# Influence of C-Peptide on Glucose Utilisation

Authors: B. Wilhelm; P. Kann; A. Pfützner
Journal: Experimental Diabetes Research
 (2008)

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## Abstract

During the recent years, multiple studies demonstrated that C-peptide is not an inert peptide, but exerts important physiological effects. C-peptide binds to cell membranes, stimulates the Na,K-ATPase and the endothelial nitric oxide (NO) synthase. Moreover, there is evidence that C-peptide decreases glomerular hyperfiltration and increases glucose utilisation. Nevertheless, there is still limited knowledge concerning mechanisms leading to an increased glucose utilisation either in rats or in humans. The aim of this paper is to give an overview over the published studies regarding C-peptide and glucose metabolism from in vitro studies to longer lasting studies in humans.


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## Body

## 1. IN Vitro Studies

Zierath et al. [1] showed that physiological
concentrations of human C-peptide stimulate glucose transport in human skeletal
muscle in a dose-dependent manner. In order to elucidate the mechanisms by
which C-peptide stimulates glucose transport in human skeletal muscle, they
investigated the interaction between C-peptide and insulin binding to
receptors, the potential role of C-peptide in activating the receptor tyrosine
kinase, the influence of counter-regulatory hormones on the C-peptide
activation of the glucose transport, and the effect of C-peptide in glucose
transportation in skeletal muscle from patients with insulin-dependent diabetes
mellitus [2]. They demonstrated that C-peptide partly shares a common pathway
with insulin in stimulating skeletal muscle glucose transportation as
simultaneous exposure of maximal concentrations of insulin and C-peptide did
not result in an additive effect of 3-o-methylglucose transport. C-peptide did
not alter the binding of insulin to the insulin receptor nor was shown to have
a specific binding to muscle crude membranes. C-peptide stimulates glucose
transport by mechanism independent of insulin receptor and tyrosine kinase
activity and in contrast to insulin, catecholamines did not reveal a counter-regulatory effect on the C-peptide mediated glucose transport. Under in vitro
conditions, a stimulation of glucose transportation could be also demonstrated
by patients with insulin-dependent diabetes mellitus. Despite chronic
deprivation of C-peptide in vitro, exposure of skeletal muscle strips from
patients with insulin-dependent diabetes mellitus to a physiological
concentration of C-peptide increased the glucose utilisation measured by an
augmented 3-o-methylglucose transport [2]. In vitro studies with isolated
mouse muscle showed that C-peptide did not stimulate glycogen synthesis in
isolated mouse muscle [3].


## 2. Animal Studies

In 1983 it has been demonstrated that in alloxan-treated rats,
supra-physiololgical concentrations of C-peptide increased and prolonged the
hypoglygemic effect of exogenous insulin on whole body glucose uptake [4]. As
glucose transport can be stimulated by NO [5, 6], the aim of an euglycemic clamp
study in streptozotocin-induced diabetes rats was to examine whether C-peptide
in physiological concentrations increases whole body glucose utilisation and
whether such an effect is diminished by an NO synthase inhibitor. Physiological
concentrations of homologous rat C-peptide I or II augmented significantly
glucose disposal rate (GDR) by 80–90% and metabolic clearance rate (MCR) for
glucose by 100–125% in diabetic rats, whereas no effects could be detected
in healthy control rats. A further increase in C-peptide concentrations did not
let to further effects on GDR or MCR [7]. L-NMMA, a known inhibitor of
NO-synthase, was able to block about 85% of the C-peptide-induced increase in
GDR. These results suggest that a major proportion of the C-peptide stimulation
of glucose utilisation is mediated by NO [7].Moreover, it could be shown that C-terminal fragments, but not fragments from the middle
segment of C-peptide, are as effective as the full-length peptide in
stimulating whole-body glucose turnover in streptozotocin-induced diabetes rats
[8].


## 3. Short-Term Human Studies

During a euglygemic clamp study in 11 patients with type 1 diabetes mellitus C-peptide was
infused in two periods over 60 minutes in a concentration of 5 and 30
pmol/kg/min and compared with 10 patients who received saline infusion. After
infusion of low-dose C-peptide, whole body glucose utilisation rose by
approximately 25% (P < .05), whereas no changes in the saline group
were detected. The high-dose C-peptide infusion given to 7 of the 11 patients
resulted in a small further increase of about 15% (P < .05) in glucose
utilisation [9].Forearm uptake of glucose after a 5-minute rhythmic dynamic exercise
with a handergometer increased significantly after C-Peptide infusion (−4.8±3.1 versus 13.6±3.2 umol·min-1100 mL-1) in
patients with diabetes mellitus [10]. We investigated in our study with 13
patients with type 1 diabetes mellitus and 13 healthy control glucose
utilisation after administration of C-peptide (8 pgmol/kg/body weight/min)
over 2 hours during an euglycemic clamp procedure with either a
high-dose (1.0 Ul/kg body weight/min) or a low-dose insulin infusion (0.25 mU/kg body weight/min).
The C-peptide levels reached are shown in Figure 1. After C-peptide infusion,
glucose utilisation increased in patients with diabetes mellitus (51.5±25.6 versus 74.51±22.93 g) and healthy controls (74.91±22.01
versus 99.38±24.24 g) statistically significant (P < .001)
during high-dose insulin infusion and from 16.31±13.34 to 18.8±16.2 g in the diabetic patients and from 20.74±9.96 to 35.8±13.5 g
in the healthy controls, the results are given in Figure 2 [11]. In a recent study [12], it has been discussed
that C-peptide might increase the bioavailability of insulin by promoting the
disaggregation of hexameric insulin. The combined injection of insulin and
C-peptide required a greater amount and longer duration of glucose than insulin
alone in patients with diabetes type 1. In another setting, the same group
applied insulin and C-peptide in the same and in two separate depots and found
that the reduction in plasma glucose was significantly faster when administered
in the same depot. The amount of glucose that has to be infused in order to
avoid a hypoglycaemia was 129% (P < .01) by administration in the same
depot.Figure 1
C-peptide levels in healthy controls and patients with
diabetes type 1 during the euglycemic clamp.Figure 2
Glucose utilisation in g during an euglygemic clamp with low and high
insulin concentrations in healthy controls (C), Diabetes mellitus type 1 and
after administration of C-peptide (C+C) and (D+C).


## 4. Long-Term Human Studies

In a randomized, double-blind study 18 patients with type 1 diabetes
received either regular insulin mixed with equimolar amounts of biosynthetic
human C-peptide or insulin alone for 1 month as subcutaneous infusions using an
insulin pump. At the end of the study, fructosamine levels decreased by about
16% from3.8±0.3 to 3.2±0.1 (P < .05) mmol/L and
HbA1c by about 10% from 8.0±0.7% to 7.3±0.5% (P < .05%). Fasting blood glucose tended to be lower in the insulin and C-peptide
treated group (NS). No statistically significant changes could be demonstrated
in the insulin group [13].


## 5. Discussion

C-peptide in nanomolar concentrations binds specifically to cell
membranes, assumable by a G-protein-coupled receptor. After activation of a Ca
(2+)- and MAP Kinase-dependent pathway, the Na,K-ATPase and the endothelial
nitric oxide synthase are stimulated, resulting in an increase of  nitric oxide [14]. Increased local release of
nitric oxide by C-peptide, resulting in an increased subcutaneous blood flow,
might enhance insulin absorption and therefore glucose utilisation [15].Several studies as cited above have shown that C-peptide increases
glucose utilisation either in vitro or in vivo. The effect seems to be a
consequence of the stimulation of glucose transport in the skeletal muscle,
independent of the insulin receptor or the thyrosine kinase activity, but mediated
through nitric oxide [7]. When C-peptide concentrations are increased above the
physiological range, no further stimulation of glucose utilisation can be
demonstrated [7]. This might be explained by the hypothesis that C-peptide
receptors on cell membranes are relatively few and show high-affinity binding,
thereby reaching saturation at low C-peptide concentrations [15].In conclusion, recent studies have demonstrated that C-peptide is not an
inert peptide, but a biologically active substance which has besides other
effects regulatory influence on glucose metabolism. But still many mechanisms
of C-peptide action have to be resolved.Longer lasting studies are needed in order to evaluate continuing
improvement of glucose utilisation in patients with type 1 diabetes.



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*Source: 769483-2008-03-27.xml*