Clinical trial NCT05056584: The Role of the Kidneys and Liver in the Elimination of Glucagon
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
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Kidney Diseases
Liver Cirrhosis
Hyperglucagonemia
Keywords: Metabolic clearance rate
Glucagon pharmacodynamics
Glucagon pharmacokinetics
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
Collaborators: name: The Novo Nordisk Foundation Center for Basic Metabolic Research
First posted: 2021-09-24
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Metabolic clearance rate of glucagon
timeFrame: t = 50 minutes
Secondary outcomes:
measure: Glucagon pharmacokinetic 1
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
measure: Glucagon pharmacokinetic 2
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
measure: Glucagon pharmacodynamic - amino acids
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
measure: Glucagon pharmacodynamic - glucose
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
measure: Tracers
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120
measure: Insulin
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
measure: Glucagon-like peptide 1
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
measure: Lipid metabolism
timeFrame: -120, -90, -60, -30, -15, 0, 5, 10, 20, 50, 55, 60, 62, 64, 66, 68, 70, 75, 80, 85, 90, 120 minutes
measure: Vital parameter 1
timeFrame: -120, -30, 0, 60, 120 minutes
measure: Vital parameter 2
timeFrame: -120, -30, 0, 60, 120 minutes
measure: Vital parameter 3
timeFrame: -120, -30, 0, 60, 120 minutes
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital
state: Copenhagen
Study officials:
affiliation: Center for Metabolic Research, Gentofte Hospital
name: Filip K Knop, MD, PhD
role: STUDY_DIRECTOR
affiliation: Center for Metabolic Research, Gentofte Hospital
name: Magnus FG Grøndahl, MD
role: PRINCIPAL_INVESTIGATOR
References: