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Human C-peptide acutely lowers glomerular hyperfiltration and proteinuria in diabetic rats: a dose-response study
Dan-Yang Huang1, Kerstin Richter, Alexander Breidenbach
1Department of Pharmacology, University of Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany.
Abstract:
Recent studies suggested that C-peptide treatment of C-peptide-deficient patients with type I diabetes mellitus may present a new approach to prevent diabetic nephropathy. The present study further elucidated this concept by assessing the acute effect of human C-peptide application on kidney function in anesthetized rats with streptozotocin (STZ)-induced diabetes. Human C-peptide was applied as an i.v. bolus followed by continuous infusion of a fivefold dose per hour. A dose of 6 nmol/kg plus 30 nmol/kg per h is referred to as 1x. Application of 0.1, 0.3, 1, 3 or 10x to STZ-diabetic rats elicited mean plasma human C-peptide concentrations of 0.5, 5, 24, 75 and 225 nmol/l, respectively. Under basal conditions STZ-diabetic rats exhibited as expected an increase in glomerular filtration rate (GFR) by about 30%, which was associated with a lower total renal vascular resistance (RVR) and a rise in renal blood flow (RBF) as well as enhanced urinary protein excretion (UPE) of about 70% as compared with control rats. Human C-peptide dose-dependently lowered GFR and UPE in STZ-diabetic rats without altering blood glucose levels. No significant effect of human C-peptide on RBF or RVR could be detected, which may indicate an effect on glomerular ultrafiltration coefficient. Maximum effects of human C-peptide on the diabetes-induced rises in GFR and UPE established an inhibition of 40% and 50%, respectively. Half-maximum effects on GFR and UPE were observed at plasma concentrations of human C-peptide in the range of 0.5-5 nmol/l, which is relatively close to endogenous C-peptide levels in non-diabetic rats. Unresponsiveness of non-diabetic control rats to human C-peptide further indicated specific effects.
Insights
Human C-peptide treatment may prevent diabetic nephropathy in type I diabetes. Studies show C-peptide significantly reduces elevated kidney function and protein in diabetic rats, suggesting a novel therapeutic approach.
Area of Science:
- Nephrology
- Endocrinology
- Diabetology
Background:
- Type I diabetes mellitus is associated with diabetic nephropathy.
- C-peptide deficiency is a hallmark of type I diabetes.
- C-peptide replacement therapy is being explored for preventing diabetic complications.
Purpose of the Study:
- To investigate the acute effects of human C-peptide on kidney function in streptozotocin (STZ)-induced diabetic rats.
- To determine the dose-dependency and effective plasma concentrations of human C-peptide in modulating renal parameters.
Main Methods:
- Anesthetized rats with STZ-induced diabetes were administered human C-peptide intravenously.
- Various doses of C-peptide were administered to achieve different plasma concentrations.
- Kidney function parameters including glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), and urinary protein excretion (UPE) were measured.
Main Results:
- STZ-diabetic rats showed increased GFR and UPE compared to controls.
- Human C-peptide dose-dependently reduced GFR and UPE in diabetic rats.
- Half-maximum effects were observed at plasma C-peptide concentrations of 0.5-5 nmol/l.
- No significant effects on RBF or RVR were detected, suggesting a potential impact on the glomerular ultrafiltration coefficient.
Conclusions:
- Human C-peptide exerts protective effects on kidney function in experimental diabetes.
- C-peptide treatment significantly inhibits diabetes-induced increases in GFR and UPE.
- These findings support the potential of C-peptide therapy for preventing diabetic nephropathy in type I diabetes patients.