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

Not Applicable

Completed

• Conditions: Hyperglucagonemia; Chronic Kidney Diseases; Liver Cirrhosis
• Interventions: Biological: Glucagon infusion; Biological: Primed tracer infusion

• Registration Number: NCT05056584
• Lead Sponsor: University Hospital, Gentofte, Copenhagen

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.

Study Timeline

• Study Start: 2020-08-01
• Study First Submitted: 2020-11-09
• Study First Submitted QC: 2021-09-15
• Study First Posted: 2021-09-24
• Primary Completion: 2023-03-28
• Study Completion: 2023-03-28
• Status Verified: 2023-05
• Last Update Submitted: 2023-05-11
• Last Update Posted: 2023-05-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 48

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Patients with End-stage Renal Disease	Glucagon infusion	Patients with hemodialysis-treated ESRD.
Patients with End-stage Renal Disease	Primed tracer infusion	Patients with hemodialysis-treated ESRD.
Patients with liver cirrhosis	Glucagon infusion	Patients with Child-Pugh A or B Cirrhosis
Healthy control subjects	Glucagon infusion	Healthy control subjects, matched for age, sex and BMI
Patients with liver cirrhosis	Primed tracer infusion	Patients with Child-Pugh A or B Cirrhosis
Healthy control subjects	Primed tracer infusion	Healthy control subjects, matched for age, sex and BMI

Primary Outcome Measures

Name	Time	Method
Metabolic clearance rate of glucagon	t = 50 minutes	Glucagon plasma concentration steady state glucagon concentrations

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital; 🇩🇰 Hellerup, Copenhagen, Denmark