Kidney Diseases
Conditions
Brief summary
The goal of this crossover study is to investigate to what extend glucagon affects the kidneys. The main questions it aims to answer are: Does glucagon regulate kidney function through extraction in the kidney in addition to glomerular filtration? Does glucagon regulate kidney function by increasing renal plasma flow and glomerular filtration rate? Does glucagon regulate kidney function by increasing renal salt excretion?
Detailed description
In patients with type 2 diabetes mellitus, plasma concentrations of glucagon are inappropriately high (hyperglucagonemia). Hyperglucagonemia has been speculated to contribute to the pathophysiology of diabetic kidney disease. Previously, glucagon has been assumed to cause glomerular hyperfiltration associated with urinary excretion of small proteins, a characteristic of early type 2 diabetic kidney injury. Further, glucagon has been shown to acutely increase urinary excretion of urea, sodium, and potassium, and patients with end-stage renal disease have elevated plasma levels of glucagon. The purpose of this study is to clarify the underlying mechanisms behind the physiological effects of glucagon on kidney function and the kidney's ability to clear glucagon from the blood in healthy males. Specifically, the investigators aim to answer the following questions: Does glucagon regulate kidney function through extraction in the kidney in addition to glomerular filtration? Does glucagon regulate kidney function by increasing renal plasma flow and glomerular filtration rate? Does glucagon regulate kidney function by increasing renal salt excretion? The renal extraction of glucagon and the renal effects of glucagon will be investigated during a constant glucagon infusion in 10 healthy men aged 20-60 years. The study will be placebo-controlled. Each subject will participate in three independent and randomized trial days with a washout period of at least four weeks.
Interventions
OTHERGlucagon
Glucagon infusion of 5 ng·kg-1·min-1 from 0-60 minutes and 10 ng·kg-1 ·min-1 from 60-120 minutes.
OTHERPlacebo
Placebo (0.9% NaCl).
OTHERGlucagon and exendin 9-39
Glucagon (infusion of 5 ng·kg-1·min-1 from 0-60 minutes) and glucagon (infusion of 10 ng·kg-1 ·min-1 from 60-120 minutes) + a GLP-1R antagonist, exendin 9-39 (900 pmol·kg-1·min-1 from -30-120 minutes).
Sponsors
University of Copenhagen
The Augustinus Foundation, Denmark.
The Novo Nordic Foundation
Ali Asmar
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
20 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Age: 20-60 years * Normal health ascertained through questioning and medical examination * Normal values for blood concentrations of fasting plasma glucose, fasting plasma total cholesterol, fasting triglycerides, HDL, LDL, creatinine, liver function, and electrolytes * Informed consent
Exclusion criteria
* Immunosuppressive treatment in the preceding 12 months * Alcohol abuse * Medical treatment with oral glucocorticoids, dipeptidyl peptidase-4 (DPP-4) inhibitors, or GLP-1 receptor agonists, which, in the opinion of the investigator, may interfere with glucose metabolism * Use of lithium * Medical treatment that affects insulin secretion or cardiovascular performance measures * Liver disease (ALT \> 2x normal value) * Renal impairment (se-creatinine \> 130 μM and/or albuminuria)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Natriuresis | Analyzed from urine samples at -60, 0, 60 and 120 minutes | From urine samples, unit mmol/L |
| Glucagon extraction | Analyzed from blood samples drawn at -30, 0, 20, 40, 60, 80, 100, 120, 140, 160 and 180 minutes | From blood samples, unit pmol/L |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glomerular filtration rate | Measured via Fick's principle during steady state using [99mTc]Tc-DTPA (diethylene-triamine-pentaacetate) as a tracer given as a constant infusion from -210 to 180 min. | Unit mL/min |
| Diuresis | Analyzed from urine samples at -60, 0, 60 and 120 minutes | from urine samples, unit mL/min |
| Renal Blood Flow | Measured via Fick's principle during steady state using [99mTc]Tc-DTPA (diethylene-triamine-pentaacetate) as a tracer given as a constant infusion from -210 to 180 min. | Unit mL/min |
| Urea | Analyzed from blood samples drawn at -30, 0, 20, 40, 60, 80, 100, 120, 140, 160 and 180 minutes | Unit mg/dL |
Countries
Denmark
Contacts
Primary ContactAli Asmar, MD
Backup ContactAnna Billeschou Bomholt
Outcome results
None listed