Chronic Kidney Diseases, Liver Cirrhosis, Hyperglucagonemia
Conditions
Keywords
Metabolic clearance rate, Glucagon pharmacodynamics, Glucagon pharmacokinetics
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.
Interventions
BIOLOGICALGlucagon infusion
One hour glucagon-clamp followed by one hour of blood sampling
BIOLOGICALPrimed tracer infusion
Infusion of primed isotopically labelled glucose, amino acids and lipids. From 2 hours prior to glucagon infusion and throughout the test day,
Sponsors
The Novo Nordisk Foundation Center for Basic Metabolic Research
University Hospital, Gentofte, Copenhagen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic clearance rate of glucagon | t = 50 minutes | Glucagon plasma concentration steady state glucagon concentrations |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Vital parameter 1 | -120, -30, 0, 60, 120 minutes | Systolic blood pressure |
| Vital parameter 2 | -120, -30, 0, 60, 120 minutes | Diastolic blood pressure |
| Vital parameter 3 | -120, -30, 0, 60, 120 minutes | Heart rate |
| 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 |
Countries
Denmark
Outcome results
None listed