메뉴 건너뛰기




Volumn 47, Issue 4, 2010, Pages 271-278

Insulin and its analogs: Actions via insulin and IGF receptors

Author keywords

IGF I receptor; Insulin; Insulin analogs; Insulin receptor; Insulin receptor isoforms

Indexed keywords

HUMAN INSULIN; INSULIN; INSULIN ASPART; INSULIN DERIVATIVE; INSULIN DETEMIR; INSULIN GLARGINE; INSULIN GLULISINE; INSULIN LISPRO; INSULIN RECEPTOR; INSULIN RECEPTOR A; INSULIN RECEPTOR B; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN KINASE B; SOMATOMEDIN RECEPTOR; UNCLASSIFIED DRUG;

EID: 78549247886     PISSN: 09405429     EISSN: 14325233     Source Type: Journal    
DOI: 10.1007/s00592-010-0215-3     Document Type: Review
Times cited : (58)

References (35)
  • 1
    • 70849120946 scopus 로고    scopus 로고
    • Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease
    • 1:CAS:528:DC%2BD1MXhsVyhsrbK 10.1210/er.2008-0047 19752219
    • A Belfiore F Frasca G Pandini L Sciacca R Vigneri 2009 Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease Endocr Rev 30 586 623 1:CAS:528:DC%2BD1MXhsVyhsrbK 10.1210/er.2008-0047 19752219
    • (2009) Endocr Rev , vol.30 , pp. 586-623
    • Belfiore, A.1    Frasca, F.2    Pandini, G.3    Sciacca, L.4    Vigneri, R.5
  • 2
    • 0032932822 scopus 로고    scopus 로고
    • Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells
    • 1:CAS:528:DyaK1MXislSltLk%3D 10207053
    • F Frasca G Pandini P Scalia, et al. 1999 Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells Mol Cell Biol 19 3278 3288 1:CAS:528:DyaK1MXislSltLk%3D 10207053
    • (1999) Mol Cell Biol , vol.19 , pp. 3278-3288
    • Frasca, F.1    Pandini, G.2    Scalia, P.3
  • 3
    • 51249112194 scopus 로고    scopus 로고
    • Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer
    • 1:CAS:528:DC%2BD1cXhtFaitr3M 10.1016/j.bcp.2008.07.027 18718450
    • C Blanquart J Achi T Issad 2008 Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer Biochem Pharmacol 76 873 883 1:CAS:528:DC%2BD1cXhtFaitr3M 10.1016/j.bcp.2008.07.027 18718450
    • (2008) Biochem Pharmacol , vol.76 , pp. 873-883
    • Blanquart, C.1    Achi, J.2    Issad, T.3
  • 4
    • 0032800850 scopus 로고    scopus 로고
    • Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: Evidence for a second mechanism of IGF-I signaling
    • 1:CAS:528:DyaK1MXltVCqtL8%3D 10430101
    • G Pandini R Vigneri A Costantino, et al. 1999 Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling Clin Cancer Res 5 1935 1944 1:CAS:528:DyaK1MXltVCqtL8%3D 10430101
    • (1999) Clin Cancer Res , vol.5 , pp. 1935-1944
    • Pandini, G.1    Vigneri, R.2    Costantino, A.3
  • 5
    • 0030693249 scopus 로고    scopus 로고
    • Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: Quantification of individual receptor species by selective immunoprecipitation and immunoblotting
    • 1:CAS:528:DyaK2sXmvVGktrw%3D 9355755
    • EM Bailyes BT Nave MA Soos SR Orr AC Hayward K Siddle 1997 Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting Biochem J 327 Pt 1 209 215 1:CAS:528:DyaK2sXmvVGktrw%3D 9355755
    • (1997) Biochem J , vol.327 , Issue.PART 1 , pp. 209-215
    • Bailyes, E.M.1    Nave, B.T.2    Soos, M.A.3    Orr, S.R.4    Hayward, A.C.5    Siddle, K.6
  • 6
    • 0030829490 scopus 로고    scopus 로고
    • Insulin lispro
    • DOI 10.1056/NEJM199707173370307
    • F Holleman JB Hoekstra 1997 Insulin lispro N Engl J Med 337 176 183 1:CAS:528:DyaK2sXlt1Smurs%3D 10.1056/NEJM199707173370307 9219705 (Pubitemid 27306290)
    • (1997) New England Journal of Medicine , vol.337 , Issue.3 , pp. 176-183
    • Holleman, F.1    Hoekstra, J.B.L.2
  • 7
    • 0026698991 scopus 로고
    • Altering the association properties of insulin by amino acid replacement
    • 1:CAS:528:DyaK38XmsVGksrc%3D 10.1093/protein/5.6.527 1438163
    • DN Brems LA Alter MJ Beckage, et al. 1992 Altering the association properties of insulin by amino acid replacement Protein Eng 5 527 533 1:CAS:528:DyaK38XmsVGksrc%3D 10.1093/protein/5.6.527 1438163
    • (1992) Protein Eng , vol.5 , pp. 527-533
    • Brems, D.N.1    Alter, L.A.2    Beckage, M.J.3
  • 8
    • 0003190213 scopus 로고
    • Modifications in the 28-29 position of the insulin B-chain alter binding to the IGF-I receptor with minimal effect on insulin receptor binding
    • LJ Slieker K Sundell 1991 Modifications in the 28-29 position of the insulin B-chain alter binding to the IGF-I receptor with minimal effect on insulin receptor binding Diabetes 40 Suppl 1 168A
    • (1991) Diabetes , vol.40 , Issue.SUPPL. 1
    • Slieker, L.J.1    Sundell, K.2
  • 9
    • 0027972684 scopus 로고
    • [Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin
    • 1:CAS:528:DyaK2cXhvVems7o%3D 10.2337/diabetes.43.3.396 8314011
    • DC Howey RR Bowsher RL Brunelle JR Woodworth 1994 [Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin Diabetes 43 396 402 1:CAS:528:DyaK2cXhvVems7o%3D 10.2337/diabetes.43.3.396 8314011
    • (1994) Diabetes , vol.43 , pp. 396-402
    • Howey, D.C.1    Bowsher, R.R.2    Brunelle, R.L.3    Woodworth, J.R.4
  • 10
    • 0032899682 scopus 로고    scopus 로고
    • Insulin aspart
    • DOI 10.2165/00003495-199957050-00013
    • KL Simpson CM Spencer 1999 Insulin aspart Drugs 57 759 765 1:CAS:528:DyaK1MXjs1altbc%3D 10.2165/00003495-199957050-00013 10353301 (discussion 766-757) (Pubitemid 29231892)
    • (1999) Drugs , vol.57 , Issue.5 , pp. 759-767
    • Simpson, K.L.1    Spencer, C.M.2
  • 11
    • 0342657181 scopus 로고    scopus 로고
    • Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use
    • 1:CAS:528:DC%2BD3cXjvFylu7w%3D 10.2337/diabetes.49.6.999 10866053
    • P Kurtzhals L Schaffer A Sorensen, et al. 2000 Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use Diabetes 49 999 1005 1:CAS:528:DC%2BD3cXjvFylu7w%3D 10.2337/diabetes.49.6.999 10866053
    • (2000) Diabetes , vol.49 , pp. 999-1005
    • Kurtzhals, P.1    Schaffer, L.2    Sorensen, A.3
  • 13
    • 33847208863 scopus 로고    scopus 로고
    • Insulin glulisine complementing basal insulins: A review of structure and activity
    • 1:CAS:528:DC%2BD2sXhvF2hsro%3D 10.1089/dia.2006.0035 17316105
    • RH Becker 2007 Insulin glulisine complementing basal insulins: a review of structure and activity Diabetes Technol Ther 9 109 121 1:CAS:528: DC%2BD2sXhvF2hsro%3D 10.1089/dia.2006.0035 17316105
    • (2007) Diabetes Technol Ther , vol.9 , pp. 109-121
    • Becker, R.H.1
  • 14
    • 37149053432 scopus 로고    scopus 로고
    • Clinical pharmacokinetics and pharmacodynamics of insulin glulisine
    • 1:CAS:528:DC%2BD1cXhvF2qurs%3D 10.2165/00003088-200847010-00002 18076215
    • RH Becker AD Frick 2008 Clinical pharmacokinetics and pharmacodynamics of insulin glulisine Clin Pharmacokinet 47 7 20 1:CAS:528:DC%2BD1cXhvF2qurs%3D 10.2165/00003088-200847010-00002 18076215
    • (2008) Clin Pharmacokinet , vol.47 , pp. 7-20
    • Becker, R.H.1    Frick, A.D.2
  • 15
    • 0032819174 scopus 로고    scopus 로고
    • Insulin analogues and their potential in the management of diabetes mellitus
    • DOI 10.1007/s001250051286
    • GB Bolli RD Di Marchi GD Park S Pramming VA Koivisto 1999 Insulin analogues and their potential in the management of diabetes mellitus Diabetologia 42 1151 1167 1:CAS:528:DyaK1MXmt1ymtr0%3D 10.1007/s001250051286 10525654 (Pubitemid 29459810)
    • (1999) Diabetologia , vol.42 , Issue.10 , pp. 1151-1167
    • Bolli, G.B.1    Di Marchi, R.D.2    Park, G.D.3    Pramming, S.4    Koivisto, V.A.5
  • 16
    • 0034203532 scopus 로고    scopus 로고
    • Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: Comparison with NPH insulin and the influence of different subcutaneous injection sites
    • 1:CAS:528:DC%2BD3cXnvV2isLw%3D 10.2337/diacare.23.6.813 10841002
    • DR Owens PA Coates SD Luzio JP Tinbergen R Kurzhals 2000 Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites Diabetes Care 23 813 819 1:CAS:528:DC%2BD3cXnvV2isLw%3D 10.2337/diacare.23.6.813 10841002
    • (2000) Diabetes Care , vol.23 , pp. 813-819
    • Owens, D.R.1    Coates, P.A.2    Luzio, S.D.3    Tinbergen, J.P.4    Kurzhals, R.5
  • 17
    • 9044226136 scopus 로고    scopus 로고
    • Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs
    • 1:CAS:528:DyaK28XitlaisLw%3D 10.1007/BF00418343 8721773
    • J Markussen S Havelund P Kurtzhals, et al. 1996 Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs Diabetologia 39 281 288 1:CAS:528:DyaK28XitlaisLw%3D 10.1007/BF00418343 8721773
    • (1996) Diabetologia , vol.39 , pp. 281-288
    • Markussen, J.1    Havelund, S.2    Kurtzhals, P.3
  • 18
    • 48949085613 scopus 로고    scopus 로고
    • Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin
    • 1:CAS:528:DC%2BD1cXhtVWitLbJ 10.1016/j.diabres.2008.05.007 18585815
    • T Wada M Azegami M Sugiyama H Tsuneki T Sasaoka 2008 Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin Diabetes Res Clin Pract 81 269 277 1:CAS:528:DC%2BD1cXhtVWitLbJ 10.1016/j.diabres.2008.05.007 18585815
    • (2008) Diabetes Res Clin Pract , vol.81 , pp. 269-277
    • Wada, T.1    Azegami, M.2    Sugiyama, M.3    Tsuneki, H.4    Sasaoka, T.5
  • 19
    • 33244464562 scopus 로고    scopus 로고
    • Critical nodes in signalling pathways: Insights into insulin action
    • DOI 10.1038/nrm1837, PII NRM1837
    • CM Taniguchi B Emanuelli CR Kahn 2006 Critical nodes in signalling pathways: insights into insulin action Nat Rev Mol Cell Biol 7 85 96 1:CAS:528:DC%2BD28XhtlWnsLw%3D 10.1038/nrm1837 16493415 (Pubitemid 43278292)
    • (2006) Nature Reviews Molecular Cell Biology , vol.7 , Issue.2 , pp. 85-96
    • Taniguchi, C.M.1    Emanuelli, B.2    Kahn, C.R.3
  • 21
    • 0037191919 scopus 로고    scopus 로고
    • In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A
    • DOI 10.1038/sj.onc.1206058
    • L Sciacca R Mineo G Pandini A Murabito R Vigneri A Belfiore 2002 In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A Oncogene 21 8240 8250 1:CAS:528:DC%2BD38XovVGmsL0%3D 10.1038/sj.onc.1206058 12447687 (Pubitemid 35477864)
    • (2002) Oncogene , vol.21 , Issue.54 , pp. 8240-8250
    • Sciacca, L.1    Mineo, R.2    Pandini, G.3    Murabito, A.4    Vigneri, R.5    Belfiore, A.6
  • 22
    • 0142180099 scopus 로고    scopus 로고
    • Differential Gene Expression Induced by Insulin and Insulin-like Growth Factor-II through the Insulin Receptor Isoform A
    • DOI 10.1074/jbc.M304980200
    • G Pandini E Medico E Conte L Sciacca R Vigneri A Belfiore 2003 Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A J Biol Chem 278 42178 42189 1:CAS:528:DC%2BD3sXot1amtbw%3D 10.1074/jbc.M304980200 12881524 (Pubitemid 37310484)
    • (2003) Journal of Biological Chemistry , vol.278 , Issue.43 , pp. 42178-42189
    • Pandini, G.1    Medico, E.2    Conte, E.3    Sciacca, L.4    Vigneri, R.5    Belfiore, A.6
  • 23
    • 77955515434 scopus 로고    scopus 로고
    • Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling
    • 1:CAS:528:DC%2BC3cXotVKgsL4%3D 10.1007/s00125-010-1760-6 20424816
    • L Sciacca MF Cassarino M Genua, et al. 2010 Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling Diabetologia 53 1743 1753 1:CAS:528:DC%2BC3cXotVKgsL4%3D 10.1007/s00125-010-1760-6 20424816
    • (2010) Diabetologia , vol.53 , pp. 1743-1753
    • Sciacca, L.1    Cassarino, M.F.2    Genua, M.3
  • 24
    • 0001008384 scopus 로고
    • Carcinogenic effect on female rats after 12 months administration of the insulin analog B10 Asp
    • LH Dideriksen JLN Jorgensen K Drejer 1992 Carcinogenic effect on female rats after 12 months administration of the insulin analog B10 Asp Diabetes 41 143A
    • (1992) Diabetes , vol.41
    • Dideriksen, L.H.1    Jorgensen, J.L.N.2    Drejer, K.3
  • 25
    • 0030614323 scopus 로고    scopus 로고
    • 10 insulin induction of increased mitogenic responses and phenotypic changes in human breast epithelial cells: Evidence for enhanced interactions with the insulin-like growth factor-I receptor
    • DOI 10.1002/(SICI)1098-2744(199701)18:1<19::AID-MC3>3.0.CO;2-M
    • G Milazzo L Sciacca V Papa ID Goldfine R Vigneri 1997 ASPB10 insulin induction of increased mitogenic responses and phenotypic changes in human breast epithelial cells: evidence for enhanced interactions with the insulin-like growth factor-I receptor Mol Carcinog 18 19 25 1:CAS:528: DyaK2sXhtVWrs7k%3D 10.1002/(SICI)1098-2744(199701)18:1<19::AID-MC3>3.0. CO;2-M 9022809 (Pubitemid 27107371)
    • (1997) Molecular Carcinogenesis , vol.18 , Issue.1 , pp. 19-25
    • Milazzo, G.1    Sciacca, L.2    Papa, V.3    Goldfine, I.D.4    Vigneri, R.5
  • 26
    • 0027097641 scopus 로고
    • The bioactivity of insulin analogues from in vitro receptor binding to in vivo glucose uptake
    • 1:CAS:528:DyaK3sXisVOks7o%3D 10.1002/dmr.5610080305 1338040
    • K Drejer 1992 The bioactivity of insulin analogues from in vitro receptor binding to in vivo glucose uptake Diabetes Metab Rev 8 259 285 1:CAS:528:DyaK3sXisVOks7o%3D 10.1002/dmr.5610080305 1338040
    • (1992) Diabetes Metab Rev , vol.8 , pp. 259-285
    • Drejer, K.1
  • 27
    • 77949760139 scopus 로고    scopus 로고
    • In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites
    • 10.1371/journal.pone.0009540 20209060
    • MR Sommerfeld G Muller G Tschank, et al. 2010 In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites PLoS One 5 e9540 10.1371/journal.pone.0009540 20209060
    • (2010) PLoS One , vol.5 , pp. 9540
    • Sommerfeld, M.R.1    Muller, G.2    Tschank, G.3
  • 28
    • 0024358352 scopus 로고
    • Insulin-like growth factor i receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor i and insulin receptor heterodimers
    • 1:CAS:528:DyaL1MXkvFSrtb4%3D 2546949
    • CP Moxham V Duronio S Jacobs 1989 Insulin-like growth factor I receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers J Biol Chem 264 13238 13244 1:CAS:528:DyaL1MXkvFSrtb4%3D 2546949
    • (1989) J Biol Chem , vol.264 , pp. 13238-13244
    • Moxham, C.P.1    Duronio, V.2    Jacobs, S.3
  • 29
    • 0037131385 scopus 로고    scopus 로고
    • Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved
    • DOI 10.1074/jbc.M202766200
    • G Pandini F Frasca R Mineo L Sciacca R Vigneri A Belfiore 2002 Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved J Biol Chem 277 39684 39695 1:CAS:528:DC%2BD38XnvVeiu74%3D 10.1074/jbc.M202766200 12138094 (Pubitemid 35190951)
    • (2002) Journal of Biological Chemistry , vol.277 , Issue.42 , pp. 39684-39695
    • Pandini, G.1    Frasca, F.2    Mineo, R.3    Sciacca, L.4    Vigneri, R.5    Belfiore, A.6
  • 30
    • 34249899156 scopus 로고    scopus 로고
    • Glargine blood biotransformation: Invitro appraisal with human insulin immunoassay
    • DOI 10.1016/j.diabet.2006.12.002, PII S1262363607000523
    • A Agin N Jeandidier F Gasser D Grucker R Sapin 2007 Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay Diabetes Metab 33 205 212 1:CAS:528:DC%2BD2sXptFGnurg%3D 10.1016/j.diabet.2006.12.002 17360218 (Pubitemid 46863409)
    • (2007) Diabetes and Metabolism , vol.33 , Issue.3 , pp. 205-212
    • Agin, A.1    Jeandidier, N.2    Gasser, F.3    Grucker, D.4    Sapin, R.5
  • 31
    • 4344701890 scopus 로고    scopus 로고
    • The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin
    • DOI 10.1023/B:PHAM.0000036926.54824.37
    • S Havelund A Plum U Ribel, et al. 2004 The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin Pharm Res 21 1498 1504 1:CAS:528:DC%2BD2cXmtlGntbg%3D 10.1023/B:PHAM.0000036926.54824.37 15359587 (Pubitemid 39149667)
    • (2004) Pharmaceutical Research , vol.21 , Issue.8 , pp. 1498-1504
    • Havelund, S.1    Plum, A.2    Ribel, U.3    Jonassen, I.4    Volund, A.5    Markussen, J.6    Kurtzhals, P.7
  • 32
    • 24944452289 scopus 로고    scopus 로고
    • Effects of new insulin analogues HMR1964 (insulin glulisine) and HMR1423 on insulin receptors
    • DOI 10.1007/s00125-005-1870-8
    • AM Hennige V Strack E Metzinger G Seipke HU Haring M Kellerer 2005 Effects of new insulin analogues HMR1964 (insulin glulisine) and HMR1423 on insulin receptors Diabetologia 48 1891 1897 1:CAS:528:DC%2BD2MXhtVSqtL%2FI 10.1007/s00125-005-1870-8 16052329 (Pubitemid 41317845)
    • (2005) Diabetologia , vol.48 , Issue.9 , pp. 1891-1897
    • Hennige, A.M.1    Strack, V.2    Metzinger, E.3    Seipke, G.4    Haring, H.-U.5    Kellerer, M.6
  • 33
    • 0031918749 scopus 로고    scopus 로고
    • The long acting human insulin analog HOE 901: Characteristics of insulin signalling in comparison to Asp(B10) and regular insulin
    • 1:CAS:528:DyaK1cXitVClt7w%3D 10.1055/s-2007-978849 9566852
    • L Berti M Kellerer B Bossenmaier E Seffer G Seipke HU Haring 1998 The long acting human insulin analog HOE 901: characteristics of insulin signalling in comparison to Asp(B10) and regular insulin Horm Metab Res 30 123 129 1:CAS:528:DyaK1cXitVClt7w%3D 10.1055/s-2007-978849 9566852
    • (1998) Horm Metab Res , vol.30 , pp. 123-129
    • Berti, L.1    Kellerer, M.2    Bossenmaier, B.3    Seffer, E.4    Seipke, G.5    Haring, H.U.6
  • 34
    • 0031565279 scopus 로고    scopus 로고
    • Growth promoting and metabolic activity of the human insulin analogue [Gly(A21),Arg(B31),Arg(B32)]insulin (HOE 901) in muscle cells
    • DOI 10.1016/S0014-2999(96)00903-X, PII S001429999600903X
    • M Bahr T Kolter G Seipke J Eckel 1997 Growth promoting and metabolic activity of the human insulin analogue [GlyA21, ArgB31, ArgB32]insulin (HOE 901) in muscle cells Eur J Pharmacol 320 259 265 1:STN:280:DyaK2s3htlSrsA%3D%3D 10.1016/S0014-2999(96)00903-X 9059862 (Pubitemid 27076754)
    • (1997) European Journal of Pharmacology , vol.320 , Issue.2-3 , pp. 259-265
    • Bahr, M.1    Kolter, T.2    Seipke, G.3    Eckel, J.4


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.