C‐peptide, Na+,K+‐ATPase, and Diabetes
Authors: Vague P. , Coste T. C. , Jannot M. F. , Raccah D. , Tsimaratos M. 
Published: April 2004

Na+,K+‐ATPase is an ubiquitous membrane enzyme
that allows the extrusion of three sodium ions from the cell
and two potassium ions from the extracellular fluid. Its activity
is decreased in many tissues of streptozotocin‐induced
diabetic animals. This impairment could be at least partly
responsible for the development of diabetic complications.
Na+,K+‐ATPase activity is decreased in the red blood cell
membranes of type 1 diabetic individuals, irrespective of the
degree of diabetic control. It is less impaired or even normal
in those of type 2 diabetic patients. The authors have
shown that in the red blood cells of type 2 diabetic patients,
Na+,K+‐ATPase activity was strongly related to blood C‐peptide
levels in non–insulin‐treated patients (in whom C‐peptide
concentration reflects that of insulin) as well as in
insulin‐treated patients. Furthermore, a gene‐environment
relationship has been observed. The alpha‐1 isoform of the
enzyme predominant in red blood cells and nerve tissue is
encoded by the ATP1A1 gene.Apolymorphism in the intron
1 of this gene is associated with lower enzyme activity in patients
with C‐peptide deficiency either with type 1 or type
2 diabetes, but not in normal individuals. There are several
lines of evidence for a low C‐peptide level being responsible
for low Na+,K+‐ATPase activity in the red blood cells.
Short‐term C‐peptide infusion to type 1 diabetic patients
restores normal Na+,K+‐ATPase activity. Islet transplantation,
which restores endogenous C‐peptide secretion, enhances
Na+,K+‐ATPase activity proportionally to the rise
in C‐peptide. This C‐peptide effect is not indirect. In fact,
incubation of diabetic red blood cells with C‐peptide at
physiological concentration leads to an increase of Na+,K+‐ATPase activity. In isolated proximal tubules of rats or
in the medullary thick ascending limb of the kidney, C‐peptide stimulates in a dose‐dependent manner Na+,K+‐ATPase activity. This impairment in Na+,K+‐ATPase activity,
mainly secondary to the lack of C‐peptide, plays probably
a role in the development of diabetic complications.
Arguments have been developed showing that the diabetesinduced
decrease in Na+,K+‐ATPase activity compromises
microvascular blood flow by two mechanisms: by affecting
microvascular regulation and by decreasing red blood cell
deformability, which leads to an increase in blood viscosity.
C‐peptide infusion restores red blood cell deformability
and microvascular blood flow concomitantly with Na+,K+‐ATPase activity. The defect in ATPase is strongly related to
diabetic neuropathy. Patients with neuropathy have lower
ATPase activity than those without. The diabetes‐induced
impairment in Na+,K+‐ATPase activity is identical in red
blood cells and neural tissue. Red blood cell ATPase activity
is related to nerve conduction velocity in the peroneal
and the tibial nerve of diabetic patients. C‐peptide infusion
to diabetic rats increases endoneural ATPase activity in rat.
Because the defect in Na+,K+‐ATPase activity is also probably
involved in the development of diabetic nephropathy and
cardiomyopathy, physiological C‐peptide infusion could be
beneficial for the prevention of diabetic complications.