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

Study Overview
=================
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.

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

Conditions
-----------------
Chronic Kidney Diseases, Liver Cirrhosis, Hyperglucagonemia

Intervention / Treatment
-----------------
* Biological: Glucagon infusion
* Biological: Primed tracer infusion


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metabolic clearance rate, Glucagon pharmacodynamics, Glucagon pharmacokinetics