heart rate	-120, -30, 0, 60, 120 minutes

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen
• Collaborators: The Novo Nordisk Foundation Center for Basic Metabolic Research
• Investigators: Study Director: Filip K Knop, MD, PhD, Center for Metabolic Research, Gentofte Hospital; Principal Investigator: Magnus FG Grøndahl, MD, Center for Metabolic Research, Gentofte Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2020
• Primary Completion (Actual): March 28, 2023
• Study Completion (Actual): March 28, 2023

Study Registration Dates

• First Submitted: November 9, 2020
• First Submitted That Met QC Criteria: September 15, 2021
• First Posted (Actual): September 24, 2021

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Metabolic clearance rate; Glucagon pharmacodynamics; Glucagon pharmacokinetics
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Urologic Diseases; Liver Diseases; Renal Insufficiency; Fibrosis; Kidney Diseases; Renal Insufficiency, Chronic; Liver Cirrhosis; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: H-16043802

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