C-peptide as a Mediator of Lesion
Development in Early Diabetes—
A Novel Hypothesis
Nikolaus Marx ⁎
Patients with insulin resistance and early type 2 diabetes exhibit an
increased propensity to develop a diffuse and extensive pattern of
arteriosclerosis. Various risk factors such as hypertension, dyslipidemia,
and a proinflammatory and prothrombotic state contribute to ather-
ogenesis in this high-risk population, but the pathophysiologic mechan-
isms leading to this characteristic pattern remain largely unexplored.
Recent data suggest that the proinsulin cleavage product C-peptide could
play a causal role in atherogenesis by promoting monocyte and CD4-
positive lymphocyte recruitment in early arteriosclerotic lesions and by
inducing the proliferation of vascular smooth muscle cells. The following
review will summarize the effects of C-peptide in vascular cells and
discuss the potential relevance of such C-peptide effects on atherogenesis
in diabetic patients. (Trends Cardiovasc Med 2008;18:67–71) n 2008,
Elsevier Inc.
Introduction
Macrovascular events such as myocar-
dial infarction and stroke are the major
causes of death in patients with diabetes
mellitus. These patients as well as those
with insulin resistance typically exhibit
an increased propensity to develop a
diffuse and extensive pattern of arterio-
sclerosis (Beckman et al. 2002). Various
risk factors such as hypertension, dysli-
pidemia, and a proinflammatory and
prothrombotic state contribute to ather-
ogenesis in this high-risk population,
but the pathophysiologic mechanisms
leading to this characteristic pattern
remain largely unexplored. Several fac-
tors such as high glucose and advanced
glycation end products–receptors for
advanced glycation end products (AGE–
RAGE) interaction are considered to be of
importance in this context, and recent
data suggest that the proinsulin cleavage
product C-peptide could play a causal role
in atherogenesis. The following review
will summarize the effects of C-peptide
in vascular cells and discuss the potential
relevance of such C-peptide effects on
atherogenesis in diabetic patients.
Arteriosclerosis Development
According to our current understanding,
atherogenesis is an inflammatory process
in the vessel wall with different phases and
stages (Ross 1999). The early phase is
characterized by a disturbance of regular
endothelial function, called endothelial
dysfunction. Under certain circumstances
and under the influence of risk factor such
as hypertension or diabetes, the endothe-
lium exhibits an increased permeability,
which allows plasma compounds such as
lipoproteins to enter the vessel wall and to
be deposited there. In addition, the
endothelium is activated in this phase,
thus, releasing chemotactic proteins such
as MCP-1, a monocyte chemoattractant, or
RANTES and IP-10, both chemoattrac-
tants for lymphocytes. These chemokines
attract inflammatorycells,mainlymono-
cytes and CD4-positive lymphocytes, to
adhere to endothelial adhesion molecules,
with subsequent migration of these cells
into the vessel wall. Monocytes, once
migrated into the subendothelial space,
become macrophages, expressing scaven-
ger receptors on their surface, which
mediate the uptake of lipoprotein particles
such as oxidized low-density lipoprotein
(LDL). Through lipid uptake, these cells
differentiate to foam cells, the classic
cellular substrate of arteriosclerotic
lesions. These macrophage foam cells
then express additional proinflammatory
and proatherogenic mediators such as
cytokines, matrix metalloproteinases, and
reactive oxygen species, as well as procoa-
gulant molecules such as tissue factor,
whichallactonothercellsinthevessel
wall, thus, promoting lesion development.
The second inflammatory cell type
recruited during endothelial dysfunction
istheCD4-positivelymphocyte.Thesecells
are also attracted by chemokines and enter
the vessel wall as naïve or so-called Th0
cells. In the subendothelial space, these
Th0 cells encounter antigens like oxidized
LDL and subsequently differentiate to Th1
cells, thus, secreting proinflammatory
cytokines such as interferon γ,tumor
necrosis factor α,andinterleukin2.Some
of these cytokines, such as interferon γ,
increase the expression of chemokines in
the endothelium, thus, creating a vicious
cycle of cell recruitment and cell activa-
tion. Moreover, these chemokines activate
other cells in the vessel wall, such as
macrophages and vascular smooth muscle
cells (SMCs), thus, orchestrating the
inflammatory response in the vasculature
(Hansson 2005). Once these cells have
entered the vessel wall, their contribution
to the local inflammatory process leads to
the development of fatty streaks. These
fatty streaks are characterized by foam
cells, proinflammatory CD4-positive lym-
phocytes, as well as vascular SMCs, which
proliferate in the media and then migrate
into the developing lesion. As plaque
development continues, advanced and
potentially complicated lesions occur.
Two types of plaques can be distinguished
here. The stable plaque is characterized
by a necrotic lipid core, which is covered
Nikolaus Marx is at the Department of Inter-
nal Medicine II—Cardiology, University of
Ulm, Germany.
⁎ Address correspondence to: Dr. Nikolaus
Marx, Department of Internal Medicine II—
Cardiology, University of Ulm, Robert-Koch-
Str. 8, D-89081 Ulm, Germany. Tel.: (+49)
731 500 45000; fax: (+49) 731 500 45025;
e-mail: nikolaus.marx@uniklinik-ulm.de.
© 2008, Elsevier Inc. All rights reserved.
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TCM Vol. 18, No. 2, 2008