The role of liver-derived insulin-like growth factor-I

Endocrine Reviews

Volumn 30, Issue 5, 2009, Pages 494-535

  Ohlsson, Claes ^a   Mohan, Subburaman ^c   Sjögren, Klara ^a   Tivesten, Åsa ^a   Isgaard, Jörgen ^a   Isaksson, Olle ^a   Jansson, John Olov ^b   Svensson, Johan ^a  

^a SAHLGRENSKA UNIVERSITY HOSPITAL   (Sweden)

^b UNIVERSITY OF GOTHENBURG   (Sweden)

^c Jerry L Pettis Memorial VA Medical Center   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; GROWTH HORMONE; INSULIN; RECOMBINANT SOMATOMEDIN C; SOMATOMEDIN C;

ADENOID HYPERTROPHY; ARTHRALGIA; BODY COMPOSITION; BODY FAT; BODY GROWTH; BONE GROWTH; BONE MASS; BRAIN FUNCTION; CARBOHYDRATE METABOLISM; CARDIOVASCULAR SYSTEM; CENTRAL NERVOUS SYSTEM; CLINICAL TRIAL; COARSE FACE; CORTICAL BONE; DIABETES MELLITUS; DRUG POTENTIATION; GENE DELETION; GENE INACTIVATION; GENE MUTATION; GROWTH HORMONE DEFICIENCY; GROWTH HORMONE RELEASE; GROWTH PLATE; GROWTH RETARDATION; HIPPOCAMPUS; HORMONE DEFICIENCY; HORMONE RELEASE; HUMAN; HYPERTROPHY; HYPOGLYCEMIA; INJECTION SITE LIPOHYPERTROPHY; INJECTION SITE REACTION; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN SENSITIVITY; INTRACRANIAL PRESSURE; KIDNEY; KIDNEY SIZE; LIPID METABOLISM; LIVER; LIVER FUNCTION; LIVER REGENERATION; LIVER SIZE; MYALGIA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORGAN SIZE; PHENOTYPE; PRIORITY JOURNAL; PROSTATE; PROSTATE HYPERTROPHY; PROTEIN EXPRESSION; REVIEW; SHORT STATURE; SIDE EFFECT; SODIUM RETENTION; SOMATOMEDIN C DEFICIENCY; SPATIAL MEMORY; TONSIL HYPERTROPHY; TRABECULAR BONE; TUMOR; VASCULAR RESISTANCE;

ANIMALS; BODY COMPOSITION; BONE AND BONES; BONE DEVELOPMENT; GROWTH HORMONE; HUMANS; INSULIN-LIKE GROWTH FACTOR I; LIVER;

EID: 68549092476     PISSN: 0163769X     EISSN: None     Source Type: Journal    
DOI: 10.1210/er.2009-0010     Document Type: Review

References (388)

1. Daughaday WH, Rotwein P 1989 Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10:68-91
2. Isaksson OG, Lindahl A, Nilsson A, Isgaard J 1987 Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth. Endocr Rev 8:426-438
3. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC 1998 Growth hormone and bone. Endocr Rev 19:55-79
4. Le Roith D, Bondy C, Yakar S, Liu JL, Butler A 2001 The somatomedin hypothesis: 2001. Endocr Rev 22:53-74
5. Samani AA, Yakar S, LeRoith D, Brodt P 2007 The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28:20-47
6. Yakar S, Sun H, Zhao H, Pennisi P, Toyoshima Y, Setser J, Stannard B, Scavo L, Leroith D 2005 Metabolic effects of IGF-I deficiency: lessons from mouse models. Pediatr Endocrinol Rev 3:11-19
7. Jansson JO, Edén S, Isaksson O 1985 Sexual dimorphism in the control of growth hormone secretion. Endocr Rev 6:128-150
8. Rajaram S, Baylink DJ, Mohan S 1997 Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 18:801-831
9. Jones JI, Clemmons DR 1995 Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3-34
10. Boisclair YR, Rhoads RP, Ueki I, Wang J, Ooi GT 2001 The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. J Endocrinol 170:63-70
11. Sjögren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Törnell J, Isaksson OG, Jansson JO, Ohlsson C 1999 Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci USA 96:7088-7092
12. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D 1999 Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 96:7324-7329
13. Sims NA, Clément-Lacroix P, Da Ponte F, Bouali Y, Binart N, Moriggl R, Goffin V, Coschigano K, Gaillard-Kelly M, Kopchick J, Baron R, Kelly PA 2000 Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5. J Clin Invest 106:1095-1103
14. Sjögren K, Bohlooly-Y M, Bohlooly YM, Olsson B, Coschigano K, Törnell J, Mohan S, Isaksson OG, Baumann G, Kopchick J, Ohlsson C 2000 Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor -/- mice. Biochem Biophys Res Commun 267:603-608
15. Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, LozykowskiM,OkadaS, Cataldo L, Coschigamo K,Wagner TE, Baumann G, Kopchick JJ 1997Amammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci USA 94:13215-13220
16. Wit JM, van UnenH1992 Growth of infants with neonatal growth hormone deficiency. Arch Dis Child 67:920-924
17. Savage MO, Blum WF, Ranke MB, Postel-Vinay MC, Cotterill AM, Hall K, Chatelain PG, Preece MA, Rosenfeld RG 1993 Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab 77:1465-1471
18. Wajnrajch MP, Gertner JM, Harbison MD, Chua Jr SC, Leibel RL 1996 Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet 12:88-90
19. Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A 2001 Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 229:141-162
20. Efstratiadis A 1998 Genetics of mouse growth. Int J Dev Biol 42:955-976
21. Baker J, Liu JP, Robertson EJ, Efstratiadis A 1993 Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73-82
22. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A 1993 Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59-72
23. Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Dalton D, Gillett N, Stewart TA 1993 IGF-I is required for normal embryonic growth in mice. Genes Dev 7:2609-2617
24. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, KiessW,Klammt J, Kratzsch J, Osgood D, Pfäffle R, Raile K, Seidel B, Smith RJ, Chernausek SD 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349: 2211-2222
25. Woods KA, Camacho-Hübner C, Savage MO, Clark AJ 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335:1363-1367
26. Arends N, Johnston L, Hokken-Koelega A, van Duijn C, de Ridder M, Savage M, Clark A 2002 Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab 87:2720
27. Vaessen N, Janssen JA, Heutink P, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM 2002 Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight. Lancet 359:1036-1037
28. Walenkamp MJ, WitJM2007 Genetic disorders in theGH IGF-I axis in mouse and man. Eur J Endocrinol 157(Suppl 1):S15-S26
29. Eigenmann JE, Amador A, Patterson DF 1988 Insulin-like growth factor I levels in proportionate dogs, chondrodystrophic dogs and in giant dogs. Acta Endocrinol (Copenh) 118:105-108
30. Tryfonidou MA, Holl MS, Vastenburg M, Oosterlaken-Dijksterhuis MA, Birkenhäger-Frenkel DH, van den Brom WE, Hazewinkel HA 2003 Hormonal regulation of calcium homeostasis in two breeds of dogs during growth at different rates. J Anim Sci 81:1568-1580
31. Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA 2007 A single IGF1 allele is a major determinant of small size in dogs. Science 316:112-115
32. Daughaday WH, Hall K, Raben MS, Salmon Jr WD, van den Brande JL, van Wyk JJ 1972 Somatomedin: proposed designation for sulphation factor. Nature 235:107
33. DaughadayW1981 Growth hormone and the somatomedins. In: DaughadayWH,ed. Endocrine control of growth. New York: Elsevier; 1-24
34. D'Ercole AJ, Applewhite GT, Underwood LE 1980 Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev Biol 75:315-328
35. D'Ercole AJ, Stiles AD, Underwood LE 1984 Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action. Proc Natl Acad Sci USA 81:935-939
36. Isgaard J, Carlsson L, Isaksson OG, Jansson JO 1988 Pulsatile intravenous growth hormone (GH) infusion to hypophysectomized rats increases insulin-like growth factor I messenger ribonucleic acid in skeletal tissues more effectively than continuous GH infusion. Endocrinology 123: 2605-2610
37. Isgaard J,Möller C, Isaksson OG, Nilsson A, Mathews LS, Norstedt G 1988 Regulation of insulin-like growth factor messenger ribonucleic acid in rat growth plate by growth hormone. Endocrinology 122:1515-1520
38. Lowe Jr WL, Roberts Jr CT, Lasky SR, LeRoith D 1987 Differential expression of alternative 5' untranslated regions in mRNAs encoding rat insulin-like growth factor I. Proc Natl Acad Sci USA 84:8946-8950
39. Lowe Jr WL, Lasky SR, LeRoith D, Roberts Jr CT 1988 Distribution and regulation of rat insulin-like growth factor I messenger ribonucleic acids encoding alternative carboxyterminal E-peptides: evidence for differential processing and regulation in liver. Mol Endocrinol 2:528-535
40. Roberts Jr CT, Lasky SR, Lowe Jr WL, Seaman WT, Le-RoithD1987 Molecular cloning of rat insulin-like growth factor I complementary deoxyribonucleic acids: differential messenger ribonucleic acid processing and regulation by growth hormone in extrahepatic tissues. Mol Endocrinol 1:243-248
41. Isaksson OG, Jansson JO, Gause IA 1982 Growth hormonestimulates longitudinal bone growth directly. Science 216:1237-1239
42. RussellSM,SpencerEM1985 Local injections ofhumanor rat growth hormone or of purified human somatomedin-C stimulate unilateral tibial epiphyseal growth in hypophysectomized rats. Endocrinology 116:2563-2567
43. Isgaard J, Nilsson A, Lindahl A, Jansson JO, Isaksson OG 1986 Effects of local administration of GH and IGF-1 on longitudinal bone growth in rats. Am J Physiol 250:E367-E372
44. Nilsson A, Isgaard J, Lindahl A, Dahlström A, Skottner A, IsakssonOG1986 Regulation by growth hormone of number of chondrocytes containing IGF-I in rat growth plate. Science 233:571-574
45. Schlechter NL, Russell SM, Greenberg S, Spencer EM, Nicoll CS 1986 A direct growth effect of growth hormone in rat hindlimb shown by arterial infusion. Am J Physiol 250:E231-E235
46. Isaksson OG, Ohlsson C, Nilsson A, Isgaard J, Lindahl A 1991 Regulation of cartilage growth by growth hormone and insulin-like growth factor I. Pediatr Nephrol 5:451-453
47. Schlechter NL, Russell SM, Spencer EM, Nicoll CS 1986 Evidence suggesting that the direct growth-promoting effect of growth hormone on cartilage in vivo is mediated by local production of somatomedin. Proc Natl Acad Sci USA 83:7932-7934
48. Savage MO, Attie KM, David A, Metherell LA, Clark AJ, Camacho-Hübner C 2006 Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders. Nat Clin Pract Endocrinol Metab 2:395-407
49. Backeljauw PF, Underwood LE 2001 Therapy for 6.5-7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center study. J Clin Endocrinol Metab 86: 1504-1510
50. Mohan S, Richman C, Guo R, Amaar Y, Donahue LR, Wergedal J, Baylink DJ 2003 Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormone-dependent and -independent mechanisms. Endocrinology 144:929-936
51. Kühn R, Schwenk F, Aguet M, RajewskyK1995 Inducible gene targeting in mice. Science 269:1427-1429
52. Govoni KE, Lee SK, Chung YS, Behringer RR, Wergedal JE, Baylink DJ, Mohan S 2007 Disruption of insulin-like growth factor-I expression in type IIαI collagen-expressing cells reduces bone length and width in mice. Physiol Genomics 30:354-362
53. Govoni KE, Wergedal JE, Florin L, Angel P, Baylink DJ, Mohan S 2007 Conditional deletion of insulin-like growth factor-I in collagen type 1α2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion. Endocrinology 148:5706-5715
54. Stratikopoulos E, Szabolcs M, Dragatsis I, Klinakis A, EfstratiadisA2008Thehormonalaction ofIGF1in postnatal mouse growth. Proc Natl Acad Sci USA 105:19378-19383
55. Ohlsson C, Sjögren K, Jansson JO, Isaksson OG 2000 The relative importance of endocrine versus autocrine/paracrine insulin-like growth factor-I in the regulation of body growth. Pediatr Nephrol 14:541-543
56. Fan Y, Menon RK, Cohen P, Hwang D, Clemens T, Digirolamo DJ, Kopchick JJ, Leroith D, Trucco M, Sperling MA 2009 Liver-specific deletion of the growth hormone receptor reveals essential role of GH signaling in hepatic lipid metabolism. J Biol Chem 284:19937-19944
57. Wallenius K, Sjögren K, Peng XD, Park S, Wallenius V, Liu JL, Umaerus M, Wennbo H, Isaksson O, Frohman L, Kineman R, Ohlsson C, JanssonJO2001 Liver-derived IGF-I regulates GH secretion at the pituitary level in mice. Endocrinology 142:4762-4770
58. Sjögren K, Sheng M, Movérare S, Liu JL, Wallenius K, Törnell J, Isaksson O, Jansson JO, Mohan S, Ohlsson C 2002 Effects of liver-derived insulin-like growth factor I on bone metabolism in mice. J Bone Miner Res 17:1977-1987
59. LeRoith D 2008 Clinical relevance of systemic and local IGF-I: lessons from animal models. Pediatr Endocrinol Rev 5(Suppl 2):739-743
60. Ueki I,OoiGT,TremblayML,HurstKR,Bach LA, Boisclair YR 2000 Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. Proc Natl Acad Sci USA 97:6868-6873
61. Yakar S, Rosen CJ, Bouxsein ML, Sun H, Mejia W, Kawashima Y, Wu Y, Emerton K, Williams V, Jepsen K, Schaffler MB, Majeska RJ, Gavrilova O, Gutierrez M, Hwang D, Pennisi P, Frystyk J, Boisclair Y, Pintar J, Jasper H, Domene H, Cohen P, Clemmons D, LeRoith D 2009 Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. FASEB J 23:709-719
62. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, Le-Roith D 2002 Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 110:771-781
63. Chin E, Zhou J, Dai J, Baxter RC, Bondy CA 1994 Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complex. Endocrinology 134:2498-2504
64. Jaques G, Noll K, Wegmann B, Witten S, Kogan E, Radulescu RT, Havemann K 1997 Nuclear localization of insulin-like growth factor binding protein 3 in a lung cancer cell line. Endocrinology 138:1767-1770
65. Schedlich LJ, Young TF, Firth SM, Baxter RC 1998 Insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 share a common nuclear transport pathway in T47D human breast carcinoma cells. J Biol Chem 273: 18347-18352
66. Yamanaka Y, Fowlkes JL, Wilson EM, Rosenfeld RG, Oh Y 1999 Characterization of insulin-like growth factor binding protein-3 (IGFBP-3) binding to human breast cancer cells: kinetics of IGFBP-3 binding and identification of receptor binding domain on the IGFBP-3 molecule. Endocrinology 140:1319-1328
67. Schedlich LJ, Le Page SL, Firth SM, Briggs LJ, Jans DA, Baxter RC 2000 Nuclear import of insulin-like growth factor-binding protein-3 and -5 is mediated by the importin β subunit. J Biol Chem 275:23462-23470
68. Lee KW, Ma L, Yan X, Liu B, Zhang XK, Cohen P 2005 Rapid apoptosis induction by IGFBP-3 involves an insulinlike growth factor-independent nucleomitochondrial translocation of RXRα/Nur77. J Biol Chem 280:16942-16948
69. Kaplan SA, Cohen P 2007 The somatomedin hypothesis 2007: 50 years later. J Clin Endocrinol Metab 92:4529 - 4535
70. Liao L, Dearth RK, Zhou S, Britton OL, Lee AV,XuJ 2006 Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency. Endocrinology 147:3877-3888
71. Ohlsson C, Nilsson A, Isaksson OG, LindahlA1992 Effect of growth hormone and insulin-like growth factor-I on DNA synthesis and matrix production in rat epiphyseal chondrocytes in monolayer culture. J Endocrinol 133:291-300
72. Nilsson A, Ohlsson C, Isaksson OG, Lindahl A, Isgaard J 1994 Hormonal regulation of longitudinal bone growth. Eur J Clin Nutr 48(Suppl 1):S150-S158; discussion S158-S160
73. Ohlsson C, Nilsson A, Isaksson O, LindahlA1992 Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate. Proc Natl Acad Sci USA 89:9826-9830
74. Wang J, Zhou J, Cheng CM, Kopchick JJ, Bondy CA 2004 Evidence supporting dual, IGF-I-independent and IGF-Idependent, roles for GH in promoting longitudinal bone growth. J Endocrinol 180:247-255
75. Gevers EF, Hannah MJ, Waters MJ, Robinson IC 9 April 2009 Regulation of rapid Stat5 phosphorylation in the resting cells of the growth plate and in the liver by growth hormone and feeding. Endocrinology 150:3627-3636
76. Hunziker EB, Wagner J, Zapf J 1994 Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo. J Clin Invest 93:1078-1086
77. Wang J, Zhou J, Bondy CA 1999 Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J 13:1985-1990
78. Pfäffle RW, DiMattia GE, Parks JS, Brown MR, Wit JM, Jansen M, Van der Nat H, Van den Brande JL, Rosenfeld MG, Ingraham HA 1992 Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 257:1118-1121
79. Tatsumi K, Miyai K, Notomi T, Kaibe K, Amino N, Mizuno Y, Kohno H 1992 Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1:56-58
80. Phillips 3rd JA, Cogan JD 1994 Genetic basis of endocrine disease. 6. Molecular basis of familial human growth hormone deficiency. J Clin Endocrinol Metab 78:11-16
81. Maheshwari HG, Silverman BL, Dupuis J, Baumann G 1998 Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: Dwarfism of Sindh. J Clin Endocrinol Metab 83:4065-4074
82. Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips 3rd JA, RosenfeldMG1998 Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 18:147-149
83. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Francke U 1999 Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab 84:4436-4443
84. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG 2003 Growth hormone insensitivity associated with a STAT5b mutation.NEngl J Med 349:1139-1147
85. Laron Z 2004 Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. J Clin Endocrinol Metab 89:1031-1044
86. Vidarsdottir S, Walenkamp MJ, PereiraAM,KarperienM, van Doorn J, van Duyvenvoorde HA, White S, Breuning MH, Roelfsema F, Kruithof MF, van Dissel J, Janssen R, Wit JM, Romijn JA 2006 Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J Clin Endocrinol Metab 91:3482-3485
87. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J 1994 Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 15:369-390
88. WalenkampMJ,KarperienM,PereiraAM,Hilhorst-Hofstee Y, van Doorn J, Chen JW, Mohan S, Denley A, Forbes B, van Duyvenvoorde HA, van Thiel SW, Sluimers CA, Bax JJ, de Laat JA, Breuning MB, Romijn JA, Wit JM 2005 Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin EndocrinolMetab90:2855-2864
89. Bonapace G, Concolino D, Formicola S, Strisciuglio P 2003 A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. J Med Genet 40:913-917
90. Woods KA, Camacho-Hübner C, Bergman RN, Barter D, Clark AJ, Savage MO 2000 Effects of insulin-like growth factor-I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion. J Clin Endocrinol Metab 85:1407-1411
91. Inagaki K, Tiulpakov A, Rubtsov P, Sverdlova P, PeterkovaV,YakarS, TerekhovS,LeRoithD2007Afamilial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J Clin Endocrinol Metab 92:1542-1548
92. Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J, Ohtsuka Y, Hisatome I, Ninomoya H, Nanba E, Fukushima T, Takahashi S 2005 Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab 90:4679-4687
93. Raile K, Klammt J, Schneider A, Keller A, Laue S, Smith R, Pfäffle R, Kratzsch J, Keller E, Kiess W 2006 Clinical and functional characteristics of the human Arg59Ter insulinlike growth factor I receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R. J Clin Endocrinol Metab 91:2264-2271
94. Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF, Breuning MH, Romijn JA, Karperien M, Wit JM 2006 A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab 91:3062-3070
95. Okubo Y, Siddle K, Firth H, O'Rahilly S, Wilson LC, Willatt L, Fukushima T, Takahashi S, Petry CJ, Saukkonen T, Stanhope R, Dunger DB 2003 Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab 88:5981-5988
96. Walenkamp MJ, de Muinck Keizer-Schrama SM, de Mos M, Kalf ME, van Duyvenvoorde HA, Boot AM, Kant SG, White SJ, Losekoot M, Den Dunnen JT, Karperien M, Wit JM 2008 Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2-qter deletion detected by multiplex ligation probe amplification. J Clin Endocrinol Metab 93:2421-2425
97. Kant SG, Kriek M, Walenkamp MJ, Hansson KB, van Rhijn A, Clayton-Smith J, Wit JM, BreuningMH2007 Tall stature and duplication of the insulin-like growth factor I receptor gene. Eur J Med Genet 50:1-10
98. Domené HM, Bengolea SV, Martínez AS, Ropelato MG, Pennisi P, Scaglia P, Heinrich JJ, Jasper HG 2004 Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 350:570-577
99. Domené HM, Martínez AS, Frystyk J, Bengolea SV, RopelatoMG,Scaglia PA,ChenJW,HeuckC, WolthersOD, Heinrich JJ, JasperHG2007 Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency. Horm Res 67:243-249
100. Domené HM, Scaglia PA, Lteif A, Mahmud FH, Kirmani S, Frystyk J, Bedecarrás P, Gutiérrez M, Jasper HG 2007 Phenotypic effects of null and haploinsufficiency of acidlabile subunit in a family with two novel IGFALS gene mutations. J Clin Endocrinol Metab 92:4444-4450
101. Hwa V, Haeusler G, Pratt KL, Little BM, Frisch H, Koller D, Rosenfeld RG 2006 Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab 91:1826-1831
102. van Duyvenvoorde HA, Kempers MJ, Twickler TB, van Doorn J, Gerver WJ, Noordam C, Losekoot M, Karperien M, Wit JM, Hermus AR 2008 Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. Eur J Endocrinol 159:113-120
103. Heath KE, Argente J, Barrios V, Pozo J, Díaz-González F, Martos-Moreno GA, Caimari M, Gracia R, Campos-Barros A2008Primaryacid- labile subunit deficiencydueto recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia. J Clin Endocrinol Metab 93:1616-1624
104. Canalis E 1997 Insulin-like growth factors and osteoporosis. Bone 21:215-216
105. Mohan S, Baylink DJ 1996 Insulin-like growth factor system components and the coupling of bone formation to resorption. Horm Res 45(Suppl 1):59-62
106. Mohan S, Baylink D 1998 Mechanism of age-related bone loss: growth hormone/IGFs. In: Rosen CJ, ed. The aging skeleton. San Diego: Academic Press; 457-496
107. Mohan S, Baylink D 1999 IGF system components and their role in bone metabolism. In: Rosenfeld RG, Roberts C, eds. IGFs in health and diseases. Totowa, NJ: Humana Press; 457-496
108. Rosen CJ, Donahue LR 1998 Insulin-like growth factors and bone: the osteoporosis connection revisited. Proc Soc Exp Biol Med 219:1-7
109. Mohan S, Baylink D 1999 Role of growth hormone/insulin-like growth factor axis. In: Rosen CJ, Bilezikian, JP, eds. The aging skeleton. San Diego: Academic Press; 209-219
110. Mohan S, Bautista CM, Wergedal J, Baylink DJ 1989 Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: a potential local regulator of IGF action. Proc Natl Acad Sci USA 86:8338-8342
111. Mohan S, Nakao Y, Honda Y, Landale E, Leser U, Dony C, Lang K, Baylink DJ 1995 Studies on the mechanisms by which insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) and IGFBP-5 modulate IGF actions in bone cells. J Biol Chem 270:20424-20431
112. Kasukawa Y, Miyakoshi N, Mohan S 2004 The anabolic effects of GH/IGF system on bone. Curr Pharm Des 10: 2577-2592
113. Nilsson A, Swolin D, Enerback S, Ohlsson C 1995 Expression of functional growth hormone receptors in cultured human osteoblast-like cells. J Clin Endocrinol Metab 80: 3483-3488
114. Ernst M, Froesch ER 1988 Growth hormone dependent stimulation of osteoblast-like cells in serum-free cultures via local synthesis of insulin-like growth factor I. Biochem Biophys Res Commun 151:142-147
115. Canalis E 1993 Insulin like growth factors and the local regulation of bone formation. Bone 14:273-276
116. Canalis E, Gabbitas B 1995 Skeletal growth factors regulate the synthesis of insulin-like growth factor binding protein-5 in bone cell cultures. J Biol Chem 270:10771-10776
117. Conover CA 2000 In vitro studies of insulin-like growth factor I and bone. Growth Horm IGF Res 10(Suppl B): S107-S110
118. Mohan S, Baylink DJ 1991 Bone growth factors. Clin Orthop Relat Res:30-48
119. Rosen CJ, Donahue LR, Hunter SJ 1994 Insulin-like growth factors and bone: the osteoporosis connection. Proc Soc Exp Biol Med 206:83-102
120. Bikle DD 2008 Growth hormone/insulin-like growth factor-1/PTH axis in bone. J Bone Miner Res 23:581-583
121. Jilka RL 2007 Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40:1434-1446
122. Pettway GJ, Meganck JA, Koh AJ, Keller ET, Goldstein SA, McCauley LK 2008 Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation. Bone 42:806-818
123. Linkhart TA, Mohan S 1989 Parathyroid hormone stimulates release of insulin-like growth factor-I (IGF-I) and IGF-II from neonatal mouse calvaria in organ culture. Endocrinology 125:1484-1491
124. McCarthy TL, Centrella M, Canalis E 1989 Parathyroid hormone enhances the transcript and polypeptide levels of insulin-like growth factor I in osteoblast-enriched cultures from fetal rat bone. Endocrinology 124:1247-1253
125. Bikle DD, Sakata T, Leary C, Elalieh H, Ginzinger D, Rosen CJ, Beamer W, Majumdar S, Halloran BP 2002 Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone. J Bone Miner Res 17:1570-1578
126. Maulén NP, Henríquez EA, Kempe S, Cárcamo JG, Schmid-Kotsas A, Bachem M, Grünert A, Bustamante ME, Nualart F, Vera JC 2003 Up-regulation and polarized expression of the sodium-ascorbic acid transporter SVCT1 in post-confluent differentiated CaCo-2 cells. J Biol Chem 278:9035-9041
127. Miyakoshi N, Kasukawa Y, Linkhart TA, Baylink DJ, Mohan S 2001 Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology 142:4349-4356
128. Yamaguchi M, Ogata N, Shinoda Y, Akune T, Kamekura S, Terauchi Y, Kadowaki T, Hoshi K, Chung UI, Nakamura K, Kawaguchi H 2005 Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice. Endocrinology 146:2620-2628
129. Yakar S, Bouxsein ML, Canalis E, Sun H, Glatt V, Gundberg C, Cohen P, Hwang D, Boisclair Y, Leroith D, Rosen CJ 2006 The ternary IGF complex influences postnatal bone acquisitionandthe skeletal response to intermittent parathyroid hormone. J Endocrinol 189:289-299
130. Bassett JH, Williams GR 2008 Critical role of the hypothalamic-pituitary-thyroid axis in bone. Bone 43:418-426
131. Göthe S, Wang Z, Ng L, Kindblom JM, Barros AC, Ohlsson C, Vennström B, Forrest D 1999 Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev 13:1329-1341
132. Ohlsson C, Nilsson A, Isaksson O, Bentham J, Lindahl A 1992 Effects of tri-iodothyronine and insulin-like growth factor-I (IGF-I) on alkaline phosphatase activity, [3H]thymidine incorporation and IGF-I receptor mRNA in cultured rat epiphyseal chondrocytes. J Endocrinol 135:115-123
133. Huang BK, Golden LA, Tarjan G, Madison LD, Stern PH 2000 Insulin-like growth factor I production is essential for anabolic effects of thyroid hormone in osteoblasts. J Bone Miner Res 15:188-197
134. Canalis E, Bilezikian JP, Angeli A, Giustina A 2004 Perspectives on glucocorticoid-induced osteoporosis. Bone 34:593-598
135. Cheng SL, Zhang SF, Mohan S, Lecanda F, Fausto A, Hunt AH, Canalis E, Avioli LV 1998 Regulation of insulin-like growth factors I and II and their binding proteins in human bone marrow stromal cells by dexamethasone. J Cell Biochem 71:449-458
136. Mehls O, Himmele R, Homme M, Kiepe D, Klaus G 2001 The interaction of glucocorticoids with the growth hormoneinsulin-like growth factor axis and its effects on growth plate chondrocytes and bone cells. J Pediatr Endocrinol Metab 14(Suppl 6):1475-1482
137. Robson H, Siebler T, Shalet SM, Williams GR 2002 Interactions between GH, IGF-I, glucocorticoids, and thyroid hormones during skeletal growth. Pediatr Res 52: 137-147
138. Swolin D, Brantsing C, Matejka G, Ohlsson C 1996 Cortisol decreases IGF-I mRNA levels in human osteoblastlike cells. J Endocrinol 149:397-403
139. van der Eerden BC, Karperien M, Wit JM 2003 Systemic and local regulation of the growth plate. Endocr Rev 24: 782-801
140. Vidal NO, Brändström H, Jonsson KB, Ohlsson C 1998 Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: down-regulation by glucocorticoids. J Endocrinol 159:191-195
141. Zhou M, Graham R, Russell G, Croucher PI 2001 MDC-9 (ADAM-9/Meltrin γ) functions as an adhesion molecule by binding the α(v) β(5) integrin. Biochem Biophys Res Commun 280:574-580
142. Raab-Cullen DM, Thiede MA, Petersen DN, Kimmel DB, Recker RR 1994 Mechanical loading stimulates rapid changes in periosteal gene expression. Calcif Tissue Int 55:473-478
143. Lean JM, Jagger CJ, Chambers TJ, Chow JW 1995 Increased insulin-like growth factor I mRNA expression in rat osteocytes in response to mechanical stimulation. Am J Physiol 268:E318-E327
144. Bikle DD 2008 Integrins, insulin like growth factors, and the skeletal response to load. Osteoporos Int 19:1237-1246
145. Kapur S, Mohan S, Baylink DJ, Lau KH 2005 Fluid shear stress synergizes with insulin-like growth factor-I (IGF-I) on osteoblast proliferation through integrin-dependent activation of IGF-I mitogenic signaling pathway. J Biol Chem 280:20163-20170
146. Sakata T, Wang Y, Halloran BP, Elalieh HZ, Cao J, Bikle DD 2004 Skeletal unloading induces resistance to insulinlike growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways. J Bone Miner Res 19:436-446
147. Saban J, Schneider GB, Bolt D, King D 1996 Erythroidspecific expression of human growth hormone affects bone morphology in transgenic mice. Bone 18:47-52
148. Zhao G, Monier-Faugere MC, Langub MC, Geng Z, Nakayama T, Pike JW, Chernausek SD, Rosen CJ, Donahue LR, Malluche HH, Fagin JA, Clemens TL 2000 Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 141:2674-2682
149. Jiang J, Lichtler AC, Gronowicz GA, Adams DJ, Clark SH, Rosen CJ, Kream BE 2006 Transgenic mice with osteoblast-targeted insulin-like growth factor-I show increased bone remodeling. Bone 39:494-504
150. Zhang M, Faugere MC, Malluche H, Rosen CJ, Chernausek SD, Clemens TL 2003 Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic
151. Qin X, Wergedal JE, Rehage M, Tran K, Newton J, Lam P, Baylink DJ, Mohan S 2006 Pregnancy-associated plasma protein-A increases osteoblast proliferation in vitro and bone formation in vivo. Endocrinology 147:5653-5661
152. Zhang M, Xuan S, Bouxsein ML, von Stechow D, Akeno N, FaugereMC,Malluche H, Zhao G, Rosen CJ, Efstratiadis A, Clemens TL 2002 Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem 277:44005-44012
153. Bikle D, Majumdar S, Laib A, Powell-Braxton L, Rosen C, Beamer W, Nauman E, Leary C, Halloran B 2001 The skeletal structure of insulin-like growth factor I-deficient mice. J Bone Miner Res 16:2320-2329
154. Kasukawa Y, Baylink DJ, Wergedal JE, Amaar Y, Srivastava AK,GuoR,MohanS2003Lack of insulin-like growth factor I exaggerates the effect of calcium deficiency on bone accretion in mice. Endocrinology 144:4682-4689
155. LindbergMK,Svensson J,VenkenK, Chavoshi T, Andersson N, Movérare Skrtic S, Isaksson O, Vanderschueren D, Carlsten H, Ohlsson C 2006 Liver-derived IGF-I is permissive for ovariectomy-induced trabecular bone loss. Bone 38:85-92
156. Tannenbaum GS, Martin JB 1976 Evidence for an endog-enous ultradian rhythm governing growth hormone secretion in the rat. Endocrinology 98:562-570
157. Edén S 1979 Age- and sex-related differences in episodic growth hormone secretion in the rat. Endocrinology 105: 555-560
158. MacLeod JN, Pampori NA, Shapiro BH 1991 Sex differences in the ultradian pattern of plasma growth hormone concentrations in mice. J Endocrinol 131:395-399
159. Gustafsson JA, Mode A, Norstedt G, Skett P 1983 Sex steroid induced changes in hepatic enzymes. Annu Rev Physiol 45:51-60
160. Jansson JO, Ekberg S, Hoath SB, Beamer WG, Frohman LA 1988 Growth hormone enhances hepatic epidermal growth factor receptor concentration in mice. J Clin Invest 82:1871-1876
161. Ekberg S, Carlsson L, Carlsson B, Billig H, Jansson JO 1989 Plasma growth hormone pattern regulates epidermal growth factor (EGF) receptor messenger ribonucleic acid levels and EGF binding in the rat liver. Endocrinology 125: 2158-2166
162. Johansson S, Husman B, Norstedt G, Andersson G 1989 Growth hormone regulates the rodent hepatic epidermal growth factor receptor at a pretranslational level. J Mol Endocrinol 3:113-120
163. Kashimata M, Hiramatsu M, MinamiN1989 Differential secretory rhythm of growth hormone controls the number of hepatic epidermal growth factor receptors in the rat. J Endocrinol 123:75-81
164. Norstedt G, Palmiter R 1984 Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver. Cell 36:805-812
165. Clark RG, Jansson JO, Isaksson O, Robinson IC 1985 Intravenous growth hormone: growth responses to patterned infusions in hypophysectomized rats. J Endocrinol 104:53-61
166. Bick T, Hochberg Z, Amit T, Isaksson OG, Jansson JO 1992 Roles of pulsatility and continuity of growth hormone (GH) administration in the regulation of hepatic GH-receptors, and circulating GH-binding protein and insulin-like growth factor-I. Endocrinology 131:423-429
167. Tannenbaum GS, Ling N 1984 The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology 115:1952-1957
168. Plotsky PM, ValeW1985 Patterns of growth hormonereleasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science 230: 461-463
169. Frohman LA, Jansson JO 1986 Growth hormone-releasing hormone. Endocr Rev 7:223-253
170. Smith RG, Van der Ploeg LH, Howard AD, Feighner SD, Cheng K, Hickey GJ, Wyvratt Jr MJ, Fisher MH, Nargund RP, Patchett AA 1997 Peptidomimetic regulation of growth hormone secretion. Endocr Rev 18:621-645
171. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656-660
172. Bowers CY, Momany FA, Reynolds GA, HongA1984On the in vitro and the in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 114:1537-1545
173. Dickson SL, Leng G, Robinson IC 1993 Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons. Neuroscience 53:303-306
174. Guillaume V, Magnan E, Cataldi M, Dutour A, Sauze N, Renard M, Razafindraibe H, Conte-Devolx B, Deghenghi R, Lenaerts V, Oliver C 1994 Growth hormone (GH)-releasing hormone secretion is stimulated by a new GH-releasing hexapeptide in sheep. Endocrinology 135:1073-1076
175. Dickson SL, Luckman SM 1997 Induction of c-fos mRNA in NPY and GRF neurones in the rat arcleus nucleus following systemic injection of the growth hormone secretagogue, GHRP-6. Endocrinology 138:771-777
176. Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, SleemanMW2005 Absence of ghrelin protects against early-onset obesity. J Clin Invest 115:3573-3578
177. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Williams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK 2005 Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 115: 3564-3572
178. Eicher EM, BeamerWG1976 Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. J Hered 67:87-91
179. Jansson JO, Downs TR, Beamer WG, Frohman LA 1986 Receptor-associated resistance to growth hormone-releasing factor in dwarf "little" mice. Science 232:511-512
180. Holst B, SchwartzTW2006 Ghrelin receptor mutations-too little height and too much hunger. J Clin Invest 116: 637-641
181. Chapman IM, PescovitzOH,Murphy G, Treep T, Cerchio KA, Krupa D, Gertz B, Polvino WJ, Skiles EH, Pezzoli SS, Thorner MO 1997 Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GHdeficient adults. J Clin Endocrinol Metab 82:3455-3463
182. Svensson J, Lönn L, Jansson JO, Murphy G, Wyss D, Krupa D, Cerchio K, Polvino W, Gertz B, Boseaus I, Sjöström L, Bengtsson BA 1998 Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab 83:362-369
183. Tannenbaum GS 1980 Evidence for autoregulation of growth hormone secretion via the central nervous system. Endocrinology 107:2117-2120
184. SatoM,Chihara K, Kita T, Kashio Y,OkimuraY, Kitajima N, Fujita T 1989 Physiological role of somatostatin-mediated autofeedback regulation for growth hormone: importance of growth hormone in triggering somatostatin release during a trough period of pulsatile growth hormone release in conscious male rats. Neuroendocrinology 50: 139-151
185. Carlsson L, Jansson JO 1990 Endogenous growth hormone (GH) secretion in male rats is synchronized to pulsatile GH infusions given at 3-hour intervals. Endocrinology 126:6-10
186. Farhy LS, StraumeM,JohnsonML,Kovatchev B, Veldhuis JD 2002 Unequal autonegative feedback byGHmodels the sexual dimorphism in GH secretory dynamics. Am J Physiol Regul Integr Comp Physiol 282:R753-R764
187. Chowen JA, García-Segura LM, González-Parra S, Argente J 1996 Sex steroid effects on the development and functioning of the growth hormone axis. Cell Mol Neurobiol 16:297-310
188. Berelowitz M, Szabo M, Frohman LA, Firestone S, Chu L, Hintz RL 1981 Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 212:1279-1281
189. Tannenbaum GS, Guyda HJ, Posner BI 1983 Insulin-like growth factors: a role in growth hormone negative feedback and body weight regulation via brain. Science 220: 77-79
190. Kamegai J, Unterman TG, Frohman LA, KinemanRD1998 Hypothalamic/pituitary-axis of the spontaneous dwarf rat: autofeedback regulation of growth hormone (GH) includes suppression ofGHreleasing-hormone receptor messenger ribonucleic acid. Endocrinology 139:3554-3560
191. Sato M, Frohman LA 1993 Differential effects of central and peripheral administration of growth hormone (GH) andinsulin- likegrowthfactoronhypothalamicGH-releasing hormone and somatostatin gene expression in GH-deficient dwarf rats. Endocrinology 133:793-799
192. Harel Z, Tannenbaum GS 1992 Synergistic interaction between insulin-like growth factors-I and -II in central regulation of pulsatile growth hormone secretion. Endocrinology 131:758-764
193. Tannenbaum GS, Choi HK, Gurd W, Waxman DJ 2001 Temporal relationship between the sexually dimorphic spontaneousGHsecretory profiles and hepatic STAT5 activity. Endocrinology 142:4599-4606
194. Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW 1997 Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci USA 94:7239-7244
195. Waxman DJ, O'Connor C 2006 Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol 20:2613-2629
196. Caro JF, Poulos J, Ittoop O, Pories WJ, Flickinger EG, Sinha MK 1988 Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. J Clin Invest 81:976-981
197. Santos A, Yusta B, Fernández-Moreno MD, Blázquez E 1994 Expression of insulin-like growth factor-I (IGF-I) receptor gene in rat brain and liver during development and in regenerating adult rat liver. Mol Cell Endocrinol 101: 85-93
198. Pennisi PA, Kopchick JJ, Thorgeirsson S, LeRoith D, Yakar S 2004 Role of growth hormone (GH) in liver regeneration. Endocrinology 145:4748-4755
199. DaveyHW,Park SH, GrattanDR,McLachlan MJ,Waxman DJ 1999 STAT5b-deficient mice are growth hormone pulseresistant. Role of STAT5b in sex-specific liver p450 expression. J Biol Chem 274:35331-35336
200. Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN 1998 Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93:841-850
201. Klover P, Hennighausen L 2007 Postnatal body growth is dependent on the transcription factors signal transducers and activators of transcription 5a/b in muscle: a role for autocrine/paracrine insulin-like growth factor I. Endocrinology 148:1489-1497
202. Giustina A, Veldhuis JD 1998 Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717-797
203. Jaffe CA, Ocampo-Lim B, Guo W, Krueger K, Sugahara I, DeMott-Friberg R, Bermann M, Barkan AL 1998 Regulatory mechanisms of growth hormone secretion are sexually dimorphic. J Clin Invest 102:153-164
204. Jessup SK, Dimaraki EV, Symons KV, Barkan AL 2003 Sexual dimorphism of growth hormone (GH) regulation in humans: endogenous GH-releasing hormone maintains basal GH in women but not in men. J Clin Endocrinol Metab 88:4776-4780
205. Veldhuis JD, Keenan DM, Bailey JN, Adeniji A, Miles JM, Paulo R, Cosma M, Soares-Welch C 2008 Estradiol supplementation in postmenopausal women attenuates suppression of pulsatile growth hormone secretion by recombinant human insulin-like growth factor type I. J Clin Endocrinol Metab 93:4471-4478
206. Veldhuis JD, Keenan DM, Bailey JN, Adeniji A, Miles JM, Paulo R, Cosma M, Soares-Welch C 2009 Testosterone supplementation in older men restrains insulin-like growth factor's dose-dependent feedback inhibition of pulsatile growth hormone secretion. J Clin Endocrinol Metab 94: 246-254
207. Leung KC, Johannsson G, Leong GM, Ho KK 2004 Estrogen regulation of growth hormone action. Endocr Rev 25:693-721
208. Veldhuis JD, Bidlingmaier M, Anderson SM, Wu Z, Strasburger CJ 2001 Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthywomenand men. J Clin Endocrinol Metab 86:3304-3310
209. HartmanML,ClaytonPE,JohnsonML,CelnikerA,Perlman AJ, Alberti KG, Thorner MO 1993 A low dose euglycemic infusion of recombinant insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growthhormonesecretion in humans. J Clin Invest 91:2453-2462
210. Inagaki T, Lin VY, Goetz R,MohammadiM,Mangelsdorf DJ, Kliewer SA 2008 Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 8:77-83
211. Sjögren K, Wallenius K, Liu JL, Bohlooly-Y M, Pacini G, Svensson L, Törnell J, Isaksson OG, Ahrén B, Jansson JO, Ohlsson C 2001 Liver-derived IGF-I is of importance for normal carbohydrate and lipid metabolism. Diabetes 50: 1539-1545
212. Yakar S, Liu JL, FernandezAM,WuY, SchallyAV,Frystyk J, Chernausek SD, Mejia W, Le Roith D 2001 Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes 50:1110-1118
213. Haluzik M, Yakar S, Gavrilova O, Setser J, Boisclair Y, LeRoith D 2003 Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes 52:2483-2489
214. Yakar S, Setser J, Zhao H, Stannard B, Haluzik M, Glatt V, Bouxsein ML, Kopchick JJ, LeRoith D 2004 Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest 113:96-105
215. Yu R, Yakar S, Liu YL, Lu Y, LeRoith D, Miao D, Liu JL 2003 Liver-specific IGF-I gene deficient mice exhibit accelerated diabetes in response to streptozotocin, associated with early onset of insulin resistance. Mol Cell Endocrinol 204:31-42
216. HennigeAM,Burks DJ, Ozcan U, Kulkarni RN, Ye J, Park S, Schubert M, Fisher TL,DowMA,Leshan R, Zakaria M, Mossa-Basha M, White MF 2003 Upregulation of insulin receptor substrate-2 in pancreatic βcells prevents diabetes. J Clin Invest 112:1521-1532
217. Holt RI, Simpson HL, Sönksen PH 2003 The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis. Diabet Med 20:3-15
218. Simpson HL, Jackson NC, Shojaee-Moradie F, Jones RH, Russell-Jones DL, Sönksen PH, Dunger DB, UmplebyAM 2004 Insulin-like growth factor I has a direct effect on glucose and protein metabolism, but no effect on lipid metabolism in type 1 diabetes. J Clin Endocrinol Metab 89: 425-432
219. Ning Y, Schuller AG, Bradshaw S, Rotwein P, Ludwig T, Frystyk J, Pintar JE 2006 Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. Mol Endocrinol 20:2173-2186
220. Leroith D, Accili D 2008 Mechanisms of disease: using genetically altered mice to study concepts of type 2 diabetes. Nat Clin Pract Endocrinol Metab 4:164-172
221. Xuan S, Kitamura T, Nakae J, Politi K, Kido Y, Fisher PE, Morroni M, Cinti S, White MF, Herrera PL, Accili D, Efstratiadis A 2002 Defective insulin secretion in pancreatic βcells lacking type 1 IGF receptor. J Clin Invest 110: 1011-1019
222. Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M,MagnusonMA,KahnCR2002 β-Cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass. Nat Genet 31: 111-115
223. Ueki K, Okada T, Hu J, Liew CW, Assmann A, Dahlgren GM,Peters JL, Shackman JG, Zhang M, Artner I, Satin LS, Stein R, Holzenberger M, Kennedy RT, Kahn CR, Kulkarni RN 2006 Total insulin and IGF-I resistance in pancreatic β-cells causes overt diabetes. Nat Genet 38: 583-588
224. Lu Y, Herrera PL, Guo Y, Sun D, Tang Z, LeRoith D, Liu JL 2004 Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. Diabetes 53:3131-3141
225. Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J 1995 Transient increase in obese gene expression after food intake or insulin administration. Nature 377:527-529
226. Leroy P, Dessolin S, Villageois P, Moon BC, Friedman JM, Ailhaud G, Dani C 1996 Expression of ob gene in adipose cells. Regulation by insulin. J Biol Chem 271:2365-2368
227. Böni-Schnetzler M, Gosteli-Peter MA, Moritz W, Froesch ER, Zapf J 1996 Reduced ob mRNA in hypophysectomised rats is not restored by growth hormone (GH), but further suppressed by exogenously administered insulinlike growth factor (IGF) I. Biochem Biophys Res Commun 225:296-301
228. Böni-Schnetzler M, Hauri C, Zapf J 1999 Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGF I) in normal rats. Diabetologia 42: 160-166
229. Tang Z, Yu R, Lu Y, Parlow AF, Liu JL 2005 Age-dependent onset of liver-specific IGF-I gene deficiency and its persistence in old age: implications for postnatal growth and insulin resistance in LID mice. Am J Physiol Endocrinol Metab 289:E288-E295
230. Rajkumar K, Modric T, Murphy LJ 1999 Impaired adipogenesis in insulin-like growth factor binding protein-1 transgenic mice. J Endocrinol 162:457-465
231. Sonntag WE, Steger RW, Forman LJ, Meites J 1980 Decreased pulsatile release of growth hormone in old male rats. Endocrinology 107:1875-1879
232. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE 1990 Effects of human growth hormone in men over 60 years old. N Engl J Med 323:1-6
233. Wheatcroft SB, Kearney MT, Shah AM, Ezzat VA, Miell JR, Modo M, Williams SC, Cawthorn WP, Medina-Gomez G, Vidal-Puig A, Sethi JK, Crossey PA 2007 IGFbinding protein-2 protects against the development of obesity and insulin resistance. Diabetes 56:285-294
234. Moses AC, Young SC, Morrow LA, O'Brien M, Clemmons DR 1996 Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 45:91-100
235. Clemmons DR, Moses AC, McKay MJ, Sommer A, Rosen DM, Ruckle J 2000 The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity. J Clin Endocrinol Metab 85:1518-1524
236. Merimee TJ, Hollander W, Fineberg SE 1972 Studies of hyperlipidemia in the HGH-deficient state. Metabolism 21:1053-1061
237. Winter RJ, Thompson RG, Green OC 1979 Serum cholesterol and triglycerides in children with growth hormone deficiency. Metabolism 28:1244-1249
238. de Boer H, Blok GJ,Vander VeenEA1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev 16: 63-86
239. Drake WM, Howell SJ, Monson JP, Shalet SM 2001 Optimizing GH therapy in adults and children. Endocr Rev 22:425-450
240. Parini P, Angelin B, Rudling M 1999 Cholesterol and lipoprotein metabolism in aging: reversal of hypercholesterolemia by growth hormone treatment in old rats. Arterioscler Thromb Vasc Biol 19:832-839
241. Russo VC, Gluckman PD, Feldman EL, Werther GA 2005 The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev 26:916-943
242. D'Ercole AJ, Ye P, O'Kusky JR 2002 Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides 36:209-220
243. Messier C, Teutenberg K 2005 The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer's disease. Neural Plast 12:311-328
244. JosephD'Ercole A, Ye P 2008 Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149:5958-5962
245. Shea BT, Hammer RE, Brinster RL 1987 Growth allometry of the organs in giant transgenic mice. Endocrinology 121:1924-1930
246. Chen L, Lund PK, Burgess SB, Rudisch BE, McIlwain DL 1997 Growth hormone, insulin-like growth factor I, and motoneuron size. J Neurobiol 32:202-212
247. Carson MJ, Behringer RR, Brinster RL, McMorris FA 1993 Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 10:729-740
248. Dentremont KD, Ye P, D'Ercole AJ, O'Kusky JR 1999 Increased insulin-like growth factor-I (IGF-I) expression during early postnatal development differentially increases neuron number and growth in medullary nuclei of the mouse. Brain Res Dev Brain Res 114:135-141
249. O'Kusky JR, Ye P, D'Ercole AJ 2000 Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 20:8435-8442
250. O'Kusky JR, Ye P, D'Ercole AJ 2003 Increased expression of insulin-like growth factor augments the progressive phase of synaptogenesis without preventing synapse elimination in the hypoglossal nucleus. J Comp Neurol 464: 382-391
251. Zhong J, Deng J, Phan J, Dlouhy S, Wu H, Yao W, Ye P, D'Ercole AJ, Lee WH 2005 Insulin-like growth factor-I protects granule neurons from apoptosis and improves ataxia in weaver mice. J Neurosci Res 80:481-490
252. Beck KD, Powell-Braxton L, Widmer HR, Valverde J, Hefti F 1995 Igfl gene disruption results in reduced brain size,CNShypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 14:717-730
253. Holzenberger M, Hamard G, Zaoui R, Leneuve P, Ducos B, Beccavin C, Périn L, Le Bouc Y 2001 Experimental IGF-I receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 142:4469-4478
254. Vicario-Abejón C, Yusta-Boyo MJ, Fernández-Moreno C, de Pablo F 2003 Locally born olfactory bulb stem cells proliferate in response to insulin-related factors and require endogenous insulin-like growth factor-I for differentiation into neurons and glia. J Neurosci 23:895-906
255. Kappeler L, Filho CM, Dupont J, Leneuve P, Cervera P, Périn L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M 2008 Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 28:e254
256. Markowska AL, Mooney M, Sonntag WE 1998 Insulinlike growth factor-I ameliorates age-related behavioral deficits. Neuroscience 87:559-569
257. Svensson J, Söderpalm B, Sjögren K, Engel J, Ohlsson C 2005 Liver-derived IGF-I regulates exploratory activity in old mice.AmJ Physiol Endocrinol Metab 289:E466-E473
258. Söderpalm B, Ericson M, Bohlooly M, Engel JA, Törnell J 1999 Bovine growth hormone transgenic mice display alterations in locomotor activity and brain monoamine neurochemistry. Endocrinology 140:5619-5625
259. Bohlooly-Y M, Olsson B, Gritli-Linde A, Brusehed O, Isaksson OG, Ohlsson C, Söderpalm B, Törnell J, Ola B 2001 Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms. Endocrinology 142:4560-4567
260. Sonntag WE, Lynch CD, Cooney PT, Hutchins PM 1997 Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1. Endocrinology 138:3515-3520
261. Thornton PL, Ingram RL, Sonntag WE 2000 Chronic [D-Ala2]-growth hormone-releasing hormone administration attenuates age-related deficits in spatial memory. J Gerontol A Biol Sci Med Sci 55:B106-B112
262. Trejo JL, Carro E, Torres-Aleman I 2001 Circulating insulinlike growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628-1634
263. Lopez-Lopez C, LeRoith D, Torres-Aleman I 2004 Insulinlike growth factor I is required for vessel remodeling in the adult brain. Proc Natl Acad Sci USA 101:9833-9838
264. Trejo JL, Llorens-Martín MV, Torres-Alemán I 2008 The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci 37:402-411
265. Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I2002Seruminsulin-likegrowthfactor I regulates brainamyloid-βlevels. Nat Med 8:1390-1397
266. Carro E, Spuch C, Trejo JL, Antequera D, Torres-Aleman I 2005 Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. J Neurosci 25:10884-10893
267. Lopez-Lopez C, Dietrich MO, Metzger F, Loetscher H, Torres-Aleman I 2007 Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of Alzheimer's disease. J Neurosci 27:824-831
268. Svensson J, Diez M, Engel J, Wass C, Tivesten A, Jansson JO, Isaksson O, Archer T, Hökfelt T, Ohlsson C 2006 Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice. J Endocrinol 189:617-627
269. Trejo JL, Piriz J, Llorens-Martin MV, Fernandez AM, Bolós M, LeRoith D, Nuñez A, Torres-Aleman I 2007 Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Mol Psychiatry 12:1118-1128
270. Reinhardt RR, BondyCA1994 Insulin-like growth factors cross the blood-brain barrier. Endocrinology 135:1753-1761
271. Nilsson L, Sara VR, Nordberg A 1988 Insulin-like growth factor I stimulates the release of acetylcholine from rat cortical slices. Neurosci Lett 88:221-226
272. Araujo DM, Lapchak PA, Collier B, Chabot JG, Quirion R 1989 Insulin-like growth factor-I (somatomedin-C) receptors in the rat brain: distribution and interaction with the hippocampal cholinergic system. Brain Res 484:130-138
273. Kar S, Seto D, Doré S, Hanisch U, Quirion R 1997 Insulinlike growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation. Proc Natl Acad Sci USA 94:14054-14059
274. Burns JM, Donnelly JE, Anderson HS, Mayo MS, Spencer-Gardner L, Thomas G, Cronk BB, Haddad Z, Klima D, Hansen D, BrooksWM2007 Peripheral insulin and brain structure in early Alzheimer disease. Neurology 69:1094-1104
275. Falleti MG, Maruff P, Burman P, Harris A 2006 The effects of growth hormone (GH) deficiency andGHreplacement on cognitive performance in adults: a meta-analysis of the current literature. Psychoneuroendocrinology 31:681-691
276. Rollero A, Murialdo G, Fonzi S, Garrone S, Gianelli MV, Gazzerro E, Barreca A, Polleri A 1998 Relationship between cognitive function, growth hormone and insulin-like growth factor plasma levels in aged subjects. Neuropsychobiology 38:73-79
277. Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, Idei T, Iguchi T 2005 Relationship between serum insulin-like growth factor-1 levels and Alzheimer's disease and vascular dementia. J Am Geriatr Soc 53:1748-1753
278. Mustafa A, Lannfelt L, Lilius L, Islam A, Winblad B, Adem A1999 Decreased plasma insulin-like growth factor-I level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation. Dement Geriatr Cogn Disord 10:446-451
279. Vardy ER, Rice PJ, Bowie PC, Holmes JD, Grant PJ, Hooper NM 2007 Increased circulating insulin-like growth factor-1 in late-onset Alzheimer's disease. J Alzheimers Dis 12:285-290
280. Tham A, Nordberg A, Grissom FE, Carlsson-Skwirut C, Viitanen M, Sara VR 1993 Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type. J Neural Transm Park Dis Dement Sect 5:165-176
281. Isgaard J, Nilsson A, Vikman K, Isaksson OG 1989 Growth hormone regulates the level of insulin-like growth factor-I mRNA in rat skeletal muscle. J Endocrinol 120: 107-112
282. Delafontaine P, Bernstein KE, Alexander RW 1991 Insulin-like growth factor I gene expression in vascular cells. Hypertension 17:693-699
283. Mathews LS, Enberg B, NorstedtG1989 Regulation of rat growth hormone receptor gene expression. J Biol Chem 264:9905-9910
284. Isgaard J, Wåhlander H, Adams MA, Friberg P 1994 Increased expression of growth hormone receptor mRNA and insulin-like growth factor-I mRNA in volume-overloaded hearts. Hypertension 23:884-888
285. Wickman A, Friberg P, Adams MA, Matejka GL, Brantsing C, Guron G, Isgaard J 1997 Induction of growth hormone receptor and insulin-like growth factor-ImRNAin aorta and caval vein during hemodynamic challenge. Hypertension 29: 123-130
286. Guler HP, Zapf J, Scheiwiller E, Froesch ER 1988 Recombinant human insulin-like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc Natl Acad Sci USA 85:4889-4893
287. Wickman A, Isgaard J, Adams MA, Friberg P 1997 Inhibition of nitric oxide in rats. Regulation of cardiovascular structure and expression of insulin-like growth factor I and its receptor messenger RNA. J Hypertens 15:751-759
288. Saccà L, Cittadini A, Fazio S 1994 Growth hormone and the heart. Endocr Rev 15:555-573
289. Svensson J, Tivesten A, Isgaard J 2005 Growth hormone and the cardiovascular function. Minerva Endocrinol 30: 1-13
290. Pete G,HuY, WalshM,Sowers J, Dunbar JC 1996 Insulinlike growth factor-I decreases mean blood pressure and selectively increases regional blood flow in normal rats. Proc Soc Exp Biol Med 213:187-192
291. Walsh MF, Barazi M, Pete G, Muniyappa R, Dunbar JC, Sowers JR 1996 Insulin-like growth factor-I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology 137:1798-1803
292. Copeland KC, Nair KS 1994 Recombinant human insulinlike growth factor-I increases forearm bloodflow. J Clin Endocrinol Metab 79:230-232
293. Delafontaine P, Song YH, Li Y 2004 Expression, regulation, and function of IGF-1 IGF-1R and IGF-1 binding proteins in blood vessels. Arterioscler Thromb Vasc Biol 24:435-444
294. Grant MB, Wargovich TJ, Ellis EA, Tarnuzzer R, Caballero S, Estes K, Rossing M, Spoerri PE, PepineC1996 Expression of IGF-I, IGF-I receptor and IGF binding proteins -1, -2, -3, -4 and -5 inhumanatherectomy specimens. Regul Pept 67:137-144
295. Harrington SC, Simari RD, Conover CA 2007 Genetic deletion of pregnancy-associated plasma protein-A is associated with resistance to atherosclerotic lesion development in apolipoprotein E-deficient mice challenged with a high-fat diet. Circ Res 100:1696-1702
296. Juul A, Scheike T, Davidsen M, Gyllenborg J, Jørgensen T 2002 Low serum insulin-like growth factor-I is associated with increased risk of ischemic heart disease: a populationbased case-control study. Circulation 106:939-944
297. Schut AF, Janssen JA, Deinum J, Vergeer JM, Hofman A, Lamberts SW, Oostra BA, Pols HA, Witteman JC, van Duijn CM 2003 Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension. Stroke 34:1623-1627
298. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG 1992 Detection of premature atherosclerosis by high-resolution ultrasonography in symptomfree hypopituitary adults. Lancet 340:1188-1192
299. Capaldo B, Patti L, Oliviero U, Longobardi S, Pardo F, Vitale F, Fazio S, Di Rella F, Biondi B, Lombardi G, Saccà L 1997 Increased arterial intima-media thickness in childhood-onset growth hormone deficiency. J Clin Endocrinol Metab 82:1378-1381
300. Borson-Chazot F, Serusclat A, Kalfallah Y, Ducottet X, Sassolas G, Bernard S, Labrousse F, Pastene J, Sassolas A, Roux Y, Berthezène F 1999 Decrease in carotid intimamedia thickness after one-year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab 84:1329-1333
301. Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN 1999 Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab 84:453-457
302. Clemmons DR 2007 Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 6:821-833
303. Reiss K, Cheng W, Ferber A, Kajstura J, Li P, Li B, Olivetti G, Homcy CJ, Baserga R, Anversa P 1996 Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc Natl Acad Sci USA 93:8630-8635
304. Li Q,WuS, Li SY, Lopez FL, Du M, Kajstura J, Anversa P, Ren J 2007 Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage. Am J Physiol Heart Circ Physiol 292:H1398-H1403
305. Li Q, Ren J 2007 Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+homeostasis, protein damage and apoptotic protein expression. Aging Cell 6:799-806
306. Delaughter MC, Taffet GE, Fiorotto ML, Entman ML, Schwartz RJ 1999 Local insulin-like growth factor I expression induces physiologic, then
307. Guron G, Friberg P, Wickman A, Brantsing C, Gabrielsson B, Isgaard J 1996 Cardiac insulin-like growth factor I and growth hormone receptor expression in renal hypertension. Hypertension 27:636-642
308. Kim J, Wende AR, Sena S, Theobald HA, Soto J, Sloan C, Wayment BE, Litwin SE, Holzenberger M, LeRoith D, Abel ED 2008 IGF-1 receptor signaling is required for exercise-induced cardiac hypertrophy.MolEndocrinol 22: 2531-2543
309. Lembo G, Rockman HA, Hunter JJ, Steinmetz H, Koch WJ, Ma L, Prinz MP, Ross Jr J, Chien KR, Powell-Braxton L 1996 Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency. J Clin Invest 98:2648-2655
310. Palmen M, Daemen MJ, Bronsaer R, DassenWR,Zandbergen HR,KockxM,Smits JF,vanderZeeR,DoevendansPA2001 Cardiac remodelling after myocardial infarction is impaired in IGF-I deficient mice. Cardiovasc Res 50:516-524
311. Tivesten A, Bollano E, Andersson I, Fitzgerald S, Caidahl K, Sjögren K, Skøtt O, Liu JL, Mobini R, Isaksson OG, Jansson JO, Ohlsson C, Bergström G, Isgaard J 2002 Liverderived insulin-like growth factor-I is involved in the regulation of blood pressure in mice. Endocrinology 143:4235-4242
312. Bollano E, Omerovic E, Bohlooly-y M, Kujacic V, Madhu B, Törnell J, Isaksson O, Soussi B, Schulze W, Fu ML, Matejka G, Waagstein F, Isgaard J 2000 Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene. Endocrinology 141:2229-2235
313. Li Q, Yang X, Sreejayan N, Ren J 2007 Insulin-like growth factor I deficiency prolongs survival and antagonizes paraquat-induced cardiomyocyte dysfunction: role of oxidative stress. Rejuvenation Res 10:501-512
314. Li Q, Ceylan-Isik AF, Li J, Ren J 2008 Deficiency of insulinlike growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction. Rejuvenation Res 11:725-733
315. Feld S, Hirschberg R 1996 Growth hormone, the insulinlike growth factor system, and the kidney. Endocr Rev 17:423-480
316. Cingel-Ristiæ V, Flyvbjerg A, Drop SL 2004 The physiological and pathophysiological role of the GH/IGF-axis in the kidney: lessons from experimental rodent models. Growth Horm IGF Res 14:418-430
317. Mathews LS, Hammer RE, Behringer RR, D'Ercole AJ, Bell GI, Brinster RL, Palmiter RD 1988 Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology 123:2827-2833
318. Quaife CJ,MathewsLS, PinkertCA,HammerRE, Brinster RL, Palmiter RD 1989 Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124:40-48
319. Doi T, Striker LJ, Gibson CC, Agodoa LY, Brinster RL, Striker GE 1990 Glomerular lesions in mice transgenic for growth hormone and insulin-like growth factor I. I. Relationship between increased glomerular size and mesangial sclerosis. Am J Pathol 137:541-552
320. Rogers SA, Powell-Braxton L, HammermanMR1999 Insulin-like growth factor I regulates renal development in rodents. Dev Genet 24:293-298
321. Svensson J, Tivesten A, Sjögren K, Isaksson O, Bergström G, Mohan S, Mölne J, Isgaard J, Ohlsson C 2007 Liverderived IGF-I regulates kidney size, sodium reabsorption, and renal IGF-II expression. J Endocrinol 193:359-366
322. Wolf E, Kramer R, Blum WF, Föll J, Brem G 1994 Consequences of postnatally elevated insulin-like growth factor-II in transgenic mice: endocrine changesandeffectsonbodyand organ growth. Endocrinology 135:1877-1886
323. Blackburn A, Schmitt A, Schmidt P, Wanke R, Hermanns W, Brem G, Wolf E 1997 Actions and interactions of growth hormone and insulin-like growth factor-II: body and organ growth of transgenic mice. Transgenic Res 6:213-222
324. Moerth C, Schneider MR, Renner-Mueller I, Blutke A, Elmlinger MW, Erben RG, Camacho-Hübner C, Hoeflich A, Wolf E 2007 Postnatally elevated levels of insulin-like growth factor-II (IGF-II) fail to rescue the dwarfism of IGF-I deficient mice except kidney weight. Endocrinology 148:441-451
325. Hirschberg R, Kopple JD 1989 Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats. J Clin Invest 83:326-330
326. Guler HP, Eckardt KU, Zapf J, Bauer C, Froesch ER 1989 Insulin-like growth factor I increase glomerular filtration rate and renal plasma flow in man. Acta Endocrinol (Copenh) 121:101-106
327. Guler HP, Schmid C, Zapf J, Froesch ER 1989 Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proc Natl Acad Sci USA 86:2868-2872
328. Hirschberg R 1993 Effects of growth hormone and IGF-I on glomerular ultrafiltration in growth hormone-deficient rats. Regul Pept 48:241-250
329. Giordano M, DeFronzo RA 1995 Acute effect of human recombinant insulin-like growth factor I on renal function in humans. Nephron 71:10-15
330. Blazer-Yost BL, CoxM1988 Insulin-like growth factor 1 stimulates renal epithelial Na+ transport. Am J Physiol 255:C413-C417
331. Doi T, Striker LJ, Quaife C, Conti FG, Palmiter R, Behringer R, Brinster R, Striker GE 1988 Progressive glomeruli sclerosis develops in transgenic mice chronically expressing growthhormoneandgrowthhormonereleasing factor but not in those expressing insulin-like growth factor-1. Am J Pathol 131:398-403
332. Bellush LL, Doublier S, Holland AN, Striker LJ, Striker GE, Kopchick JJ 2000 Protection against diabetes-induced nephropathy in growth hormone receptor/binding protein gene-disrupted mice. Endocrinology 141:163-168
333. Reddy GR, Pushpanathan MJ, Ransom RF, Holzman LB, Brosius 3rd FC, Diakonova M, Mathieson P, Saleem MA, List EO, Kopchick JJ, Frank SJ, Menon RK 2007 Identification of the glomerular podocyte as a target for growth hormone action. Endocrinology 148:2045-2055
334. Fausto N, Laird AD, WebberEM1995 Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration. FASEB J 9:1527-1536
335. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R 1996 Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274:1379-1383
336. Wallenius V, Wallenius K, Hisaoka M, Sandstedt J, Ohlsson C, Kopf M, Jansson JO 2001 Retarded liver growth in interleukin-6-deficient and tumor necrosis factor receptor-1-deficient mice. Endocrinology 142:2953-2960
337. Uthne K, Uthne T 1972 Influence of liver resection and regeneration on somatomedin (sulphation factor) activity in sera from normal and hypophysectomized rats. Acta Endocrinol (Copenh) 71:255-264
338. Unterman TG, Phillips LS 1986 Circulating somatomedin activity during hepatic regeneration. Endocrinology 119: 185-192
339. Ekberg S, Luther M, Nakamura T, Jansson JO 1992 Growth hormone promotes early initiation of hepatocyte growth factor gene expression in the liver of hypophysectomized rats after partial hepatectomy. J Endocrinol 135: 59-67
340. Desbois-Mouthon C, Wendum D, Cadoret A, Rey C, Leneuve P, Blaise A, Housset C, Tronche F, Le Bouc Y, Holzenberger M 2006 Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockout. FASEB J 20:773-775
341. Pietrzkowski Z, Sell C, Lammers R, Ullrich A, Baserga R 1992 Roles of insulinlike growth factor 1 (IGF-1) and the IGF-1 receptor in epidermal growth factor-stimulated growth of 3T3 cells. Mol Cell Biol 12:3883-3889
342. Skrtic S, Wallenius K, Gressner AM, Jansson JO 1999 Insulin-like growth factor signaling pathways in rat hepatic stellate cells: importance for deoxyribonucleic acid synthesis and hepatocyte growth factor production. Endocrinology 140:5729-5735
343. Lee PD, Giudice LC, Conover CA, Powell DR 1997 Insulin-like growth factor binding protein-1: recent findings and new directions. Proc Soc Exp Biol Med 216:319-357
344. Mohn KL, Melby AE, Tewari DS, Laz TM, Taub R 1991 The gene encoding rat insulinlike growth factor-binding protein 1 is rapidly and highly induced in regenerating liver. Mol Cell Biol 11:1393-1401
345. Leu JI, Crissey MA, Craig LE, Taub R 2003 Impaired hepatocyte DNA synthetic response posthepatectomy in insulin-like growth factor binding protein 1-deficient mice with defects in C/EBP βand mitogen-activated protein kinase/ extracellular signal-regulated kinase regulation. Mol Cell Biol 23:1251-1259
346. Perkel VS, Mohan S, Baylink DJ, Linkhart TA 1990 An inhibitory insulin-like growth factor binding protein (IN-IGFBP) from human prostatic cell conditioned medium reveals N-terminal sequence identity with bone derived IN-IGFBP. J Clin Endocrinol Metab 71:533-535
347. Cohen P, Peehl DM, Lamson G, Rosenfeld RG 1991 Insulin-like growth factors (IGFs), IGF receptors, and IGF binding proteins in primary culture of prostate epithelial cells. J Clin Endocrinol Metab 73:401-407
348. Cohen P, Peehl DM, Baker B, Liu F, Hintz RL, Rosenfeld RG 1994 Insulin-like growth factor abnormalities in prostate stromal cells from patients with benign prostatic hyperplasia. J Clin Endocrinol Metab 79:1410-1415
349. Cohen P, Peehl DM, Rosenfeld RG 1994 The IGF axis in the prostate. Horm Metab Res 26:81-84
350. Cohen P, Peehl DM, Graves HC, Rosenfeld RG 1994 Biological effects of prostate specific antigen as an insulinlike growth factor binding protein-3 protease. J Endocrinol 142:407-415
351. Kaplan PJ, Mohan S, Cohen P, Foster BA, GreenbergNM 1999 The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (Tramp) model. Cancer Res 59:2203-2209
352. Meinbach DS, Lokeshwar BL 2006 Insulin-like growth factors and their binding proteins in prostate cancer: cause of consequence? Urol Oncol 24:294-306
353. Ghosh PK, Bartke A 1993 Effects of the expression of bovine growth hormone on the testes and male accessory reproductive glands in transgenic mice. Transgenic Res 2:79-83
354. Reiter E, Bonnet P, Sente B, Dombrowicz D, de Leval J, Closset J, Hennen G 1992 Growth hormone and prolactin stimulate androgen receptor, insulin-like growth factor-I (IGF-I) and IGF-I receptor levels in the prostate of immature rats. Mol Cell Endocrinol 88:77-87
355. Ruan W, Powell-Braxton L, Kopchick JJ, Kleinberg DL 1999 Evidence that insulin-like growth factor-I and growth hormone are required for prostate gland development. Endocrinology 140:1984-1989
356. DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltrán L, Moats S, Ramirez A, Jorcano J, Conti C 2000 Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci USA 97:3455-3460
357. Kaplan-LefkoPJ, SutherlandBW,EvangelouAI, HadsellDL, Barrios RJ, Foster BA, Demayo F, GreenbergNM2008 Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene 27:2868-2876
358. Sutherland BW, Knoblaugh SE, Kaplan-Lefko PJ, Wang F, Holzenberger M, Greenberg NM 2008 Conditional deletion of insulin-like growth factor-I receptor in prostate epithelium. Cancer Res 68:3495-3504
359. Svensson J, Kindblom J, Shao R, Movérare-Skrtic S, Lagerquist MK, Andersson N, Sjögren K, Venken K, Vanderschueren D, Jansson JO, Isaksson O, Ohlsson C 2008 Liver-derived IGF-I enhances the androgenic response in prostate. J Endocrinol 199:489 -497
360. Kleinberg DL, Ruan W, Yee D, Kovacs KT, Vidal S 2007 Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice. Endocrinology 148:1080-1088
361. Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS 1992 The effect of finasteride in men with benign prostatic hyperplasia.NEngl J Med 327:1185-1191
362. Lepor H 1998 Natural history, evaluation, and nonsurgical management of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan Jr ED, Wein AJ, eds. Campbell's urology. Philadelphia: WB Saunders; 1453-1477
363. Murakoshi M, Ikeda R, Fukui N, Nakayama T 2001 Relationship between prostatic atrophy and apoptosis in the canine spontaneous benign prostatic hyperplasia (BPH) following chlormadinone acetate (CMA). Tokai J Exp Clin Med 26:71-75
364. Colao A, Marzullo P, Ferone D, Spiezia S, Cerbone G, Marinò V, Di Sarno A, Merola B, Lombardi G 1998 Prostate hyperplasia: an unknown feature of acromegaly. J Clin Endocrinol Metab 83:775-779
365. Colao A, DiSommaC, Spiezia S, Filippella M, Pivonello R, Lombardi G 2003 Effect of growth hormone (GH) and/or testosterone replacement on the prostate in GH-deficient adult patients. J Clin Endocrinol Metab 88:88-94
366. Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE 2007 Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab 92:902-910
367. Cohen A, Levy R, Blethen S, Kuntze J, Hertz J, Frane J, The growth response to insulin-like growth factor-1 treatment during the first year of therapy in prepubertal children is dependent on mean Increlex dose. Program of the 90th Annual Meeting of The Endocrine Society, San Francisco, CA, 2008 (Abstract P2-563)
368. Rogol A, Frane J, von Stein T, Bright G, Analysis of safety events in clinical trials of rhIGF-1 replacement therapy in children with IGF-1 deficiency. Program of the 90th Annual Meeting of The Endocrine Society, San Francisco, CA, 2008 (Abstract P2-565)
369. Mahesh S, Kaskel F 2008 Growth hormone axis in chronic kidney disease. Pediatr Nephrol 23:41-48
370. Tönshoff B, Kiepe D, Ciarmatori S 2005 Growth hormone/ insulin-like growth factor system in children with chronic renal failure. Pediatr Nephrol 20:279-289
371. Blum WF, Ranke MB, Kietzmann K, Tönshoff B, MehlsO 1991 Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uraemia. Pediatr Nephrol 5:539-544
372. Tönshoff B, Blum WF, Wingen AM, MehlsO1995 Serum insulin-like growth factors (IGFs) and IGF binding proteins 1, 2, and 3 in children with chronic renal failure: relationship to height and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. J Clin Endocrinol Metab 80:2684-2691
373. Haffner D, Schaefer F, Nissel R, Wühl E, Tönshoff B, MehlsO2000 Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. N Engl J Med 343:923-930
374. Hazel SJ, GillespieCM,Moore RJ, ClarkRG,Jureidini KF, Martin AA 1994 Enhanced body growth in uremic rats treated with IGF-I and growth hormone in combination. Kidney Int 46:58-68
375. Kovács GT, Oh J, Kovács J, Tönshoff B, Hunziker EB, Zapf J, MehlsO1996 Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia. Kidney Int 49:1413-1421
376. Poulsen JE 1953 Houssay phenomenon in man: recovery from retinopathy in a case of diabetes with Simmonds disease. Diabetes 2:7-12
377. Wright AD, Kohner EM, Oakley NW, Hartog M, Joplin GF, FraserTR1969 Serum growth hormone levels and the response of diabetic retinopathy to pituitary ablation. Br Med J 2:346-348
378. Lundbaek K, Christensen N, Jensen V, Johansen K, Olsen T, Hansen A, Orskov H, Osterby R 1970 Diabetes, diabetic angiopathy, and growth hormone. Lancet 2:131-133
379. Janssen JA, Lamberts SW 2000 Circulating IGF-I and its protective role in the pathogenesis of diabetic angiopathy. Clin Endocrinol (Oxf) 52:1-9
380. Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR 2003 Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest 111:1835-1842
381. Cheetham TD, Jones J, Taylor AM, Holly J, Matthews DR, Dunger DB 1993 The effects of recombinant insulin-like growthfactor I administrationongrowthhormonelevelsand insulin requirements in adolescents with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 36:678-681
382. Acerini CL, Patton CM, Savage MO, Kernell A, Westphal O, Dunger DB 1997 Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus. Lancet 350:1199-1204
383. Carroll PV, Umpleby M, Ward GS, Imuere S, Alexander E, Dunger D, Sönksen PH, Russell-Jones DL 1997 rhIGF-I administration reduces insulin requirements, decreases growth hormone secretion, and improves the lipid profile in adults with IDDM. Diabetes 46:1453-1458
384. Acerini CL, Harris DA, Matyka KA, Watts AP, Umpleby AM, Russell-Jones DL, Dunger DB 1998 Effects of lowdose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus. Metabolism 47:1481-1489
385. Carroll PV, Christ ER, UmplebyAM,Gowrie I, Jackson N, Bowes SB, Hovorka R, Croos P, Sönksen PH, Russell-Jones DL 2000 IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Diabetes 49:789-796
386. Zenobi PD, Jaeggi-Groisman SE, Riesen WF, Røder ME, Froesch ER 1992 Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus. J Clin Invest 90:2234-2241
387. Clemmons DR, Moses AC, Sommer A, Jacobson W, Rogol AD, Sleevi MR, Allan G 2005 Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose. Growth Horm IGF Res 15:265-274
388. Clemmons DR, Sleevi M, Allan G, Sommer A 2007 Effects of combined recombinant insulin-like growth factor (IGF)-I and IGF binding protein-3 in type 2 diabetic patients on glycemic control and distribution of IGF-I and IGF-II among serum binding protein complexes. J Clin Endocrinol Metab 92:2652-2658