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

Primary Purpose

Chronic Kidney Diseases, Liver Cirrhosis, Hyperglucagonemia

Status
Completed
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
Glucagon infusion
Primed tracer infusion
Sponsored by
University Hospital, Gentofte, Copenhagen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Chronic Kidney Diseases focused on measuring Metabolic clearance rate, Glucagon pharmacodynamics, Glucagon pharmacokinetics

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Healthy control subjects

Patients with End-stage Renal Disease

Patients with liver cirrhosis

Arm Description

Healthy control subjects, matched for age, sex and BMI

Patients with hemodialysis-treated ESRD.

Patients with Child-Pugh A or B Cirrhosis

Outcomes

Primary Outcome Measures

Metabolic clearance rate of glucagon
Glucagon plasma concentration steady state glucagon concentrations

Secondary Outcome Measures

Glucagon pharmacokinetic 1
Elimination half-life
Glucagon pharmacokinetic 2
volume of distribution of Glucagon
Glucagon pharmacodynamic - amino acids
Effect of glucagon on amino acid plasma levels before, during and after infusion
Glucagon pharmacodynamic - glucose
Effect of glucagon on plasma glucose levels before, during and after infusion
Tracers
Tracer-to-tracee ratio of labelled isotopes
Insulin
Excursions of plasma concentrations of insulin
Glucagon-like peptide 1
Excursions of plasma concentrations of GLP-1
Lipid metabolism
Effect of glucagon on lipid metabolism, through lipidomics
Vital parameter 1
Systolic blood pressure
Vital parameter 2
Diastolic blood pressure
Vital parameter 3
Heart rate

Full Information

First Posted
November 9, 2020
Last Updated
May 11, 2023
Sponsor
University Hospital, Gentofte, Copenhagen
Collaborators
The Novo Nordisk Foundation Center for Basic Metabolic Research
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1. Study Identification

Unique Protocol Identification Number
NCT05056584
Brief Title
The Role of the Kidneys and Liver in the Elimination of Glucagon
Acronym
MCR_EndCir
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
August 1, 2020 (Actual)
Primary Completion Date
March 28, 2023 (Actual)
Study Completion Date
March 28, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Gentofte, Copenhagen
Collaborators
The Novo Nordisk Foundation Center for Basic Metabolic Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Kidney Diseases, Liver Cirrhosis, Hyperglucagonemia
Keywords
Metabolic clearance rate, Glucagon pharmacodynamics, Glucagon pharmacokinetics

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Healthy control subjects
Arm Type
Experimental
Arm Description
Healthy control subjects, matched for age, sex and BMI
Arm Title
Patients with End-stage Renal Disease
Arm Type
Experimental
Arm Description
Patients with hemodialysis-treated ESRD.
Arm Title
Patients with liver cirrhosis
Arm Type
Experimental
Arm Description
Patients with Child-Pugh A or B Cirrhosis
Intervention Type
Biological
Intervention Name(s)
Glucagon infusion
Intervention Description
One hour glucagon-clamp followed by one hour of blood sampling
Intervention Type
Biological
Intervention Name(s)
Primed tracer infusion
Intervention Description
Infusion of primed isotopically labelled glucose, amino acids and lipids. From 2 hours prior to glucagon infusion and throughout the test day,
Primary Outcome Measure Information:
Title
Metabolic clearance rate of glucagon
Description
Glucagon plasma concentration steady state glucagon concentrations
Time Frame
t = 50 minutes
Secondary Outcome Measure Information:
Title
Glucagon pharmacokinetic 1
Description
Elimination half-life
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Title
Glucagon pharmacokinetic 2
Description
volume of distribution of Glucagon
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Title
Glucagon pharmacodynamic - amino acids
Description
Effect of glucagon on amino acid plasma levels before, during and after infusion
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Title
Glucagon pharmacodynamic - glucose
Description
Effect of glucagon on plasma glucose levels before, during and after infusion
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Title
Tracers
Description
Tracer-to-tracee ratio of labelled isotopes
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120
Title
Insulin
Description
Excursions of plasma concentrations of insulin
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Title
Glucagon-like peptide 1
Description
Excursions of plasma concentrations of GLP-1
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Title
Lipid metabolism
Description
Effect of glucagon on lipid metabolism, through lipidomics
Time Frame
-120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
Title
Vital parameter 1
Description
Systolic blood pressure
Time Frame
-120, -30, 0, 60, 120 minutes
Title
Vital parameter 2
Description
Diastolic blood pressure
Time Frame
-120, -30, 0, 60, 120 minutes
Title
Vital parameter 3
Description
Heart rate
Time Frame
-120, -30, 0, 60, 120 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Filip K Knop, MD, PhD
Organizational Affiliation
Center for Metabolic Research, Gentofte Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Magnus FG Grøndahl, MD
Organizational Affiliation
Center for Metabolic Research, Gentofte Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital
City
Hellerup
State/Province
Copenhagen
ZIP/Postal Code
2900
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
No

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The Role of the Kidneys and Liver in the Elimination of Glucagon

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