IGF-I

インスリン様成長因子-I insulin-like growth factor-I

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1. the 9th letter of the Roman alphabet (同)i

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1. 『私は』私が
2. iodineの化学記号

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/07 13:41:49」(JST)

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Insulin-like growth factor 1 (somatomedin C)
PDB rendering based on 1bqt.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1B9G, 1BQT, 1GZR, 1GZY, 1GZZ, 1H02, 1H59, 1IMX, 1PMX, 1TGR, 1WQJ, 2DSP, 2DSQ, 2DSR, 2GF1, 3GF1, 3LRI
Identifiers
Symbols	IGF1; IGF-I; IGF1A; IGFI
External IDs	OMIM: 147440 MGI: 96432 HomoloGene: 515 GeneCards: IGF1 Gene
Gene Ontology Molecular function • insulin receptor binding • insulin-like growth factor receptor binding • integrin binding • hormone activity • protein binding • growth factor activity Cellular component • extracellular region • extracellular space • plasma membrane • insulin-like growth factor binding protein complex • platelet alpha granule lumen Biological process • skeletal system development • blood vessel remodeling • platelet degranulation • DNA replication • cellular component movement • signal transduction • Ras protein signal transduction • muscle organ development • blood coagulation • positive regulation of cell proliferation • negative regulation of cell proliferation • glycolate metabolic process • glial cell differentiation • positive regulation of cardiac muscle hypertrophy • positive regulation of phosphatidylinositol 3-kinase cascade • satellite cell maintenance involved in skeletal muscle regeneration • muscle hypertrophy • myotube cell development • positive regulation of smooth muscle cell migration • positive regulation of cerebellar granule cell precursor proliferation • water homeostasis • proteoglycan biosynthetic process • platelet activation • mammary gland development • exocrine pancreas development • regulation of establishment or maintenance of cell polarity • positive regulation of protein import into nucleus, translocation • negative regulation of smooth muscle cell apoptotic process • multicellular organism growth • bone mineralization involved in bone maturation • regulation of multicellular organism growth • positive regulation of activated T cell proliferation • positive regulation of tyrosine phosphorylation of Stat5 protein • negative regulation of apoptotic process • positive regulation of DNA binding • positive regulation of MAPK cascade • positive regulation of insulin-like growth factor receptor signaling pathway • cellular protein metabolic process • myoblast differentiation • positive regulation of osteoblast differentiation • positive regulation of glycogen biosynthetic process • positive regulation of DNA replication • positive regulation of glycolysis • positive regulation of mitosis • positive regulation of transcription, DNA-dependent • positive regulation of transcription from RNA polymerase II promoter • positive regulation of glucose import • positive regulation of Ras protein signal transduction • insulin-like growth factor receptor signaling pathway • phosphatidylinositol-mediated signaling • positive regulation of fibroblast proliferation • lung alveolus development • positive regulation of smooth muscle cell proliferation • branching morphogenesis of an epithelial tube • inner ear development • chondroitin sulfate proteoglycan biosynthetic process • positive regulation of epithelial cell proliferation • positive regulation of peptidyl-tyrosine phosphorylation • myoblast proliferation • positive regulation of protein kinase B signaling cascade • lung vasculature development • lung lobe morphogenesis • Type I pneumocyte differentiation • Type II pneumocyte differentiation • prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis • prostate gland growth • prostate gland stromal morphogenesis • negative regulation of androgen receptor signaling pathway • negative regulation of ERK1 and ERK2 cascade • positive regulation of calcineurin-NFAT signaling cascade • negative regulation of release of cytochrome c from mitochondria • positive regulation of myoblast proliferation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3479	16000
Ensembl	ENSG00000017427	ENSMUSG00000020053
UniProt	P05019	P05017
RefSeq (mRNA)	NM_000618	NM_001111274
RefSeq (protein)	NP_000609	NP_001104744
Location (UCSC)	Chr 12: 102.79 – 102.87 Mb	Chr 10: 87.86 – 87.94 Mb
PubMed search	[1]	[2]

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s.

IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin is used for the treatment of growth failure.

IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7,649 daltons.

Synthesis and circulation

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio.

In rat experiments the amount of IGF-1 mRNA in the liver was positively associated with dietary casein and negatively associated with a protein-free diet.

Recently, an efficient plant expression system was developed to produce biologically active recombinant human IGF-I (rhIGF-I) in transgenic rice grains.

Mechanism of action

Its primary action is mediated by binding to its specific receptor, the Insulin-like growth factor 1 receptor, abbreviated as ""IGF1R"", present on many cell types in many tissues. Binding to the IGF1R, a receptor tyrosine kinase, initiates intracellular signaling; IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death.

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.

Deficiency of either growth hormone or IGF-1 therefore results in diminished stature. GH-deficient children are given recombinant GH to increase their size. IGF-1 deficient humans, who are categorized as having Laron syndrome, or Laron's dwarfism, are treated with recombinant IGF-1. In beef cattle, circulating IGF-1 concentrations are related to reproductive performance.

Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. Phosphorylation of eukaryotic initiation factor 4e (eif-4E) [4EBP] by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism.W

Receptors

IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGF1R), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than the IGF-1 that is bound to the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase - meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia)..

IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

Other IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity.

Related growth factors

IGF-1 is closely related to a second protein called "IGF-2". IGF-2 also binds the IGF-1 receptor. However, IGF-2 alone binds a receptor called the "IGF-2 receptor" (also called the mannose-6 phosphate receptor). The insulin-like growth factor-II receptor (IGF2R) lacks signal transduction capacity, and its main role is to act as a sink for IGF-2 and make less IGF-2 available for binding with IGF-1R. As the name "insulin-like growth factor 1" implies, IGF-1 is structurally related to insulin, and is even capable of binding the insulin receptor, albeit at lower affinity than insulin. In contrast to the development of muscle and joint strength, IGF-1 has been seen to decrease to the Bulbospongiosus muscle in males.

A splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano growth factor (MGF).

Factors influencing the levels in the circulation

3-d model of IGF-1

Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals - see also endocrine disruptor. In free-ranging animals, nutrition and predators may influences levels of IGF-1.

Fasting, including intermittent fasting, can reduce IGF-1 levels rapidly and dramatically.

Clinical significance

Contribution to aging

It is now widely accepted that signaling through the insulin/IGF-1-like receptor pathway is a significant contributor to the biological aging process in many organisms. This avenue of research first achieved prominence with the work of Cynthia Kenyon, who showed that mutations in the daf-2 [[gene]ouble the lifespan of the roundworm C. elegans. daf-2 encodes the worm's unified insulin/IGF-1-like receptor. Despite the impact of IGF1-like on C. elegans longevity, direct application to mammalian aging is not as clear as mammals do not form dauer like developmental stages.

Insulin/IGF-1-like signaling is conserved from worms to humans. In vitro experiments show that mutations that reduce insulin/IGF-1 signaling have been shown to decelerate the degenerative aging process and extend lifespan in a wide range of organisms, including Drosophila melanogaster, mice, and possibly humans. Reduced IGF-1 signaling is also thought to contribute to the "anti-aging" effects of Calorie restriction.

Nevertheless the situation in vivo is evidently different, Anabolic deficiency in men with chronic heart failure is prevalent and could have an associated detrimental impact on survival. Deficiency of anabolic hormones identifies groups with a higher mortality.

Neuropathy

Therapeutic administration with neurotrophic proteins (IGF I) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.

Dwarfism

Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed Laron dwarfism does not respond at all to growth hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below -3 standard deviations (SD), and IGF-1 levels below -3SD. Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. As a result, these patients cannot be expected to respond to GH treatment.

People with Laron syndrome have strikingly low rates of cancer and diabetes.

Cancer

The IGF signaling pathway has a pathogenic role in cancer. Studies have shown that increased levels of IGF lead to increased growth of existing cancer cells. People with Laron syndrome have also recently been shown to be of much less risk to develop cancer.

Diagnostic test

Reference ranges for IGF-1 (in ng/mL)
Age	Females		Males
	2.5th centile	97.5th centile	2.5th centile	97.5th centile
20	111	423	156	385
25	102	360	119	343
30	94	309	97	306
35	86	271	84	275
40	79	246	76	251
45	73	232	71	233
50	68	228	66	221
55	64	231	61	214
60	61	237	55	211
65	59	241	49	209
70	57	237	46	207
75	55	219	48	202

IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess in acromegaly and gigantism.

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential management over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.

As a therapeutic agent

Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure. IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli.

Several companies have evaluated IGF-1 in clinical trials for a variety of additional indications, including type 1 diabetes, type 2 diabetes, amyotrophic lateral sclerosis (ALS aka "Lou Gehrig's Disease"), severe burn injury and myotonic muscular dystrophy (MMD). Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing hemoglobin A1C levels, as well as daily insulin consumption. However, the sponsor, Genentech, discontinued the program due to an exacerbation of diabetic retinopathy in patients coupled with a shift in corporate focus towards oncology. Cephalon and Chiron conducted two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second was equivocal, and the product has never been approved by the FDA.

However, in the last few years, two additional companies Tercica and Insmed compiled enough clinical trial data to seek FDA approval in the United States. In August 2005, the FDA approved Tercica's IGF-1 drug, Increlex, as replacement therapy for severe primary IGF-1 deficiency based on clinical trial data from 71 patients. In December 2005, the FDA also approved Iplex, Insmed's IGF-1/IGFBP-3 complex. The Insmed drug is injected once a day versus the twice-a-day version that Tercica sells.

Insmed was found to infringe on patents licensed by Tercica, which then sought to get a U.S. district court judge to ban sales of Iplex. To settle patent infringement charges and resolve all litigation between the two companies, Insmed in March 2007 agreed to withdraw Iplex from the U.S. market, leaving Tercica's Increlex as the sole version of IGF-1 available in the United States.

By delivering Iplex in a complex, patients might get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia^{[citation needed]}. This medication might emulate IGF-1's endogenous complexing, as in the human body 97–99% of IGF-1 is bound to one of six IGF binding proteins^{[citation needed]}. IGFBP-3 is the most abundant of these binding proteins, accounting for approximately 80% of IGF-1 binding.

In a clinical trial of an investigational compound MK-677, which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms. Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients, but other studies shown strong beneficial effects of IGF-I replacement therapy in ALS patients, and therefore IGF-I may have the potential to be an effective and safe medicine against ALS, however other studies had conflicting results.

IGFBP-3 is a carrier for IGF-1, meaning that IGF-1 binds IGFBP-3, creating a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life in serum. Without binding to IGFBP-3, IGF-1 is cleared rapidly through the kidney, due to its low molecular weight. But when bound to IGFBP-3, IGF-1 evades renal clearance. Also, since IGFBP-3 has a lower affinity for IGF-1 than IGF-1 has for its receptor, IGFR, its binding does not interfere with IGF-1 function. For these reasons, an IGF-1/IGFBP-3 combination approach was approved for human treatment... brought forward by a small company called Insmed. However, Insmed fell afoul patent issues, and was ordered to desist in this approach.

IGF-1 has also been shown to be effective in animal models of stroke when combined with Erythropoietin. Both behavioural and cellular improvements were found.

Miscellaneous uses

Numerous sources have claimed that Deer Antler Spray, purportedly extracted from cervid sources, contains IGF-1. Credence to this claim comes from the fact that deer's antlers grow extremely rapidly and that the associated cellular factors can similarly aid in skeletal healing in humans. IGF-1 is currently a substance banned by various sporting bodies. However sprays and pills claiming to be 'deer antler extracts' are freely available on the market.

Interactions

Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 Binding Proteins (IGFBPs), of which there are six (IGFBP1-6).

Specific references are provided for interactions with IGFBP3, IGFBP4, and IGFBP7.

References

Further reading

• Butler AA, Yakar S, LeRoith D (2002). "Insulin-like growth factor-I: compartmentalization within the somatotropic axis?". News Physiol. Sci. 17: 82–5. PMID 11909998. 
• Maccario M, Tassone F, Grottoli S, et al. (2002). "Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity". Ann. Endocrinol. (Paris) 63 (2 Pt 1): 140–4. PMID 11994678. 
• Camacho-Hübner C, Woods KA, Clark AJ, Savage MO (2003). "Insulin-like growth factor (IGF)-I gene deletion". Reviews in endocrine & metabolic disorders 3 (4): 357–61. doi:10.1023/A:1020957809082. PMID 12424437. 
• Dantzer B, Swanson, EM (2012). "Mediation of vertebrate life histories via insulin-like growth factor-1.". Biological Reviews 87 (2): 414–429. doi:10.1111/j.1469-185X.2011.00204.x. 
• Trojan LA, Kopinski P, Wei MX, et al. (2004). "IGF-I: from diagnostic to triple-helix gene therapy of solid tumors". Acta Biochim. Pol. 49 (4): 979–90. PMID 12545204. 
• Winn N, Paul A, Musaró A, Rosenthal N (2003). "Insulin-like growth factor isoforms in skeletal muscle aging, regeneration, and disease". Cold Spring Harb. Symp. Quant. Biol. 67: 507–18. doi:10.1101/sqb.2002.67.507. PMID 12858577. 
• Delafontaine P, Song YH, Li Y (2005). "Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels". Arterioscler. Thromb. Vasc. Biol. 24 (3): 435–44. doi:10.1161/01.ATV.0000105902.89459.09. PMID 14604834. 
• Trejo JL, Carro E, Garcia-Galloway E, Torres-Aleman I (2004). "Role of insulin-like growth factor I signaling in neurodegenerative diseases". J. Mol. Med. 82 (3): 156–62. doi:10.1007/s00109-003-0499-7. PMID 14647921. 
• Rabinovsky ED (2004). "The multifunctional role of IGF-1 in peripheral nerve regeneration". Neurol. Res. 26 (2): 204–10. doi:10.1179/016164104225013851. PMID 15072640. 
• Rincon M, Muzumdar R, Atzmon G, Barzilai N (2005). "The paradox of the insulin/IGF-1 signaling pathway in longevity". Mech. Ageing Dev. 125 (6): 397–403. doi:10.1016/j.mad.2004.03.006. PMID 15272501. 
• Conti E, Carrozza C, Capoluongo E, et al. (2005). "Insulin-like growth factor-1 as a vascular protective factor". Circulation 110 (15): 2260–5. doi:10.1161/01.CIR.0000144309.87183.FB. PMID 15477425. 
• Wood AW, Duan C, Bern HA (2005). "Insulin-like growth factor signaling in fish". Int. Rev. Cytol. 243: 215–85. doi:10.1016/S0074-7696(05)43004-1. PMID 15797461. 
• Sandhu MS (2005). "Insulin-like growth factor-I and risk of type 2 diabetes and coronary heart disease: molecular epidemiology". Endocrine development. Endocrine Development 9: 44–54. doi:10.1159/000085755. ISBN 3-8055-7926-8. PMID 15879687. 
• Ye P, D'Ercole AJ (2006). "Insulin-like growth factor actions during development of neural stem cells and progenitors in the central nervous system". J. Neurosci. Res. 83 (1): 1–6. doi:10.1002/jnr.20688. PMID 16294334. 
• Gómez JM (2006). "The role of insulin-like growth factor I components in the regulation of vitamin D". Current pharmaceutical biotechnology 7 (2): 125–32. doi:10.2174/138920106776597621. PMID 16724947. 
• Federico G, Street ME, Maghnie M, et al. (2006). "Assessment of serum IGF-I concentrations in the diagnosis of isolated childhood-onset GH deficiency: a proposal of the Italian Society for Pediatric Endocrinology and Diabetes (SIEDP/ISPED)". J. Endocrinol. Invest. 29 (8): 732–7. PMID 17033263. 
• Zakula Z, Koricanac G, Putnikovic B, et al. (2007). "Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes". Med. Hypotheses 69 (2): 302–6. doi:10.1016/j.mehy.2006.11.045. PMID 17289286. 
• Trojan J, Cloix JF, Ardourel MY, et al. (2007). "Insulin-like growth factor type I biology and targeting in malignant gliomas". Neuroscience 145 (3): 795–811. doi:10.1016/j.neuroscience.2007.01.021. PMID 17320297. 
• Venkatasubramanian G, Chittiprol S, Neelakantachar N, Naveen MN, Thirthall J, Gangadhar BN, Shetty KT (October 2007). "Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia". Am J Psychiatry 164 (10): 1557–60. doi:10.1176/appi.ajp.2007.07020233. PMID 17898347. 

External links

• Insulin-Like Growth Factor I at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. インスリン様成長因子1の生理学 physiology of insulin like growth factor 1
• 2. 先端巨大症の診断 diagnosis of acromegaly
• 3. 小児における成長ホルモン欠乏症の診断 diagnosis of growth hormone deficiency in children
• 4. 思春期に生じる多嚢胞性卵巣症候群の診断的評価 diagnostic evaluation of polycystic ovary syndrome in adolescents
• 5. 成人における成長ホルモン欠乏症 growth hormone deficiency in adults

English Journal

• Insulin-like growth factor I (IGF-1) deficiency ameliorates sex difference in cardiac contractile function and intracellular Ca(2+) homeostasis.

• Ceylan-Isik AF, Li Q, Ren J.SourceCenter for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
• Toxicology letters.Toxicol Lett.2011 Oct 10;206(2):130-8. Epub 2011 Jul 7.
• Sex difference in cardiac contractile function exists which may contribute to the different prevalence in cardiovascular diseases between genders. However, the precise mechanisms of action behind sex difference in cardiac function are still elusive. Given that sex difference exists in insulin-like g
• PMID 21763763

• Chondroprotective effects of pulsed electromagnetic fields on human cartilage explants.

• Ongaro A, Pellati A, Masieri FF, Caruso A, Setti S, Cadossi R, Biscione R, Massari L, Fini M, De Mattei M.SourceDepartment of Morphology and Embryology, University of Ferrara, Ferrara, Italy. ngrlss@unife.it.
• Bioelectromagnetics.Bioelectromagnetics.2011 Oct;32(7):543-51. doi: 10.1002/bem.20663. Epub 2011 Mar 15.
• This study investigated the effects of pulsed electromagnetic fields (PEMFs) on proteoglycan (PG) metabolism of human articular cartilage explants from patients with osteoarthritis (OA). Human cartilage explants, recovered from lateral and medial femoral condyles, were classified according to the In
• PMID 21412809

Japanese Journal

• 初期卵胞発育における卵子と莢膜細胞の細胞間ネットワーク

• 折坂 誠,服部 克成,福田 真,小辻 文和
• Journal of mammalian ova research = 日本哺乳動物卵子学会誌 28(1), 2-7, 2011-04-01
• NAID 10028123694

• P1-13-2 低酸素がインスリン様成長因子-I(IGF-I)とその結合タンパク-1(IGFBP-1)におよぼす影響(Group21 妊娠・分娩・産褥の生理・病理4 IUGR・PIH,一般演題,第63回日本産科婦人科学会学術講演会)

• 綱脇 智法,酒井 啓治,岩下 光利
• 日本産科婦人科學會雜誌 63(2), 525, 2011-02-01
• NAID 110008509001

Related Links

• IGF-1とは

IGF-1(別名：ソマトメジンC)とは、成長ホルモンによって肝臓などから分泌が促進されるインスリンに類似した働きを持つ成長因子です。実は、成長ホルモンによる体の成長、細胞の修復や再生と言った作用の一部は、IGF-1によっ ...

• IGF-Ⅰ (ソマトメジンC) | SRL総合検査案内

IGF-Ⅰ (ソマトメジンC)のページです。IGF-1（Insulin-like Growth Factor I）はソマトメジンCとも呼ばれ、GH（Growth factor Hormone；成長ホルモン）の作用により主に肝臓で産生されるホルモンです。GHの分泌異常を反映するため、先端巨大 ...

• IGF-I基準値｜成人の成長ホルモン分泌不全症

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★リンクテーブル★

国試過去問	「109B056」「109A056」「107I067」
リンク元	「神経性食思不振症」「成長ホルモン」「下垂体前葉ホルモン」「基準値」「インスリン様成長因子-I」
拡張検索	「IGF-II受容体」「IGF-II receptor」「IGF-II」「IGF-IIレセプター」
関連記事	「I」「IGF」「Id」

「109B056」

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• 家族歴：父親が胃癌。
• 現症：意識は清明。身長 170cm、体重 80kg。体温 36.5℃。脈拍 68/分、整。血圧 130/94mmHg。呼吸数 18/分。眉弓部の膨隆、下顎の突出、鼻と口唇の肥大および巨大舌を認める。眼瞼結膜と眼球結膜とに異常を認めない。咽頭に発赤を認めない。頸静脈の怒張を認めない。甲状腺腫と頸部リンパ節とを触知しない。心音と呼吸音とに異常を認めない。手足の体積の増大を認める。腹部は平坦、軟で、肝・脾を触知しない。腱反射に異常を認めない。
• 検査所見：尿所見：蛋白(-)、糖(-)、ケトン体(-)、潜血(±)、沈渣に白血球を認めない。血液所見：赤血球 487万、Hb 14.6g/dL、Ht 43%、白血球 4,000、血小板 23万、PT 115%(基準 80～120)。血液生化学所見：総蛋白 7.2g/dL、アルブミン 4.2g/dL、総ビリルビン 0.6mg/dL、AST 21IU/L、ALT 28IU/L、LD 185IU/L(基準 176～353)、ALP 277IU/L(基準 115～359)、γ-GTP 34IU/L(基準 8～50)、アミラーゼ 76IU/L(基準 37～160)、CK 135IU/L(基準 30～140)、尿素窒素 14mg/dL、クレアチニン 0.7mg/dL、尿酸 5.9mg/dL、血糖 127mg/dL、HbA1c 7.0%(基準 4.6～6.2)、トリグリセリド 162mg/dL、HDLコレステロール 75mg/dL、LDLコレステロール 146mg/dL、Na 142mEq/L、K 4.6mEq/L、Cl 102mEq/L、Ca 9.3mg/dL、P 4.0mg/dL、TSH 0.6μU/mL(基準 0.4～4.0)、FT4 1.1ng/dL(基準 0.8～1.8)。心電図に異常を認めない。胸部エックス線写真で心胸郭比 54%。頭部エックス線写真(別冊No. 8)を別に示す。頭部MRIで下垂体に限局した腫瘤を認める。
• この患者に行うべき検査として有用でないのはどれか。

• a　GHの測定
• b　プロラクチンの測定
• c　フロセミド負荷試験
• d　75g経口グルコース負荷試験
• e　インスリン様成長因子-I(IGF-I)の測定

[正答]

C

※国試ナビ4※　［109B055］←［国試_109］→［109B057］

「109A056」

　　[★]

• 33歳の女性。未経妊。無月経を主訴に来院した。初経13歳。月経周期は不規則であり、29歳以降無月経となっていたがそのままにしていた。身長 161cm、体重 58kg。脈拍76/分、整。血圧 114/74mmHg。胸腹部と四肢とに異常を認めない。恥毛は正常女性型。血液生化学所見：血糖 86mg/dL、TSH 1.3μU/mL(基準 0.4～4.0)、LH 2.0mIU/mL(基準 1.8～7.6)、FSH 6.4mIU/mL(基準 5.2～14.4)、プロラクチン 79ng/mL(基準 15以下)、FT4 0.8ng/dL(基準 0.8～1.8)、コルチゾール 10ng/dL(基準 5.2～12.6)、エストラジオール 15pg/mL(基準 25～75)、IGF-I 155ng/mL(基準 93～236)。頭部造影MRIのT1強調冠状断像(別冊No. 30)を別に示す。
• この患者にみられる可能性が高いのはどれか。

• a　慢性甲状腺炎
• b　染色体異常
• c　視野障害
• d　低血糖症
• e　乳汁漏出

[正答]

E

※国試ナビ4※　［109A055］←［国試_109］→［109A057］

「107I067」

　　[★]

• 62歳の女性。手のしびれ感を主訴に来院した。8年前から高血圧症のため自宅近くの診療所で治療を受けており、2年前から血糖値の軽度上昇を指摘されていた。ほぼ同時期から両手の第2～4指の先端部に｢ピリピリする｣感じを自覚し、徐々に増悪してボタンが留めにくくなった。身長165cm、体重67kg。脈拍64/分、整。血圧150/86mmHg。声はこもった低音である。顔と手の写真(別冊No.22Ａ、Ｂ)を別に示す。
• 確定診断のために測定するホルモンとして最も適切なのはどれか。

• a　インスリン
• b　コルチゾール
• c　プロラクチン
• d　アルドステロン
• e　インスリン様成長因子-I(IGF-I)

[正答]

E

※国試ナビ4※　［107I066］←［国試_107］→［107I068］

「神経性食思不振症」

　　[★]

ラ

anorexia nervosa, AN

同

神経性食欲不振症、神経性無食欲症

also see KPS. 798

概念

• 器質的・特定の精神的疾患がないのに、拒食や過食などの食行動の異常、極端なやせ、無月経など種々の身体・精神症状をきたす病態。

• 身体像(ボディイメージ)の障害、やせ願望や肥満恐怖などによる。

病型

• 制限型：少食でやせを維持
• むちゃ食い/排出型：過食しながら自己嘔吐や下剤・利尿薬の乱用でやせを維持

病因

• 1. 遺伝的要因
• 2. 環境要因(人格的脆弱性、生活環境、社会文化的要因)など　→　ストレスを適切に処理できないために発症

• 性格：内向的、自己中心的、小心、完全癖、潔癖症など
• 生活環境：家庭内の葛藤、学業や人間関係の悩み

• 病態的には、心理的ストレスが大脳皮質を介して視床下部摂食中枢のコルチコトロピン放出ホルモン系を活性化することなどにより、食欲抑制や性機能障害をきたす。

疫学

• 1980年代より増加傾向。日本の有病率は0.4-1.0%(摂食異常調査表による調査)(IMD.922)
• 12-25歳に好発(YN.D-166)。10代後半-20代前半、15歳以下の発症例も増加傾向(IMD.922)。
• 99%が女性(YN.D-166)。男性例は5%以下(IMD.922)

症状

• やせ、無月経
• 病識なし、活動性亢進、むちゃ食い/排出型の場合は自己嘔吐や下剤・利尿薬乱用の習慣化
• 飢餓症候群

• 生活すべてが食とやせの維持に振り回され、ついには飢餓に伴う精神症状が出現
• 集中力・判断力の低下、抑うつ、不安、過敏性、不眠、自傷行為など

身体所見(IMD.922, YN.D-166)

低栄養だが、性ホルモンは比較的維持。

• 低血圧、低体温、便秘、徐脈　←　自律神経失調
• (背中)うぶ毛密生、貧血、浮腫、肝機能障害、
• カロチン症
• 循環障害による皮膚色の変化や凍瘡、末梢神経麻痺
• やせに比して乳房は比較的保たれ、腋毛・恥毛は脱落しないことが多い。

検査

• 白血球数減少、貧血、血小板減少
• 肝機能障害、低血糖、低蛋白血症
• (むちゃ食い/排出型)低Na・低K血症、代謝性アルカローシスや高アミラーゼ血症　←　低K血症(循環血漿量減少　→　RAA系の亢進　→　アルドステロンによるKの排出)
• 血清コレステロール値：(軽症)上昇、(重症)低下
• 骨密度の低下
• 甲状腺：T4：→/↑、T3：↓、reverse T3：↑(低T3症候群)。
• 成長ホルモン：↑、インスリン様成長因子-I(IGF-I)：↓　　←　末梢でIGF-Iの産生が低下、負のフィードバックにより成長ホルモンが増加
• ACTH、コルチゾール：↑

• 卵胞刺激ホルモン(FSH)：→/↑
• 黄体ホルモン(LH)：↓

血算	ヘモグロビン	減少(貧血)
	白血球	減少
	リンパ球	比較的増加
生化学	Na	低Na血症(自己嘔吐・下剤使用例)
	K	低Ka血症(自己嘔吐・下剤使用例)
	AST	上昇
	ALT	上昇
	LDH	上昇
	T-Cho	上昇
	血糖	低下
血清学	IgG	低下(易感染性はない)
内分泌	T3	低下
	reverse T3	上昇
	GH	↑
	LH	↓
	FSH	→ or ↑
	コルチゾール	→ or ↑

診断

診断基準(厚生省特定疾患・神経性食欲不振症調査研究班, 1990年)

• (2) 標準体重の －20%以上のやせ
• (3) 食行動の異常(不食、大食、隠れ食いなど)
• (4) 体重や体型についての歪んだ認識(体重増加に対する極端な恐怖など)
• (1) 発症年齢：30歳以下
• (5) (女性ならば)無月経
• (6) やせの原因と考えられる器質性疾患がない

• やせや無月経をきたす器質性疾患：視床下部腫瘍、下垂体機能低下症、糖尿病、慢性膵炎、甲状腺機能亢進症、炎症性腸疾患、結核などの感染症、悪性腫瘍

鑑別診断

食思不振症とか錐体機能低下症の比較 IMD.923改変

		神経性食思不振症	下垂体機能低下症		ANについて
好発年齢		思春期	全年齢
性差		女>>男	なし
体重		著明に減少	不定
食欲不振		高度	希
食行動の異常		高頻度	なし
精神運動異常		活発	無欲状
月経異常		あり(体重減少に先行)	あり
産毛の増加		あり	なし？
恥毛・腋毛脱落		なし	あり		LH, FSHが少しは存在するため。
乳腺萎縮		軽度 やせに比して乳房は保たれる	著明
下垂体機能	GH	正常～高値	低値		IGF-I低値
	ACTH	正常～高値	低値
	LH, FSH	低値	低値
	TSH	正常	低値
甲状腺機能		低T3症候群	機能低下		T4正常、reverse T3上昇
副腎皮質機能		正常 (コルチゾール高値例あり)	機能低下 (コルチゾール低値)
頭部CT・MRI		異常なし	異常例有り (下垂体腫瘍, empty sellaなど)
症状		背部のうぶ毛の増加、便秘、 低血圧、徐脈、下腿浮腫、 循環障害による皮膚色の変化や 凍瘡、末梢神経麻痺、 カロチン症など

神経性食思不振症では成長ホルモンと糖質コルチコイドの上昇、末梢の甲状腺ホルモンの異常(reverse T3↑のこと？)、インスリン分泌の異常が認められることがある。(参考6)　　←　甲状腺、副腎機能は正常と言い切っている書物もあるが、、、

治療

• 医師と患者の信頼関係が重要。体重増加を受け入れてもらう
• 栄養療法：少量・低エネルギー食より開始。栄養不良が著しい場合には静脈栄養/経腸栄養
• 心理社会的療法(認知行動療法)

予後

• 改善50%、不変25%、悪化25%、死亡率5-8%(YN.D-167)　←　過食性食思不振症に比して予後が悪い

参考

• 1. 思春期やせ症

http://www.aiiku.or.jp/aiiku/jigyo/contents/kaisetsu/ks0712/ks0712_4.pdf

• 5. [charged] Patient information: Anorexia nervosa (TheBasics) - uptodate [1]
• 6. [charged] 成人における神経性食思不振症：診断、随伴する臨床的特徴、および評価 - uptodate [2]
• 7. [charged] 成人における神経性食思不振症：合併症の評価およびこれらの合併症管理のための入院基準 - uptodate [3]
• 8. [charged] 成人における神経性食思不振症：薬物療法 - uptodate [4]
• 9. [charged] 成人および思春期における神経性食思不振症：再栄養症候群 - uptodate [5]
• 10. [charged] 成人および思春期における神経性食思不振症：内科的合併症およびその管理 - uptodate [6]
• 11. [charged] 摂食障害：疫学、病因、および臨床的特徴の概要 - uptodate [7]
• 12. [charged] 摂食障害：治療および転帰 - uptodate [8]

「成長ホルモン」

　　[★]

英

growth hormone (Z), GH

同？

ソマトトロピン somatotropin、ソマトトロピックホルモン somatotropic hormone STH

関

成長ホルモン

関

ホルモン、下垂体成長ホルモン、組換え型成長ホルモン

基準値

• 血清：M:0.4±0.1 ng/ml, F:3.2±0.4 ng/ml　　→　性差(エストロゲンが分泌促進作用を持つため？生物学的意義は？)

分類

• 下垂体ホルモン

• 下垂体前葉ホルモン

性状

• ペプチド

産生組織

• 下垂体前葉

• 好酸性細胞

作用

SP.883

• 1.IGF分泌促進

• 肝臓を含む種々の組織でインスリン様成長因子 IGFの産生を亢進させる。

• インスリン様成長因子-I IGF-I：細胞増殖作用、蛋白同化作用、糖質同化作用、脂質同化作用
• インスリン様成長因子-II IGF-II：細胞増殖作用、蛋白同化作用、糖質同化作用、脂質同化作用

• 2. 成長促進作用

• 成長を促進：各組織における細胞分裂による増殖(細胞分裂、DNA,RNA,蛋白合成)と細胞の分化

• 3. 中間代謝に対する作用

• 3-1. タンパク同化作用

• GH存在下でアミノ酸が組織に取り込まれ蛋白合成のために用いられる。内臓臓器、骨格筋、皮膚、および結合組織などほとんど全ての組織がGHに反応して肥大。

• 3-2. 糖代謝

• (抗インスリン作用->血糖上昇)筋肉、脂肪へのグルコース取り込みを減少させ、肝臓からのグルコース放出を増加させる。膵臓に作用しインスリン分泌を促進する。　←　GHは何がしたいの？

• 3-3. 脂質代謝

• (中性脂肪分解作用->血中遊離脂肪酸増加)中性脂肪を分解し、末梢血でFFAを増加させ、グルコースの代わりにエネルギー源として利用される。(おそらくFFA増加により)ケトン体が増加する。

• 3-4. 電解質代謝

• (骨形成に向かう反応。リン酸濃度上昇、カルシウム濃度上昇)近位尿細管でのリン酸の再吸収促進、腸からのカルシウム促進。Na,K,Cl濃度増加、細胞外液増加

分泌の調整

分泌刺激	分泌促進	分泌抑制
神経刺激	睡眠(StageIII&IV)	REM睡眠
	ストレス	愛情剥脱
	α受容体刺激薬	α受容体拮抗薬
	β受容体拮抗薬	β受容体刺激薬
	ドパミン受容体作動薬
	アセチルコリン受容体作動薬	アセチルコリン受容体拮抗薬
代謝刺激	低血糖	高血糖
	絶食、神経性食思不振症
	脂肪酸の低下	脂肪酸の増加
	アミノ酸
	コントロール不良糖尿病	肥満
	尿毒症
	肝硬変
ホルモン	GHRH
	IGF-I低値	IGF-I高値
	エストロゲン	甲状腺機能低下症
	グルカゴン	グルココルチコイド高値
	ADH(AVP)

• 分泌促進：成長ホルモン放出ホルモン(GHRH)、グレリン、基礎分泌レベルのコルチゾール、ドパミンアゴニスト(ブロモクリプチン)　　←　　GH産生には甲状腺ホルモンが必須
• 分泌抑制：過剰量のコルチゾール

分子機構

• 受容体はG蛋白共役型受容体(Gsαサブユニット)
• 細胞内シグナル伝達系は成長ホルモン、プロラクチン、サイトカインで似ており、JAK/STATを介する。

臨床関連

• 巨人症
• 先端巨大症
• 下垂体性糖尿症

• インスリン抵抗性

• 成長の遅れ：成長ホルモン分泌が低下している場合、3歳頃から身長の伸びが遅れる。

• 成長ホルモン分泌不全症
• 成長ホルモン欠乏症
• 成長ホルモン欠損症
• 成長ホルモン分泌低下症

国試

• 106G021、095B059

「下垂体前葉ホルモン」

　　[★]

英

anterior pituitary hormone

関

下垂体前葉、下垂体、下垂体ホルモン、ホルモン

分泌されるホルモン

• 単純ペプチドホルモン

• 成長ホルモン(growth hormone, GH)
• 副腎皮質刺激ホルモン(adrenocorticotropic hormone, ACTH)
• プロラクチン(prolactin)

• 糖タンパク質ホルモン

• 甲状腺刺激ホルモン(thyroid-stimulating hormone,TSH)
• 卵胞刺激ホルモン(follicle-stimulating hormone,FSH)
• 黄体形成ホルモン(luteinizing hormone, LH)

GOO. chapter 55

名称		構造	分泌細胞	下垂体前葉細胞 全細胞に対する 産生細胞の割合	染色性		サブユニット	残基数 (aa.)	分子量 (kDa)	その他
成長ホルモン	GH	ペプチド	somatotroph	40-50%	好酸性		1	191	22
プロラクチン	PRL		mammotroph	10-25%	好酸性		1	199	23
副腎皮質刺激ホルモン	ACTH		corticotroph	0.1	好塩基性	嫌色素性	1	39	4.5	POMC由来
甲状腺刺激ホルモン	TSH	糖タンパク	thyrotroph	0.05	好塩基性		2	α: 92, β:118	28	αサブユニットは共通
卵胞刺激ホルモン	FSH		gonadotroph	10-15%	好塩基性		2	α: 92, β:111	32.6
黄体形成ホルモン	LH				好塩基性		2	α: 92, β:121	29.4

HIM.2196

Table 333-1 Anterior Pituitary Hormone Expression and Regulation
Cell	corticotrope	somatotrope	lactotrope	thyrotrope	gonadotrope
Tissue-specific transcription factor	T-Pit	Prop-1, Pit-1	Prop-1, Pit-1	Prop-1, Pit-1, TEF	SF-1, DAX-1
Fetal appearance	6 weeks	8 weeks	12 weeks	12 weeks	12 weeks
Hormone	POMC	GH	PRL	TSH	FSH LH
Chromosomal locus	2p	17q	6	－6q; －1p	－11p; －19q
Protein	ポリペプチド			糖タンパク
Amino acids	266 (ACTH 1–39)	191	199	211	210 204
Stimulators	CRH, AVP, gp-130 cytokines	GHRH, ghrelin, bromocriptine(1)	estrogen, TRH, VIP	TRH	GnRH, activins, estrogen
Inhibitors	glucocorticoids	somatostatin, IGF-I	dopamine	T3, T4, dopamine, somatostatin, glucocorticoids	sex steroids, inhibin
Target gland	adrenal	liver, other tissues	breast, other tissues	thyroid	ovary, testis
Trophic effect	steroid production	IGF-I production, growth induction, insulin antagonism	milk production	T4 synthesis and secretion	sex steroid production, follicle growth, germ cell maturation

(1):QB.D-253

「基準値」

　　[★]

英

reference value

関

正常値 normal value

QBの基準値

■電解質
ナトリウム	Na	135-147	140	mEq/l
カリウム	K	3.7-4.8	4	mEq/l
塩素	Cl	99-106	103	mEq/l
カルシウム	Ca	8.6-10.2	9.5	mg/dl
リン	P	2.5-4.5	3.5	mg/dl

新生児・乳児・小児の検査値

• 年齢と共に増加。幼小児　＜　成人

• 1. 乳児期以降に成人値

• アルブミン
• コレステロール

• 2. 小児期以降に成人値

• 総蛋白
• BUN
• IgM

• 3. 学童期以降に成人値

• クレアチニン
• 尿酸
• IgA　：　粘膜免疫の完成は遅いのですかね。上気道感染症がこのころに少なくなるのかも？

• 年齢とと共に減少。幼小児　＞　成人

• 1. 乳児期以降に成人値

• 赤血球
• カリウム
• TSH

• 2. 小児期以降に成人値

• 白血球
• カルシウム

• 3. 学童期以降に成人値

• LDH
• リン

• 特異な変化

• 1. 乳児期と思春期にピーク

• ALP　：　骨形成と関連

• 2. 思春期にピーク

• インスリン様成長因子-I IGF-I　：　成長ホルモン依存的な成長のスパート

• 3. 出生児に高く、乳児期に低下し、その後漸増

• 鉄　：母胎からの移行鉄を使い果たし、その後自ら貯蔵する
• IgG　：母体からの移行抗体による

「インスリン様成長因子-I」

　　[★]

英

insulin-like growth factor I insuline-like growth factor-I IGF-I IGF-1

同

インスリン様増殖因子I、インスリン様成長因子I。ソマトメジンC somatomedin C, ソマトメジン somatomedin

性状

• ペプチド

産生組織

• 肝臓を始めとする多くの臓器

標的組織

• 血行性にホルモンとして、自己分泌的、傍分泌的に作用。

作用

• IGF-IはGH依存性に種々の組織で合成、分泌され、主にオートクリン作用によって組織の増殖を促進する。

分泌の調整

• 分泌促進：成長ホルモン、インスリン
• 分泌抑制：絶食(GH↑だが)、エストロゲン、コルチゾール

「IGF-II受容体」

　　[★]

英

IGF-II receptor

関

マンノース6リン酸受容体、IGF受容体2型、IGF-2受容体、IGF-IIレセプター、インスリン様増殖因子II受容体

「IGF-II receptor」

　　[★]

• IGF-II受容体、IGF-IIレセプター

関

IGF type 2 receptor、IGF-2 receptor、insulin-like growth factor II receptor、mannose 6-phosphate receptor

「IGF-II」

　　[★]

• インスリン様増殖因子II、インスリン様成長因子II

関

IGF-2、insulin-like growth factor II

「IGF-IIレセプター」

　　[★]

英

IGF-II receptor

関

IGF-II受容体

「I」

　　[★]

• イソロイシン isoleucine
• イノシン inosine
• 阻害剤 inhibitor
• iodine
• ヨード iodide
• I因子 factor I

　 　 　

「IGF」

　　[★]

• インスリン様増殖因子 インスリン様成長因子 insulin-like growth factor

「Id」

　　[★]

• イディオタイプ idiotype idiotypic
• inhibitor of DNA binding