Table Of ContentTHE IGF SYSTEM
CoNTEMPORARY ENDOCRINOLOGY
P. Michael Conn, SERIEs BorroR
19. Human Growth Hormone: Basics and Clinical Research, edited by RoY G. SMITH
AND MICHAEL 0. THORNER, 1999
18. Menopause: Endocrinology and Management, edited by DAVID B. SEIFER AND
EliZABETH A. KENNARD, 1999
17. The IGF System: Molecular Biology, Physiology, and Clinical Applications,
edited by RoN G. RosENFELD AND CHARLES T. RoBERTS JR., 1999
16. Neurosteroids: A New Regulatory Function in the Nervous System, edited by
ETIENNE-EMILE BAULIEU, MICHAEL SCHUMACHER, AND PAUL ROBEL, 1999
15. Autoimmune Endocrinopathies, edited by RoBERT VoLPE, 1999
14. Hormone Resistance Syndromes, edited by J. LARRY JAMESON, 1999
13. Hormone Replacement Therapy, edited by A. WAYNE MEIKLE, 1999
12. Insulin Resistance: The Metabolic Syndrome X, edited by GERALD M. REAVEN
AND AMI LAWS, 1999
11. Endocrinology of Breast Cancer, edited by ANDREA MANNI, 1999
10. Molecular and Cellular Pediatric Endocrinology, edited by
STUARTHANDWERGER, 1999
9. The Endocrinology of Pregnancy, edited by FuLLER W. BAZER, 1998
8. Gastrointestinal Endocrinology, edited by GEoRGE H. GREELEY, JR., 1999
7. Clinical Management of Diabetic Neuropathy, edited by ARISTIDIS VEVES, 1998
6. G Proteins, Receptors, and Disease, edited by ALLEN M. SPIEGEL, 1998
5. Natriuretic Peptides in Health and Disease, edited by WILLIS K. SAMSON
AND ELLIS R. LEVIN, 1997
4. Endocrinology of Critical Diseases, edited by K. PATRICK 0BER, 1997
3. Diseases of the Pituitary: Diagnosis and Treatment, edited by
MARGARET E. WIERMAN, 1997
2. Diseases of the Thyroid, edited by LEWIS E. BRAVERMAN, 1997
1. Endocrinology of the Vasculature, edited by JAMES R. SowERS, 1996
THE IGF
SYSTEM
Molecular Biology, Physiology, and Clinical Applications
Edited by
G.c
RoN RoSENFELD, MD
T.
RoBERTs, JR.,
CHARLES PhD
Oregon Health Sciences University
Portland, OR
• SPRINGER SCTENCE+BUSTNESS MEDIA, LLC
© 1999 Springer Science+B usiness Media New York
Originally published by Humana Press Inc. in 1999
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Library of Congress Cataloging-in-Publication Data
The IGF system : molecular biology, physiology, and clinical applications/edited by Ron
G. Rosenfeld, Charles T. Roberts, Jr.
p. em. --(Contemporary endocrinology ; 17)
Includes index.
ISBN 978-1-61737-138-7 ISBN 978-1-59259-712-3 (eBook)
DOI 10.1007/978-1-59259-712-3
1. Somatomedin--Physiological effects. 2. Somatomedin--Pathophysiology. 3.
Insulin-like grow factor-binding proteins. I. Roberts, Charles T. II. Rosenfeld,
Ron G. III. Series: Contemporary endocrinology (Totowa, N.J.)
[DNLM: 1. Insulin-Like Growth Factor !--physiology. 2. Molecular Biol
ogy. 3. Insulin-Like Growth Factor !--therapeutic use. 4. Insulin-Like Growth
Factor 11--physiology. 5. Insulin-Like Growth Factor 11--therapeutic use. 6.
Insulin-Like Growth-Factor-Binding Proteins--physiology. QU 107 124 1999)
QP552.S65133 1999
612'.015756--dc21
DNLM/DLC
for Library of Congress 98-55264
CIP
PREFACE
It has been over 40 years since the original report by Salmon and Daughaday demon
strating that the ability of GH to stimulate sulfation of cartilage was mediated by a
"sulfation factor." In the ensuing decades, it has become apparent that this "sulfation
factor activity" encompasses a complex system ofligands (IGFs), receptors, and carrier
proteins that are, in tum, responsible for a wide array of cellular actions. The IGF system
has been demonstrated to be critically involved in both intrauterine and postnatal growth,
and to have important implications in cancer biology as well, owing to the ability of the
IGFs to function in endocrine, paracrine, and autocrine modes and given the wide distri
bution of IGFs in virtually every organ system.
The contributions to The /GF System reflect the wide span of interest in the IGF system
and its implications for normal and abnormal growth and metabolism. The chapters have
been divided into four broad sections: I. Molecular biology of the IGF system; II. Bio
logical actions of the IGFs; III. IGF physiology; and IV. Clinical aspects of the IGFs. We
have made every effort to highlight the major contemporary themes in IGF biology, but
as is inevitable in such a fast-moving field, perspectives will continue to change as new
information is accumulated. Most importantly, we have remained sensitive to the many
remaining gaps in our knowledge of the role( s) oft he IGF peptides, receptors, and binding
proteins in cell growth and replication, and are always aware of the admonition that "it
is better to have unanswered questions than unquestioned answers."
Ron G. Rosenfeld, MD
Charles T. Roberts,
JR., PhD
v
CONTENTS
Preface ................................................................................................... v
Contributors ......................................................................................... ix
1 Historical Perspective:
The Origins and Development of the Somatomedin Hypothesis ..... 1
William H. Daughaday and William D. Salmon, Jr.
I MOLECUlAR BIOLOGY OF THE IGF SYSTEM
2 Molecular Biology of IGF-I and IGF-II ............................................. 19
Peter Rotwein
3 Regulation of IGF Gene Expression .................................................. 37
P. Elly Holthuizen, Paul H. Steenbergh, and John S. Sussenbach
4 Molecular Biology of the Type 1 IGF Receptor ................................ 63
Haim Werner
5 Molecular Biology of the
IGF-II/Mannose-6-Phosphate Receptor ......................................... 89
Wieland Kiess
6 Molecular Biology of the IGF Binding Proteins .............................. 111
Guck T. Ooi and Yves R. Boisclair
II BIOLOGICAL ACTIONS OF THE IGFs
7 IGF-I Receptor Function: Transducing the IGF-1 Signal
into Intracellular Events ............................................................... 143
Vicky A. Blakesley, Andrew A. Butler, Anatolii P. Koval,
Yumiko Okubo, and Derek LeRoith
8 Type 2 IGF Receptor-Mediated Events ............................................ 165
S. Peter Nissley
9 Alternative IGF-Related Receptors .................................................. 199
Kenneth Siddle and Maria A. Soos
10 IGF Binding Proteins as Modulators of IGF Action ........................ 227
Janet L. Martin and Robert C. Baxter
11 IGF-Independent Actions of the IGF Binding Proteins ................... 257
Youngman Oh and Ron G. Rosenfeld
12 IGF Binding Proteins and Extracellular Matrix ............................... 273
David R. Clemmons
13 Biological Actions of Proteolytic Fragments
of the IGF Binding Proteins ......................................................... 281
Michel Binoux, Claude Lalou, and Sarah Mohseni-Zadeh
14 The IGF Binding Protein Superfamily ............................................. 315
Vivian Hwa, Youngman Oh, Christine P. Burren,
Won Kyu Choi, Donna L. Graham, Angela Ingermann,
Ho-Seong Kim, Abel Lopez-Bermejo, Giuseppe Minniti,
Srinivasa R. Nagalla, Kisoo Pai, Anna Spagnoli,
Peter Vorwerk, Don L. V. Wanek, Elizabeth M. Wilson,
Yoshitaka Yamanaka, Doo Hyun Yang, and Ron G. Rosenfeld
Vll
viii Contents
15 IGFs and Cell Growth ....................................................................... 329
Renato Baserga, Marco Prisco, and Atsushi Hongo
16 Posttranslational Modification of the IGF Binding Proteins ........... 355
Cheryl A. Conover
III IGF PHYSIOLOGY
17 IGFs in the Female Reproductive System ........................................ 379
Linda C. Giudice
18 The IGF Axis in the Male Reproductive System ............................. 407
Stuart A. Weinzimer and Pinchas Cohen
19 IGFs and the Nervous System .......................................................... 425
PhillipS. Leventhal, James W. Russell, and Eva L. Feldman
20 IGF System Components and Their Role in Bone Metabolism ...... 457
Subburaman Mohan and David J. Baylink
21 IGFs and Skeletal Muscle ................................................................. 497
Stephen M. Rosenthal
22 IGFs and the Digestive Tract.. .......................................................... 517
P. Kay Lund
23 Actions of IGF System Proteins from Studies of Transgenic
and Gene Knockout Models ......................................................... 545
A. Joseph D'Ercole
IV CLINICAL ASPECTS OF THE IGFs
24 Metabolic Effects of IGFs ................................................................ 577
Jiirgen Zap/, E. Rudolph Froesch, and Christoph Schmid
25 Clinical Uses of IGF-1 and IGF Binding ProteinA ssays ................. 617
Louis E. Underwood
26 IGF Binding Protein Proteolysis in Various Clinical States ............ 633
Laura A. Maile, Anna L. Crown, and Jeff M.P. Holly
27 IGF Deficiency .................................................................................. 651
Katie A. Woods and Martin 0. Savage
28 Tumor Hypoglycemia Linked to IGF-11 ........................................... 675
Christian A. Koch, Kristina I. Rother, and Jesse Roth
29 IGFs in the Evaluation of Acromegaly ............................................. 699
Marlys R. Drange and Shlomo Melmed
30 IGF in the Treatment of Diabetes ..................................................... 721
Robert A. Gabbay and Alan C. Moses
31 IGF-I Treatment of Growth Hormone Insensitivity ......................... 739
Arlan L. Rosenbloom
Index .................................................................................................. 771
CONTRIBUTORS
RENATO BASERGA, MD, Department of Microbiology and Immunology, Kimmel
Cancer Center, Thomas Jefferson University, Philadelphia, PA
RoBERT C. BAXTER, PHD, DSC, Kolling Institute of Medical Research, Royal North
Shore Hospital, St. Leonards, Australia
DAVID J. BAYLINK, MD, Mineral Metabolism, Jerry L. Pettis VA Medical Center;
Departments of Medicine and Biochemistry, Loma Linda University,
Loma Linda, CA
MICHEL BINoux, MD, Institut National de la Sante et de la Recherche Medicale,
Hopital Saint Antoine, Paris, France
VICKY A. BLAKESLEY, MD, PHD, Diabetes Branch, National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
YvEs R. BOISCLAIR, PHD, Department ofA nimal Science, Cornell University,
Ithaca, NY
CHRISTINE P. BuRREN, MD, Department of Pediatrics, School of Medicine, Oregon
Health Sciences University, Portland, OR
ANDREW A. BuTLER, PHD, Diabetes Branch, National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
WoN KYu CHOI, MD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
DAVID R. CLEMMONS, MD, Department of Medicine, University of North Carolina
at Chapel Hill, Chapel Hill, NC
PINCHAS CoHEN, MD, Department of Pediatrics, University of California
at Los Angeles, Los Angeles, CA
CHERYL A. CoNOVER, PHD, Endocrine Research Unit, Mayo Clinic and Mayo
Foundation, Rochester, MN
ANNAL. CROWN, MD, University of Bristol Division of Surgery, Department
of Hospital Medicine, Bristol Royal Infirmary, Bristol, United Kingdom
WILLIAM H. DAUGHADAY, MD, Balboa Island, CA
MARLYS R. DRANGE, MD, PHD, Division of Endocrinology and Metabolism,
Cedars-Sinai Medical Center, Los Angeles, CA
A. JosEPH D'ERCOLE, MD, Department of Pediatrics, University of North Carolina
at Chapel Hill, Chapel Hill, NC
EvA L. FELDMAN, MD, PHD, Department of Neurology, University of Michigan,
Ann Arbor, MI
E. RuDOLPH FROESCH, MD, Department of Internal Medicine, Division
of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland
RoBERT A. GABBAY, MD, PHD, Section of Endocrinology, Diabetes, and Metabolism,
Hershey Medical Center, Penn State Geisinger Health System, Hershey, PA
LINDA C. GIUDICE, MD, PHD, Division of Reproductive Endocrinology and Fertility,
Department of Obstetrics and Gynecology, Stanford University Medical Center,
Stanford, CA
DoNNA L. GRAHAM, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
ix
X Contributors
VIVIAN HwA, PHD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
JEFF M.P. HoLLY, PHD, University of Bristol Division of Surgery, Department
of Hospital Medicine, Bristol Royal Infirmary, Bristol, United Kingdom
P. ELLY HoLTHUIZEN, PHD, Laboratory for Physiological Chemistry, Utrecht
University, Utrecht, The Netherlands
ATSUSHI HoNGO, PHD, Department of Microbiology and Immunology, Kimmel Cancer
Center, Thomas Jefferson University, Philadelphia, PA
ANGELA lNGERMANN, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
WIELAND KIEss, MD, Children's Hospital, University of Leipzig, Leipzig, Germany
Ho-SEONG KIM, MD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
CHRISTIAN A. KocH, MD, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, MD
ANATOLII P. KovAL, PHD, Diabetes Branch, National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
CLAUDE LALOU, PHD, Institut National de la Sante et de la Recherche Medicate,
Hopital Saint Antoine, Paris, France
DEREK LEROITH, MD, PHD, Diabetes Branch, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
PHILLIP S. LEVENTHAL, PHD, Department of Neurology, University of Michigan,
Ann Arbor, MI
ABEL LOPEZ-BERMEJO, MD, Department of Pediatrics, School of Medicine, Oregon
Health Sciences University, Portland, OR
P. KAY LUND, PHD, Departments of Physiology and Pediatrics and Center
for Gastrointestinal Biology and Disease, University of North Carolina
at Chapel Hill, Chapel Hill, NC
LAURA A. MAILE, PHD, University of Bristol Division of Surgery, Department
of Hospital Medicine, Bristol Royal Infirmary, Bristol, United Kingdom
JANET L. MARTIN, PHD, Kolling Institute of Medical Research, Royal North Shore
Hospital, St. Leonards, Australia
SHLOMO MELMED, MD, Research Institute, UCLA School of Medicine, Cedars-Sinai
Medical Center, Los Angeles, CA
GIUSEPPE MINNITI, MD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
SuBBURAMAN MOHAN, PHD, Mineral Metabolism, Jerry L. Pettis VA Medical Center;
Departments of Medicine, Biochemistry, and Physiology, Lorna Linda University,
Lorna Linda, CA
SARAH MoHSENI-ZADEH, PHD, Institut National de la Sante et de Ia Recherche
Medicate, Hopital Saint Antoine, Paris, France
ALAN C. MosEs, MD, General Clinical Research Center and Division
of Endocrinology, Beth Israel Deaconess Medical Center, Harvard
Medical Center, Boston, MA
SRINIVASA R. NAGALLA, MD, Department of Pediatrics, School of Medicine, Oregon
Health Sciences University, Portland, OR
Contributors xi
S. PETER NISSLEY, MD, National Cancer Institute, National Institutes of Health,
Bethesda, MD
YouNGMAN OH, PHD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
YuMIKO OKUBO, MD, Diabetes Branch, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Bethesda, MD
GucK T. Om, PHD, Prince Henry's Institute of Medical Research, Clayton, Victoria,
Australia
K1soo PAI, MD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
MARCO PRISCO, PHD, Department of Microbiology and Immunology, Kimmel Cancer
Center, Thomas Jefferson University, Philadelphia, PA
ARLAN L. RosENBLOOM, MD, Department of Pediatrics, University of Florida College
of Medicine, Children's Medical Services Center, Gainesville, FL
RoN G. RosENFELD, MD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
STEPHEN M. RosENTHAL, MD, Department of Pediatrics, University of California
San Francisco, San Francisco, CA
JESSE RoTH, MD, FACP, Department of Medicine, Johns Hopkins University School
of Medicine, Baltimore, MD
KRISTINA I. RoTHER, MD, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, MD
PETERS. RoTWEIN, MD, Department of Medicine, Division of Molecular Medicine,
Oregon Health Sciences University, Portland, OR
JAMES W. RussELL, MD, Department of Neurology, University of Michigan,
Ann Arbor, MI
WILLIAM D. SALMON, Jr., MD
MARTIN 0. SAVAGE, MA, MD, FRCP, Paediatric Endocrinology, St. Batholomew's
Hospital, London, United Kingdom
CHRISTOPH ScHMID, MD, Department of Internal Medicine, Division of Endocrinology
and Diabetes, University Hospital, Zurich, Switzerland
KENNETH SIDDLE, PHD, Department of Clinical Biochemistry, University
of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
MARIA A. Soos, PHD, Department of Clinical Biochemistry, University of Cambridge,
Addenbrooke's Hospital, Cambridge, United Kingdom
ANNA SPAGNOLI, MD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
PAUL H. STEENBERGH, PHD, Laboratory for Physiological Chemistry, Utrecht
University, Utrecht, The Netherlands
JoHN S. SussENBACH, PHD, Laboratory for Physiological Chemistry, Utrecht
University, Utrecht, The Netherlands
Loms E. UNDERWOOD, MD, Division of Pediatric Endocrinology, School of Medicine,
University of North Carolina at Chapel Hill, Chapel Hill, NC
PETER VoRWERK, MD, Department of Pediatrics, School of Medicine, Oregon Health
Sciences University, Portland, OR
