Diabetes & C-Peptide: Scientific and Clinical Aspects

176 Pages·2011·4.324 MB·English

by  Anders A.F. Sima

C D
ONTEMPORARY IABETES
Series Editor: Aristidis Veves, MD, DSc
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Anders A.F. Sima
Editor
Diabetes & C-Peptide
Scientifi c and Clinical Aspects
Editor
Anders A.F. Sima, MD, PhD, FRCP(C)
Professor, Departments of Pathology and Neurology
Wayne State University
Detroit, MI, USA
[email protected]
ISBN 978-1-61779-390-5 e-ISBN 978-1-61779-391-2
DOI 10.1007/978-1-61779-391-2
Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2011939746
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Foreword

Type 1 diabetes has in recent years shown an alarming increase in incidence,
particularly in heavily populated regions of the globe, occurring at steadily
younger ages. This increase in incidence of type 1 diabetes will likely be
paralleled by a similar increase in the frequency of the disorder’s debilitating
secondary complications.
Since its discovery, C-peptide has evolved from a non-bioactive marker of
b -cell function to a highly signifi cant multifunctional hormone in the patho-
biology of diabetes and its complications. The wealth of information that has
appeared over the last decade and a half is reviewed in depth in this volume.
This review provides current insights into the multiple physiological func-
tions of C-peptide, its pathophysiological role in the development of chronic
complications and ultimately the signifi cance of its replacement in the pre-
vention and treatment of these complications in patients with type 1 diabetes.
The chapters are authored by the leading investigators in the fi eld. This vol-
ume of C ontemporary Diabetes provides the fi rst comprehensive collection
of current, detailed and critical reviews on C-peptide biology. It is highly
recommended to clinicians, diabetologists, residents, basic scientists, and
students who are seeking insights into C-peptide and the rapidly growing
biology surrounding this versatile and highly relevant hormone.
Ann Arbor, MI, USA Eva L. Feldman, MD, PhD
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Preface
It is well known that C-peptide, the connecting peptide of the proinsulin
molecule, is an important part in the biosynthesis of insulin in that it facilitates
its correct folding. Following the cleavage of proinsulin into insulin and
C-peptide, both peptides are stored in the secretory granules of pancreatic
b -cells and are released into the circulation in equimolar concentrations. After
its discovery in 1967 by Steiner et al, C-peptide was anticipated to have physi-
ological effects similar to those of insulin. Disappointingly, no effects could be
documented with respect to glucose or lipid metabolism, and C-peptide was
written off as a non-bioactive peptide. It was not until the 1990s that C-peptide
was revisited in a clinical setting. A series of studies were performed on type
1 diabetic patients to whom C-peptide was administered. These studies dem-
onstrated that replacement of physiological levels of C-peptide led to improve-
ments in kidney function and nerve conduction velocities in type 1 diabetic
patients. C-peptide also augmented capillary blood fl ow in skeletal muscle,
skin, and the kidney. These fi ndings led to a renewed interest in the physiologi-
cal function of C-peptide and possible pathophysiologic roles of its defi ciency
in type 1 diabetes. During the last decade and a half there has been a steadily
increasing number of reports on C-peptide, its physiology, as well as the effects
of its replacement on type 1 diabetic complications. The information to date
includes, in vitro studies pertaining to its interaction with cell membranes,
internalization into endosomes and nucleoli, its function in red blood cells, its
interaction with insulin signaling mechanisms as well as direct interaction
between insulin and C-peptide. However, a remaining obstacle in the charac-
terization of the physiological role of C-peptide is the existence of a specifi c
C-peptide receptor, which remains elusive. Instead it has been suggested that
the effects are mediated via G-protein coupled receptor mechanisms and/or by
enhancing insulin signaling via its direct interaction with insulin signaling and
with oligomeric insulin.
The revealed actions of C-peptide result in a myriad of cellular effects,
including anti-infl ammatory effects on the vasculature and the central ner-
vous system, anti-apoptotic and anti-oxidative effects, gene regulatory effects
pertaining to trophic factors, and cell-adhesive molecules perturbed in type 1
diabetes. In vivo animal studies of type 1 diabetes have described functional
and structural benefi ts on complications affecting the vasculature, kidney, and
peripheral and central nervous systems. Several clinical studies have appeared
recently, confi rming the benefi ts of C-peptide replacement on peripheral
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nerve and kidney function. Therefore, there exists today a wealth of information
attesting to a multitude of sometimes contradictory physiological effects in
different tissue systems mediated by C-peptide. The data to date strongly support
the notion that together with regular insulin therapy in type 1 diabetes,
replacement of C-peptide will have additional benefi cial effects on the pre-
vention and treatment of complications accompanying type 1 diabetes.
This volume of Contemporary Diabetes provides an update of the current
knowledge of C-peptide’s physiological function and the role of its defi ciency
in the development of type 1 diabetic complications. This rapidly moving
fi eld is dealt with in detail by the most prominent investigators in the fi eld.
The evidence summarized in this volume will hopefully convey the urgency
with which both continuing mechanistic studies and clinical trials are needed.
In refl ection, it is nearly 100 years since the discovery of insulin and yet we
have no causal and effective therapy for the complications accompanying
type 1 diabetes.
I wish to thank Professor Aristides Veves, Harvard Medical School for
inviting me to put together this volume of the Contemporary Diabetes series.
Also, I thank Richard Lansing and Maureen Alexander of Springer Verlag for
their help, encouragement, and support. I am grateful to Professor John
Wahren for his support. Finally, I wish to sincerely thank all the authors for
their relentless efforts and their invaluable contributions to this volume.
Detroit, MI, USA Anders A.F. Sima, MD, PhD, FRCP(C)
Contents
1 C-Peptide and Insulin: A Happy Marriage .............................. 1
Donald F. Steiner
2 Peptide Interactions of Proinsulin C-Peptide ........................... 7
Charlotte Nerelius, Emma Lindahl, Michael Landreh,
and Hans Jörnvall
3 The Effect of Combined C-Peptide and Zinc
on Cellular Function ................................................................... 17
Dana M. Spence
4 C-Peptide Signaling in the Kidney and Protection
from Diabetic Nephropathy ....................................................... 31
Nigel J. Brunskill
5 Role of C-Peptide in the Regulation of Microvascular
Blood Flow ................................................................................... 45
Thomas Forst, Matthias M. Weber, Thomas Kunt,
and Andreas Pfützner
6 Is NO-eNOS a Target for C-Peptide Action
and Its Protective Effects on Diabetic Nephropathy? .............. 55
Kazuhiro Kimura and Akihiro Kamikawa
7 Renoprotective Effects of C-Peptide
on Type 1 Diabetes ...................................................................... 67
Lina Nordquist, Åsa Kallas, Sara Stridh, Fredrik Palm,
and John Wahren
8 The Mechanisms Underlying the Effects of C-Peptide
on Type 1 Diabetic Neuropathy ................................................. 79
Hideki Kamiya, Wei-Xian Zhang, and Anders A.F. Sima
9 C-Peptide and Type 1 Diabetic Encephalopathy ...................... 93
Anders A.F. Sima and Wei-Xian Zhang
10 C-Peptide: A New Molecule
with Anti-Infl ammatory Properties ........................................... 111
Jaime Haidet, Vincenza Cifarelli, Xuehui Geng,
Massimo Trucco, and Patrizia Luppi
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