<p>It is generally
recognized that the connecting peptide (C-peptide) of proinsulin fulfills an important function in the biosynthesis of
insulin. It brings together the A- and B-chains such that the initial folding
and interchain disulfide bonds can be formed. Evolutionary considerations
suggest that a length of approximately 30 residues for the connecting segment,
as is the case for human C-peptide, is optimal for the efficient further processing of the molecule (i.e., its
cleavage into insulin and C-peptide). Following this, the two are stored in
secretory granules and eventually coreleased into the circulation. Because of
its intimate connection to the insulin biosynthesis, C-peptide has been used as
a marker of insulin secretion. As such, it has contributed importantly to our
understanding of the pathophysiology of several metabolic disorders, notably
type 1 and type 2 diabetes.</p> <p>The possibility
that C-peptide may possess biological effects of its own was considered but
received relatively little attention at the time of its discovery in 1968. No
detectable influence on glucose metabolism or on lipolysis of isolated fat
cells could be observed. In the absence of any insulin-like effect by C-peptide
in isolated cell systems or when administered to healthy individuals, it was
concluded that C-peptide was without biological effect other than its role in
the biosynthesis of insulin; for a review see [##REF##403392##1##]. Consequently, C-peptide as a
bioactive peptide left the scientific limelight and the interest was focused
instead on its usefulness as a marker of insulin secretion.</p> <p>It was not until
the early 1990s that direct C-peptide effects were re-evaluated. A series of
studies was undertaken involving administration of the peptide in type 1
diabetes patients, who lack C-peptide [##REF##1547915##2##]. This proved a useful
approach and it became apparent that replacement of physiological
concentrations of C-peptide in this patient group results in significant
amelioration of diabetes-induced abnormalities of regional blood flow as well
as improvements in peripheral nerve and kidney function. These surprising
findings, subsequently confirmed and extended by several laboratories, prompted
a renewed interest in C-peptide as a bioactive peptide in its own right. Since
then, a steadily increasing number of reports on new aspects of C-peptide
physiology have been presented. Today, a vast body of scientific evidence is
available comprising in vitro studies of the peptide's membrane interaction and
cellular effects, in vivo studies in animal models of type 1 diabetes defining
C-peptide's influence on functional and structural abnormalities of the kidneys
and the peripheral nerves as well as clinical trials on nerve and kidney
function in patients with type 1 diabetes, all of which attest to a wide
spectrum of physiological effects being mediated by C-peptide. In addition, the
findings provide a basis for the notion that C-peptide administration, in
combination with regular insulin therapy, may be beneficial in the prevention
and treatment of microvascular complications of type 1 diabetes.</p> <p>In the present,
special issue of <italic>Experimental Diabetes
Research</italic>, most of the
recent developments in C-peptide research are being reviewed including an
authoritative review of the history and diagnostic aspects of C-peptide. A
highly qualified attempt is made to sort out the multitude of intracellular
effects of C-peptide, seemingly contradictory when studied in different cell
systems and under varying experimental conditions. Perhaps the most compelling
end effect of C-peptide is its stimulatory influence on the microcirculation in
a number of tissues, achieved via both activation and induction of endothelial
nitric oxide synthase. These events are reviewed as are the beneficial effects
of C-peptide and its C-terminal hexa- and pentapeptide segments on the
diabetes-induced reduction of red blood cell deformability. A possible
stimulatory effect by C-peptide on glucose uptake is discussed on the basis of
both in vitro experiments and findings in type 1 diabetes patients. It is,
however, noted that interpretation of such results is confounded by the recent
observation that C-peptide may elicit disaggregation of insulin hexamers,
thereby augmenting the availability of bioactive insulin monomers [##REF##16845606##3##].</p> <p>C-peptide and
its influence on renal physiology, particularly tubular function, are discussed. Likewise, 
C-peptide effects on the peripheral and central nervous system are reviewed. Much new and valuable
information in this central area of C-peptide research has been presented from
Anders Sima's laboratory. The comprehensive findings now point towards a need
for clinical trials and the current situation regarding clinical studies in
patients with diabetic neuropathy is described. Finally, the possibility that
C-peptide may serve as a mediator in the development of atherosclerotic lesions
is discussed. Is the peptide guilty as charged or wrongly accused? Only future
studies can tell but, attesting to the rapid developments in the field of
C-peptide physiology, a study just published reports that physiological as
opposed to elevated concentrations of C-peptide serve to diminish
hyperglycemia-induced vascular smooth muscle proliferation [##UREF##0##4##].</p> <p>The purpose of
this issue is to provide an update of our understanding of C-peptide physiology
and the role of C-peptide deficiency in the development of microvascular
complications of type 1 diabetes. Clearly, there is much more to be learned
about C-peptide. Identification of a receptor or the mechanism whereby
C-peptide interacts with the cell membrane has a high priority. On the clinical
side, further trials of long duration are needed to define the possible role
for C-peptide, together with insulin, in the treatment of type 1 diabetes. A
major obstacle for extended clinical trials has been the lack of GMP-produced
C-peptide suitable for human use. It is hoped that the evidence summarized in
this issue will convey the urgency with which clinical studies are needed and
stimulate the interest of funding organizations and the pharmaceutical industry
to become involved in this rapidly developing field.</p> <p content-type="signature-group">
<named-content content-type="signature"><italic>Thomas Forst</italic>
<italic>Thomas Forst</italic>
</named-content>
</p> <p content-type="signature-group">
<named-content content-type="signature"><italic>John Wahren</italic>
<italic>John Wahren</italic>
</named-content>
</p>
[{"label": ["4"], "surname": ["Cifarelli", "Luppi", "Tse", "He", "Piganelli", "Trucco"], "given-names": ["V", "P", "HM", "J", "J", "M"], "article-title": ["Human proinsulin C-peptide reduces high glucose-induced proliferation and NF-"], "italic": ["\u03ba", "Atherosclerosis"]}]
Exp Diabetes Res. 2008 Sep 18; 2008:384219