Biological Significances, Diagnostic Values and Therapeutic Approach of Proinsulin Connecting Peptide
Gamal El-din I. Harisa
In the past years, proinsulin-connecting peptide (C-peptide) considered a biologically inactive peptide. Recently it has been demonstrated that this peptide exert insulin-independent biological effects. This review provides a summary of recent research and discusses some beneficial and detrimental effects of C-peptide. The binding of C-peptide with cell membrane inducing signal transduction through G-Protein Coupled Receptors (GPCR). This resulted in phospholipase-C (PLC) activation that provokes an increase in Ca2+ and diacylglycerol (DAG) leading to activation of many cellular signaling. The treatment of diabetic patients in particular type 2 with C-peptide resulted in improved glucose metabolism as well as blood flow. So that renal functions in addition to nerve functions are get well again. C-peptide and insulin are secreted in equimolar amounts; therefore the measurement of C-peptide permits the quantitation of insulin secretion. Due to the longer half life of C-peptide than insulin it regard as a god indicator for endogenous insulin secretion. C-peptide is sensitive to physiological degradation therefore, several strategies are taken to improve the bioavailability for C-peptide. These strategies include amino acids modification, endogenous carrier conjugation, liposome incorporation and peptidase inhibition. These data indicated that C-peptide is biologically active peptide and has many functions in treatment of diabetic associated complications. Further, studies in particular in vivo are required to explore the exact roles of C-peptide the treatment of diabetic associated complications as well as cardiovascular disease.
Received: January 03, 2011;
Accepted: February 02, 2011;
Published: May 07, 2011
Similar to secretary proteins, insulin is translated as preproinsulin that
carries a signal peptide which directs the preproinsulin to the interior of
the endoplasmatic reticulum (ER). In the ER, the signal sequence of preproinsulin
at N-terminal is cleaved and the resulting proinsulin. In the Golgi complex
proinsulin is packaged into secretory granules and converted to insulin then
C-peptide by proprotein convertases (PPCs). These products are stored in secretory
vesicles until C-peptide and insulin are co-secreted in equimolar amounts (Mares-Guia
et al., 2006). After cleavage of the C- peptide, mature insulin
is formed in the β-granules and is stored in the form of zinc-containing
hexamers until secretion (Goodge and Hutton, 2000).
C-peptide plays a functional role in proinsulin folding, linking A and B chains of the insulin moiety and thus helping to provide optimal orientation of sulfhydryl groups for intramolecular disulfide bond formation. Additionally, this peptide helps in the maintenance of the C-peptide/insulin A-chain junction structure in proinsulin, which is a recognition site for PPCs.
Furthermore, C-peptide acts as molecular guardian, i.e. proinsulin folding
is facilitated by an intramolecular chaperone-like action of this peptide (Chen
et al., 2001) and also, C-peptide regulates the kinetic folding pathway
of proinsulin (Qiao et al., 2003).
Early studies with C-peptide failed to report any therapeutic effects for C-peptide.
Conversely, In the last few years C-peptide has insulin-like actions, therefore
treatment of Type 1 diabetic (T1D) with this peptide resulted in improved renal
function, increased blood flow, augmented glucose utilization, as well as improved
nerve function. Therefore, C-peptide plays important roles in the treatment
of diabetic neuropathy. Furthermore, C-peptide administration associated with
improvement in sensory nerve functions. These effects may be attributed to C-peptide
activates insulin receptor, phosphatidylinositol 3-kinase (PI-3-K), mitogen-activated
protein kinase (MAPK) and glycogen synthase kinase-3(GSK3), Na+/K+-ATPase
and endothelial nitric oxide synthase (eNOS) (Hills and
PREPROINSULIN AND PROINSULIN
The insulin is the example for peptides that are processed from larger precursor
molecules. The insulin is synthesized as a preprohormone molecular weight (11,500
Dalton), the hydrophobic 23-amino-acids are leader sequence directs the molecule
into the interior of ER and then is removed. Proinsulin molecular weight (9.000
Dalton) is transferred to Golgi apparatus of pancreatic islet β-cells.
During the process of secretory granules maturation, proinsulin is cleaved by
endopeptidases [proprotein convertase-1 (PPC1) and proprotein convertase-2 (PPC2)]
into insulin molecular weight (6000 Dalton) and C-peptide molecular weight (3.000
Dalton). In comparison with the insulin, proinsulin has low biological potency,
low affinity for insulin receptors and prolonged half life in circulation. Proinsulin/insulin
levels are finely regulated during development, since an excess of the protein
interferes with correct morphogenesis and is deleterious for the embryo (Hernandez-Sanchez
et al., 2006).
THE PROINSULIN CONNECTING PEPTIDE
C-peptide is the 31-amino-acid peptide that connects the A and B chains the
insulin precursor molecule, therefore it named as connecting peptide. Cleavage
of C-peptide from proinsulin leads to exposure of the C terminus of the insulin
β-chain to subsequent conformational changes required for the binding of
insulin to its receptor. C-peptide is secreted in a 1:1 ratio with insulin;
it has a longer plasma half-life 20-30 min compared with 3-5 min for insulin.
SIGNAL TRANSDUCTION BY C-PEPTIDE
The mechanisms by which C-peptide signals are transduced remain incomplete
clear. But several studies reported that C-peptide binds specifically to target
cells membranes through G-Protein-coupled Receptor (GPCR) activate phospholipase
C (PLC). Therefore the intracellular level of diacylglycerol (DAG) is increase
and this activates P-I-3-K which increase inositol trisphosphate (Hills
and Brunskill, 2009).
Moreover administration of C-peptide at physiological concentrations provokes
a prompt elevation of intracellular Ca2+ concentrations (Shafqat
et al., 2002). This leads to stimulation of eNOS in renal tubular
and endothelial cells (Wallerath et al., 2003).
Moreover, C-peptide stimulates phosphorylation of protein kinase-C (PKC) (Zhong
et al., 2005).
Additionally, exposure of cell to C-peptide induced the activation of one or
more components of the MAPKs cascade in a concentration-dependent manner (Kitamura
et al., 2003). MAPKs increase transcription factor expression, apoptosis
and increased expression of eNOS. In addition to C-peptide has also been found
to mimic the effects of insulin in muscle cells (Grunberger
et al., 2001). Stimulation of the MAPK pathway also results in increased
Na+/K+ ATPase activity and activation of various transcription
DIAGNOSTIC VALUES OF C-PEPTIDE
C-peptide is a measure of endogenous insulin secretion; the normal fasting level is (1-4 ng mL-1) which may be rises after meals. C-peptide can be measured in urine and urinary concentrations correlate with those in the blood. The half-life of C-peptide in the circulation is five times longer than that of insulin. Therefore, C-peptide levels are a more stable indicator of insulin secretion. As compared to insulin C-peptide levels in peripheral venous blood are about 5-6 times greater than insulin levels. In addition, the C-peptide assay distinguishes endogenous from injected insulin. Moreover, the clinical indications for C-peptide measurement include diagnosis of insulinoma and differentiation from factitious hypoglycemia. As well, C-peptide measurement is used in follow-up of pancreatectomy and evaluation of viability of islet cell transplants. It has been suggests that C-peptide of insulin may provide a more direct tool for assessing relative energetic condition.
Unlike insulin, C-peptide does not undergo significant clearance by the liver,
meaning that it is probably a better indicator of pancreatic insulin secretion
than circulating insulin itself. Additionally, C-peptide is typically used for
clinical diagnosis of insulin resistance and other metabolic disorders, as well
as it can also be used to quantify relative energy balance. Ellison
and Valeggia (2003) used urinary C-peptide measures to track longitudinal
changes in energy balance during the postpartum period in human females, tying
resumption of cycling to C-peptide thresholds. Deschner
et al. (2008) found that C-peptide levels correlated with body mass
changes during a 2-week period of caloric restriction, as well as during the
subsequent period of recovery.
BIOLOGICAL SIGNIFICANCES OF C-PEPTIDE C-PEPTIDE AND GLUCOSE METABOLISM
The biological activity of C-peptide was the stimulation of glucose transport
in human skeletal muscle in dose-dependent manner. The supra-physiological concentrations
of C-peptide prolonged the hypoglycemic actions of insulin in diabetic rats
in comparison with normal rats. Likewise, physiological concentrations C-peptide
were found to significantly enhance the utilization rates of glucose (Wahren
et al., 2000).
The effects of C-peptide on glucose metabolism have also been examined in short-term
studies in T1D patients. The infusion of C-peptide display a 25% increase in
glucose turnover. C-peptide receptor is fully saturated at 0.9 nmol L-1
of the molecule concentration and there is no further increase in glucose metabolism
when C-peptide levels were more elevated. Enhancement of whole-body sugar utilization
under these conditions due to increased muscle uptake rather than reduced hepatic
synthesis. The hyperglycemia is associated with increase the glycation of protein
particularly hemoglobin and albumin (Mahesh and Brahatheeswaran,
2007). Moreover the same study added that the improvement of insulin secretion
and minimize the protein glycation. The administration of C-peptide and insulin
to T1D patients decrease proteins glycation as indicated by a significant lowering
of glycated albumin and glycated hemoglobin (HbA1c) (Wilhelm
et al., 2008).
C-PEPTIDE AND CIRCULATORY FUNCTION
Nitric Oxide (NO) is one of the vasodilator molecules, which regulate the blood
flow; such molecule plays an important role in regulation of cardiovascular,
nervous and immune systems functions (McGrowder and Brown,
2007). NO activity is low in diabetes, either due to increasing the destruction
of NO by oxidative stress or by decreasing NO production from L-arginine by
endothelial NO synthase (Harisa et al., 2009).
The supplementation of C-peptide at physiological level resulted in an increase
of microvascular blood flow. These effect is related to stimulation of endothelial
NO release by the activation of Ca2+ calmodulin-regulated eNOS. There
several studies demonstrated that C-peptide restore the circulatory function
through NO dependent mechanisms.
Forst et al. (2008) reported that the vascular
effect of C-peptide, indicating its role in the regulation of microvascular
blood flow. Moreover, inhibition of NOS by certain inhibitors completely abolished
the vasodilator response to C-peptide. The same study reported that C-peptide
was shown to affect microvascular blood flow and to improve nerve or renal function
in animal models of T1D and in humans with T1D. Moreover, C-peptide supplementation
was shown to increase microvascular blood flow and to enhance the recruitment
of capillaries in isolated kidneys of the rat. Moreover, C-peptide induced a
concentration dependent dilation of skeletal muscles arterioles isolated from
C-PEPTIDE AND DIABETIC RENAL FUNCTION
The elevated blood sugar level associated with several events including activation
of polyols pathway as well as increase of Reactive Oxygen Species (ROS) formation
(Abo-salem et al., 2009). Moreover, activation
of PKC, secretion of transforming growth factor-β (TGF-β), altered
expression of cyclin kinases, increased matrix proteins and decreased matrix-degrading
enzymes and metalloproteinases (Gnudi et al., 2003).
Additionally, uncontrolled hyperglycemia associated with increased glycosylation
of proteinases inhibitors like α-1-antitrypsin leading to decrease its
function. This is also one of the factors responsible for diabetic complications
in kidneys and other organs (Naderi et al., 2006).
These events are responsible for histopathological changes associated with diabetic
New signaling roles for C-peptide have recently been discovered with evidence
that it can ameliorate complications of T1D. So that C-peptide can be used as
a potential therapy for diabetic nephropathy (Hills et
al., 2010a, b).The beneficial effect of C- peptide
in diabetic nephropathy has been proved in a series of studies. Firstly, insulin
treatment in patients with newly diagnosed T1D improves but often fails to normalize
renal hyperfiltration. Secondly the patients with T2D who have maintained endogenous
insulin and C-peptide secretion generally do not develop glomerular hyperfiltration.
Moreover, previous study investigated the possibility that C-peptide may regulate
renal functional alterations, such as GFR, in diabetes. It has been founded
that C-peptide administration was accompanied by a significant fall in GFR,
whereas the GFR of controls did not change. Extending these observations in
T1D, the same investigators demonstrated that there is a 6% reduction in GFR
and a 55% reduction in proteinuria after 1 month of C-peptide and insulin administration
compared with insulin administration alone. Similarly, 3 month study in microalbuminuric
T1D patients, C-peptide administration was associated with a reduction in urinary
albumin excretion (Johansson et al., 2000). These
findings in patients have also been paralleled in animal studies. In STZ rats
with early diabetes, physiological levels of C-peptide attenuate glomerular
hypertrophy, glomerular hyperfiltration and proteinuria (Huang
et al., 2002).
In other study with an angiotensin-converting enzyme inhibitor, C-peptide was
like effective captopril in reducing glomerular hyperfiltration in STZ rats.
After 4 weeks STZ diabetic rats given C-peptide, these kidney functional improvements
were accompanied by preserved glomerular structure with significantly reduced
hypertrophy and matrix accumulation (Samnegard et al.,
2004). In STZ diabetic mice, C-peptide also reduced urinary albumin excretion,
together with glomerular expression of the pro-fibrotic cytokine, TGF-β
and type IV collagen. When mouse glomerular podocytes were exposed to C-peptide,
TGF-β induced expression of mRNAs for type IV collagen and plasminogen-activator
inhibitor 1 (PAI1) were blocked (Maezawa et al.,
Moreover, in isolated glomeruli from alloxan-induced diabetic mice have revealed
that C-peptide constricts afferent glomerular arterioles when applied via the
vessel lumen (Nordquist et al., 2008). Administration
of C-peptide prevented TNF-α-mediated apoptosis in opossum proximal tubular
cells (Al-Rasheed et al., 2006), suggesting a
protective role of C-peptide in the progression of diabetes-related kidney disease.
C-PEPTIDE AND NERVE FUNCTION
Many factors including, genetic factors, hyperglycemia, oxidative stress, activation
of polyols pathway and formation of advanced glycosylation end products are
involved in diabetic polyneuropathy (DPN). The lacking of C-peptide in T1D patients
might exert an important role in the development of neuropathy. The nerve abnormalities
in T1D animals, who lack C-peptide, includes impairment of nerve Na+/K+-ATPase
and eNOS activities, resulting in intra-axonal sodium accumulation and reduced
endoneurial blood flow (Sima, 2003). Gradually, structural
changes appear, involving axonal atrophy and characteristic nodal and paranodal
abnormalities that contribute to the progressive deterioration of nerve conduction
In contrast, hyperglycemia is the primary pathogenetic factor in T2D while
C-peptide levels in the normal range. The functional and structural abnormalities
of the peripheral nerves are less marked and show a different pattern, including
milder axonal degeneration and no or only minimal nodal and paranodal abnormalities
(Murakawa et al., 2002). Thus, the lack of C-peptide
in T1D contributes to the development of the more severe nerve dysfunction and
Studies in diabetic animals have suggested that C-peptide may prevent neuronal
dysfunction by improving endoneurial blood flow and nerve Na+/K+-ATPase
activity (Stevens et al., 2004). Zhang
et al. (2007) reported that C-peptide administration dose-dependently
improved nerve conduction velocities. The protective effect of C-peptide was
accompanied by beneficial alterations in a variety of neurotrophic factors and
receptors and was most marked if the agent was continuously administered by
an osmo-pump (Kamiya et al., 2006).
Additionally treatment with C-peptide in addition to insulin was accompanied
by improved autonomic function (Johansson et al.,
2000). Moreover, C-peptide treatment resulted in significant and substantial
improvements in neuropathic parameters as determined by both neurophysiological
measurement and clinical examination (Ekberg et al.,
2007). In the presence of insulin, C-peptide has been shown to exert antiapoptotic
effects on neuroblastoma cells and to increase the production of NF-κB
(Li et al., 2003). In addition to C-peptide has
been suggested to be beneficial in diabetic neuropathy (Sima
et al., 2004) by promoting neuronal development, regeneration and
cell survival. Furthermore C-peptide prevents neuronal apoptosis in T1D and
it induces neurite outgrowth and cell-growth of the neuroblastoma cell line
(Li et al., 2003; Li and
Sima, 2004). In neurons, C-peptide may play a pro- or antiapoptotic role,
depending on the cell type and the state of the cell, in addition to its causal
role in vascular disease (Denk et al., 2000).
C-peptide in replacement doses stimulates nerve Na+/K+-
ATPase activity, increases endoneurial blood flow and stimulates neurotrophic
factors, resulting in improved nerve conduction velocity and prevention of nerve
structural changes (Wahren et al., 2007).
C-PEPTIDE AND ERYTHROCYTE FUNCTIONS
Induction of glucose oxidation by hyperglycemia is responsible for oxidative
stress resulted in increased lipids peroxidation as well as proteins oxidation
leading to cellular damage. The oxidative stress has been implicated in erythrocytes
damage in diabetes (Serdevi et al., 2007). The
Na+/K+-ATPase controls many of cellular functions, like,
cell volume, free calcium concentrations and membrane potential. The erythrocytes
activity of Na+/K+-ATPase is attenuated under diabetic
conditions (Vague et al., 2004). Although there
are tissue specific differences in the regulations of Na+/K+-ATPase
activity, hyperglycemia and diabetes are predominantly characterized by a decrease
in Na+/K+-ATPase activity. This would result in an increase
in intracellular calcium concentration and an increased vascular tone, promoting
the development of vascular complications in diabetes mellitus. The C-peptide
restores the activity of Na+/K+-ATPase in diabetic rats.
The incubation of erythrocytes from T1D patients with C-peptide normalized erythrocyte
Na+/K+ ATPase activity (Djemli-Shipkolye
et al., 2000). Furthermore, infusion of C-peptide was found to improve
erythrocyte Na+/K+- ATPase activity in T1D patients (Forst
et al., 2000). The improvement of erythrocyte Na+/K+-ATPase
is associated with improved rheological properties of the blood and increase
the vascular blood flow (Forst et al., 2009).
C-PEPTIDE AND INFLAMMATION
C-peptide elicits insulin-independent biological effects on a number of cells
proving itself as a bioactive peptide with anti-inflammatory properties (Haidet
et al., 2009). NO from inducible NOS plays important roles in regulation
of many inflammatory and immunity processes. Moreover, NO regulation is altered
in diabetic and inflammatory states (Marx et al.,
2004). C-peptide has been shown to increase intracellular Ca2+,
in smooth muscle cells (Chakrabarti et al., 2004)
and aortic endothelial cells, thereby inducing NO production by eNOS and inducible
nitric oxide synthase (iNOS) (Tsimaratos et al.,
2003). The protective effect of C-peptide against myocardial ischemia-reperfusion
has been mediated through the release of NO (Young et
al., 2000). The same study demonstrated that C-peptide reduces polymorphonuclear
cell adherence to vascular endothelium in isolated ischemic and reperfused rat
The impaired release of NO from the vascular bed will up-regulate adhesion
molecules on endothelial cells, thereby increasing leukocyte-endothelium interactions.
In addition to a single injection of C-peptide decreased the expression of endothelial
cell adhesion molecules on the rat microvascular endothelium, leading to reduced
leukocyte adhesion as well as transmigration in mesenteric venules. This attenuation
of leukocyte-endothelial interactions is mediated by an increase in eNOS synthesis
and subsequent release of NO (Scalia et al., 2000).
Overall, these reports suggest that administration of C-peptide in physiological
doses exerts anti-inflammatory effects.
In contradiction, C-peptide has also been reported to possess proinflammatory
properties. C-peptide improves dermal wound healing associated with an increased
number of leukocytes adherent to the endothelium (Langer
et al., 2002). Also, it has been reported that C-peptide co-localize
with macrophages and monocytes in artery specimens from diabetic subjects and
to co-localize with and act as a chemoattractant for lymphocyte and monocytes
in early atherosclerotic lesions (Walcher et al.,
Furthermore, C-peptide has been shown to stimulate the transcription of inflammatory
genes, such as cyclooxygenase-2 (COX-2), via the activation of a PKC/NF-κB
signaling pathway in certain type of fibroblasts (Kitazawa
et al., 2006). It is concluded that, the role of C-peptide in the
regulation of inflammation still unclear, so that further studies are needed
in order to determine C-peptide has beneficial or detrimental function in inflammatory
C-PEPTIDE AND ANGIOGENESIS
There are indications that diabetes induces the up-regulation of oncofetal
fibronectin in the retina (Khan et al., 2004),
a substance believed to be involved in angiogenesis and normally not found in
mature tissue. Increased retinal expression of oncofetal fibronectin in diabetic
rats is completely prevented by C-peptide treatment (Chakrabarti
et al., 2004). The C-peptide normalize diabetes-induced oncofetal
fibronectin up-regulation in diabetic retinas, this suggesting that the important
role of this peptide in the development of microangiopathy (Chakrabarti
et al., 2004).
C-PEPTIDE AND ATHEROSCLEROSIS
The previous studies have demonstrated that the administrated of C-peptide
has contradictory effect on atherosclerosis. Firstly, C-peptide prevent vascular
dysfunction in diabetic rats as well as possess antiproliferative effects on
vascular smooth muscle cells (SMC) which indicate that treatment with C-peptide
may delay progression of atherosclerosis. The administration of C-peptide in
concentration range from 1 to 100 nM appears to suppress hyperglycemia induced
hyperproliferation of aortic SMC. The antiproliferative effects of C-peptide
on vascular SMC are mediated through the inhibited expression of the platelet-derived
growth factor-β (PDGF-β) receptor and increased phosphorylation of
MAPKs (Kobayashi et al., 2005).
In contradiction, there are another study reported that C-peptide may be acts
as a mitogen by the induction of vascular SMC proliferation, this finding suggesting
proatherogenic activity of this peptide. Moreover in certain cell lines, C-peptide
(1 nM) has been shown to stimulate the PKC/NF-κB signaling pathway (Kitazawa
et al., 2006). The PI-3 pathway is implicated in the pathogenesis
of diabetic endothelial dysfunction and atherosclerosis and also this pathway
has been shown to be increased by C-peptide (Brownlee, 2001;
Kitamura et al., 2001), implicating a synergistic
effect of C-peptide and TNF-α in aggravating diabetes-associated complications.
These data suggest that C-peptide is involved in regulation of cell proliferation
and apoptosis on multiple levels. Conversely, C-peptide appears to have predominantly
antiproliferative effects in SMC.
C-PEPTIDE AND INSULIN RESISTANCE
The metabolic abnormality of this disease include many factors such hyperglycemia,
hyperinsulinemia, advanced glycation end products and dyslipidemia with low
level of good cholesterol (Huq, 2007). These metabolic
alterations have been demonstrated that to stimulate SMC proliferation (Indolfi
et al., 2001).
Insulin alone is a weak mitogen but it can potentiate the effects of other
mitogens such PDGF, angiotensin II and thrombin. In insulin resistant, tyrosine
phosphorylation of the insulin receptor and signaling via the insulin receptor
substrate pathway is impaired resulting in diminished metabolic effects. In
contrast, tyrosine phosphorylation of ERK 1/2 MAPK by insulin is maintained
and perpetuated by other growth factors resulting in SMC proliferation and migration.
In this context the presence of C-peptide in atherosclerotic lesions from diabetic
patients and it is tempting to speculate that C-peptide-induced proliferation
of SMC in the setting of insulin resistance and hyperinsulinemia could provide
a previously unrecognized mechanism leading to accelerated atherosclerosis and
its complications in patients with T2D (Bruemmer, 2006).
Walcher et al. (2006) add other mechanisms promoting
SMC proliferation under conditions of hyperinsulinemia by listing C-peptide
as one of mitogens. C-peptide, secreted simultaneous to insulin activates both
the PI-3-K/Akt and ERK1/2 MAPK pathways. Activation of these pathways results
in SMC proliferation through phosphorylation of the retinoblastoma protein and
cell cycle progression the activated by PI-3-K and ERK1/2 MAPK signaling is
the cell cycle, C-peptide increased cyclin D1 expression and subsequently phosphorylation
of the retinoblastoma protein as the gatekeeper of G1-S phase cell cycle progression.
Based on these observations, C-peptide stimulates SMC proliferation through
a Src3 PI-3 kinase/ERK1/2-MAPKdependent progression of the cell cycle.
C-PEPTIDE IN TYPE 2 DIABETES
T2D is associated with insulin resistance and as the disease evolves patients
exhibit elevated insulin and C-peptide concentrations. Many T2D patients develop
nephropathy and neuropathy in the face of increased circulating C-peptide levels.
These high levels of C-peptide in T2D patients and bearing in mind the experimentally
derived affinity of C-peptide-binding sites, it is likely that any similar receptor
would be fully occupied and potentially down-regulated (Hills
and Brunskill, 2009).
Important differences also exist between the complications observed in T1D
and T2D diabetes. Neuropathy in T1D progresses more predictably and quickly
and is associated with myelin sheath and axonal derangements not present in
T1D. With respect to diabetic nephropathy, the predictable evolution of renal
disease observed in T1D is less well documented in T2D. In addition, diabetes-specific
renal lesions are found in all T1D patients with nephropathy, renal morphology
in T2D is much more heterogeneous with prominent arteriosclerosis and ischaemic
nephropathy (Ritz and Tarng, 2001). In T1D nephropathy,
chronic hyperglycemia beginning in the first 2 decades of life is usually the
only evident cause of kidney disease.
On the other hand, patients with T2D are generally over the age of 40 and have
evidence of age-related glomerulosclerosis, together with other propagators
of renal disease, such as hypertension, obesity and dyslipidemia. Thus nephropathy
in T2D reflects a heterogeneous combination of kidney diseases precipitated
by a mixture of mechanisms that may modify and overwhelm the typical renal responses
to hyperglycemia and the features of pure diabetic nephropathy (White
et al., 2007). Consequently, it has been suggested that, in terms
of responses to treatment, T1D and T2D diabetic patients should be considered
Attention has been drawn to a possible role for C-peptide in the development
of vascular inflammation and atherosclerosis in T2D diabetes. This concern is
based on observations that C-peptide deposits may be found co-localized in early
atherosclerotic lesions in T2D patients, but not in similar vascular lesions
in non-diabetics (Marx et al., 2004). Subsequent
studies demonstrated the presence of chemotactic activity of C-peptide in
vitro (Walcher et al., 2004). Although, these
findings are weakened because circulating C-peptide levels were not measured
in the diabetic subjects, they suggest that elevated C-peptide in T2D may contribute
to vascular dysfunction.
Other work has also shown that C-peptide may stimulate smooth muscle cell proliferation,
but this was contradicted by other authors (Cifarelli
et al., 2008). On contrary to these findings C-peptide may be a key
mediator in the development of vascular inflammation and atherosclerosis in
T2D. Luppi et al. (2008) have demonstrated both
an anti-inflammatory and potential anti-atherogenic role for C-peptide through
a reduction in the expression of several biochemical markers of endothelial
C-PEPTIDE AS THERAPY FOR DIABETIC COMPLICATIONS
Peripheral neuropathy is one of the most common complications of T1D and T2D
mellitus. It has been demonstrated that several small non-neural peptides possess
neurotrophic activity and exert beneficial effects on nervous system function
in experimental and clinical diabetes. The C-peptide and islet neogenesis-associated
peptide, are derived from pancreatic proteins. Moreover, derivatives of erythropoietin
possess similar effect on the nervous system. These peptides are of increasing
interest leads to new approaches in the treatment of diabetes-associated neuropathies
(Tam et al., 2006).
C-peptide treatment in rats with STZ induced diabetes is accompanied by correction
of glomerular hyperfiltration, diminished levels of microalbuminuria and regression
of glomerular hypertrophy. Likewise, when C-peptide is administered in replacement
doses to patients with T1D, there is significant reduction of both glomerular
hyperfiltration and urinary albumin excretion (Johansson
et al., 2002).
Effects of C-peptide replacement therapy on functional and structural changes
in peripheral nerves have been studied in diabetic rats. C-peptide administration
for two months was found to prevent the defect of nerve conduction velocity
(Sima et al., 2001). In patients with autonomic
nerve dysfunction, increased heart rate variability during deep breathing has
been seen following C-peptide administration.
In addition, evidence from a study involving C-peptide therapy in T1D patients
without obvious symptoms of neuropathy indicate that three months of treatment
results in significant improvement of sensory nerve conduction velocity. The
treatment with C-peptide in rats is accompanied by significant improvement in
nerve Na+/K+-ATPase activity and in nerve blood flow.
The relevance of the observed C-peptide effects is supported by the fact that
both deficient NO formation and reduced levels of Na+/K+-ATPase
are factors of pathogenetic importance for diabetic neuropathy (Johansson
et al., 2002).The present data suggest that C-peptide replacement
therapy together with insulin therapy in T1D patients may be beneficial in preventing
or retarding the development of long-term diabetic complications.
IMPROVEMENT OF C-PEPTIDE HALF LIFE
Proinsulin C-peptide is sensitive to physiological degradation therefore, it
has short plasma half life (20-30 min). Several strategies like amino acids
modification, endogenous carrier conjugation, liposome incorporation, N-acetylation,
polyethylene glycol (PEG) glycation( PEGylation) as well as peptidase inhibition,
are taken to improve the bioavailability of these small peptides could be suitable
for C-peptide. For example, the plasma half life of glucagon like peptide 1
(GLP-1), a 31-amino-acid gastrointestinal peptide with neurotrophic effects,
can be extended considerably by attachment of a polyethylene glycol (PEG) moiety
(PEGylation) (Lee et al., 2005), N-acetylation
(Liu et al., 2004) or conjugation of GLP-1 to
serum proteins such as albumin (Kim et al. (2003).
However, bioequivalence and biosafety remain principal concerns in such strategies.
These strategies may be playing an important role in the prolongation of t1/2
In the last years the study of C-peptide not explores any biological effect for this peptide. In recent times it has been demonstrated that C-peptide elicits insulin-independent biological effect. Insulin produced by biotechnology lacking the C-peptide, the lack of C-peptide may exacerbate diabetes-associated complications. Inflammation and hyperglycemia are major cause in the development of vascular dysfunction in diabetes. Given the anti-inflammatory properties of C-peptide, one may speculate dual hormone replacement therapy with both insulin and C-peptide in patients with T1D may be warranted in the future to decrease morbidity and mortality. C-peptide prevents diabetic neuropathy by improving blood flow, neuronal apoptosis and axonal swelling. An anti-proliferative effect of C-peptide on vascular smooth muscle cells may be preventing atherosclerosis. Further, molecular studies in particular in vivo experiments using either infusion or injection of C-peptide in animal models of atherosclerosis or neointimal smooth muscles cell proliferation to further exploit the contribution of C-peptide to cardiovascular disease in T2D.
The author would like to thank Kayyali Research Chair for Pharmaceutical Industries, Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia for the assistance in preparation of this review.
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