Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

The C. elegans insulin-like peptides (ILPs)

1 Hirotsu Bio Science Inc.
2 The United Graduate School of Agriculture, Tottori University

Topical Section: Mechanisms of Insulin Signaling and Insulin Resistance

Insulin and insulin-like peptides (ILPs) are conserved in living organisms to modulate homeostasis by functioning as ligands. For understanding of molecular mechanisms regulated by the ligands, the nematode Caenorhabditis elegans is a good model since: 1) the C. elegans genome size is small with over 40% homology to the human genome, 2) numerous genetic methods are available, and 3) the worms are transparent throughout the life cycle, so that the secretion of peptide hormones can be followed at cellular level in living preparations by GFP-tagged peptides. In this review, we describe the general appearance of the insulin/insulin-like growth factor (IGF)-1 signaling (IIS), and then focus on physiological functions, secretion, and transcriptional regulation of the C. elegans ILPs.
  Article Metrics

Keywords Caenorhabditis elegans; dauer; insulin-like peptide; insulin/IGF-1 signaling; lifespan

Citation: Yohei Matsunaga, Tsuyoshi Kawano. The C. elegans insulin-like peptides (ILPs). AIMS Biophysics, 2018, 5(4): 217-230. doi: 10.3934/biophy.2018.4.217


  • 1. Banting FG, Best CH, Collip JB, et al. (1922) Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 12: 141–146.
  • 2. Ryle AP, Sanger F, Smith LF, et al. (1955) The disulphide bonds of insulin. Biochem J 60: 541–556.    
  • 3. Dodson E, Harding MM, Hodgkin DC, et al. (1966) The crystal structure of insulin. 3. Evidence for a 2-fold axis in rhombohedral zinc insulin. J Mol Biol 16: 227–241.
  • 4. Mckern NM, Lawrence MC, Streltsov VA, et al. (2006) Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature 443: 218–221.    
  • 5. Haeusler RA, Mcgraw TE, Accili D (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19: 31–44.
  • 6. Vajdos FF, Ultsch M, Schaffer ML, et al. (2001) Crystal structure of humun insulin-like growth factor-1: Detergent binding inhibits binding protein interactions. Biochemistry 40: 11022–11029.    
  • 7. Hakuno F, Takahashi SI (2018) IGF1 receptor signaling pathways. J Mol Endocrinol 61: T69–T86.    
  • 8. Fernandez AM, Torres-Aleman I (2012) The many faces of insulin-like peptide signaling in the brain. Nat Rev Neurosci 13: 225–239.
  • 9. Christie AE, Roncalli V, Lenz PH (2016) Diversity of insulin-like peptide signaling system proteins in Calanus finmarchicus (Crustacea; Copepoda)-possible contributors to seasonal pre-adult diapause. Gen Comp Endocrinol 236: 157–173.    
  • 10. Lee Y, An SWA, Artan M, et al. (2015) Genes and pathways that influence longevity in Caenorhabditis elegans, In: Aging Mechanisms Mori N., Mook-Jung I, eds, 123–169.
  • 11. Giannakou ME, Partridge L (2007) Role of insulin-like signalling in Drosophila lifespan. Trends Biochem Sci 32: 180–188.    
  • 12. Fontana L, Partridge L, Longo VD (2010) Extending healthy life span-from yeast to humans. Science 328: 321–326.    
  • 13. Kenyon CJ (2010) The genetics of ageing. Nature 464: 504–512.    
  • 14. Nassel DR, Kubrak OI, Liu Y, et al. (2013) Factors that regulate insulin producing cells and their output in Drosophila. Front Physiol 4: 252.
  • 15. Grönke S, Partridge L, (2010) The functions of insulin-like peptides in insects, In: Clemmons D, Robinson I, Christen Y, eds., IGFs: Local repair and survival factors throughout life span, Research and Perspectives in Endocrine Interactions, Springer, Berlin, Heidelberg, 105–124.
  • 16. Zhang H, Liu J, Li CR, et al. (2009) Deletion of Drosophila insulin-like peptides causes growth defects and metabolic abnormalities. Proc Natl Acad Sci U S A 106: 19617–19622.    
  • 17. Colombani J, Andersen DS, Leopold P (2012) Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. Science 336: 582–585.    
  • 18. Abreu DAFD, Caballero A, Fardel P, et al. (2014) An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PLoS Genet 10: e1004225.    
  • 19. Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77: 91–94.
  • 20. Consortium CES (1998) Genome sequence of the nematode C. elegans: A platform for investigating biology. Science 282: 2012–2018.
  • 21. Fire A, Xu S, Montgomery MK, et al. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391: 806–811.    
  • 22. Zwaal RR, Broeks A, van Meurs J, et al. (1993) Target-selected gene inactivation in Caenorhabditis elegans by using a frozen transposon insertion mutant bank. Proc Natl Acad Sci U S A 90: 7431–7435.    
  • 23. Klass MR (1983) A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mech Ageing Dev 22: 279–286.    
  • 24. Friedman DB, Johnson TE (1988) A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118: 75–86.
  • 25. Friedman DB, Johnson TE (1988) Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J Gerontol Biol Sci 43: 102–109.    
  • 26. Johnson TE (1990) Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science 249: 908–912.    
  • 27. Kenyon C, Chang J, Gensch E, et al. (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366: 461–464.
  • 28. Kimura KD, Tissenbaum HA, Liu Y, et al. (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277: 942–946.    
  • 29. Murakami S, Johnson TE (1996) A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143: 1207–1218.
  • 30. Cassada RC, Russell RL (1975) The dauerlarva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans. Dev Biol 46: 326–342.    
  • 31. Riddle DL, Swanson MM, Albert PS (1981) Interacting genes in nematode dauer larva formation. Nature 290: 668–671.    
  • 32. Vowels JJ, Thomas JH (1992) Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics 130: 105–123.
  • 33. Gottlieb S, Ruvkun G (1994) daf-2, daf-16 and daf-23: Genetically interacting genes controlling Dauer formation in Caenorhabditis elegans. Genetics 137: 107–120.
  • 34. Ogg S, Ruvkun G (1998) The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell 2: 887–893.
  • 35. Gil EB, Malone LE, Liu LX, et al. (1999) Regulation of the insulin-like developmental pathway of Caenorhabditis elegans by a homolog of the PTEN tumor suppressor gene. Proc Natl Acad Sci U S A 96: 2925–2930.    
  • 36. Mihaylova VT, Borland CZ, Manjarrez L, et al. (1999) The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci U S A 96: 7427–7432.    
  • 37. Rouault JP, Kuwabara PE, Sinilnikova OM, et al. (1999) Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. Curr Biol 9: 329–332.    
  • 38. Baugh LR, Sternberg PW (2006) DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest. Curr Biol 16: 780–785.
  • 39. Lithgow GJ, White TM, Hinerfeld DA, et al. (1994) Thermotolerance of a long-lived mutant of Caenorhabditis elegans. J Gerontol 49: 270–276.
  • 40. Lithgow GJ, White TM, Melov S, et al. (1995) Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A 92: 7540–7544.    
  • 41. Babar P, Adamson C, Walker GA, et al. (1999) PI3-kinase inhibition induces dauer formation, thermotolerance and longevity in C. elegans. Neurobiol Aging 20: 513–519.    
  • 42. Walker GA, Walker DW, Lithgow GJ (1998) Genes that determine both thermotolerance and rate of aging in Caenorhabditis elegans. Ann N Y Acad Sci 851: 444–449.    
  • 43. Walker GA, White TM, McColl G, et al. (2001) Heat shock protein accumulation is upregulated in a long-lived mutant of Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci 56: B281–B287.    
  • 44. Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300: 1142–1145.    
  • 45. Honda Y, Honda S (1999) The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J 13: 1385–1393.    
  • 46. Honda Y, Honda S (2002) Oxidative stress and life span determination in the nematode Caenorhabditis elegans. Ann N Y Acad Sci 959: 466–474.    
  • 47. Scott BA, Avidan MS, Crowder CM (2002) Regulation of hypoxic death in C. elegans by the insulin/IGF receptor homolog DAF-2. Science 296: 2388–2391.
  • 48. Lamitina ST, Strange K (2005) Transcriptional targets of DAF-16 insulin signaling pathway protect C. elegans from extreme hypertonic stress. Am J Physiol -Cell Ph 288: C467–C474.
  • 49. Barsyte D, Lovejoy DA, Lithgow GJ (2001) Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. FASEB J 15: 627–634.    
  • 50. Morley JF, Morimoto RI (2004) Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15: 657–664.    
  • 51. Cohen E, Bieschke J, Perciavalle RM, et al. (2006) Opposing activities protect against age-onset proteotoxicity. Science 313: 1604–1610.    
  • 52. Keowkase R, Aboukhatwa M, Luo Y (2010) Fluoxetine protects against amyloid-beta toxicity, in part via daf-16 mediated cell signaling pathway, in Caenorhabditis elegans. Neuropharmacology 59: 358–365.    
  • 53. Ching TT, Chiang WC, Chen CS, et al. (2011) Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity. Aging Cell 10: 506–519.
  • 54. Teixeira-Castro A, Ailion M, Jalles A, et al. (2011) Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: Rescue by the DAF-16 and HSF-1 pathways. Hum Mol Genet 20: 2996–3009.
  • 55. Zhang T, Hwang HY, Hao H, et al. (2012) Caenorhabditis elegans RNA-processing protein TDP-1 regulates protein homeostasis and life span. J Biol Chem 287: 8371–8382.    
  • 56. Nagasawa H, Kataoka H, Isogai A, et al. (1984) Amino-terminal amino acid sequence of the silkworm prothoracicotropic hormone: Homology with insulin. Science 226: 1344–1345.    
  • 57. Smit AB, Vreugdenhil E, Ebberink RH, et al. (1988) Growth-controlling molluscan neurons produce the precursor of an insulin-related peptide. Nature 331: 535–538.    
  • 58. Lagueux M, Lwoff L, Meister M, et al. (1990) cDNAs from neurosecretory cells of brains of Locusta migratoria (Insecta, Orthoptera) encoding a novel member of the superfamily of insulins. Eur J Biochem 187: 249–254.    
  • 59. Chandler JC, Aizen J, Elizur A, et al. (2015) Discovery of a novel insulin-like peptide and insulin binding proteins in the Eastern rock lobster Sagmariasus verreauxi. Gen Comp Endocr 215: 76–87.    
  • 60. Duret L, Guex N, Peitsch MC, et al. (1998) New insulin-like proteins with atypical disulfide bond pattern characterized in Caenorhabditis elegans by comparative sequence analysis and homology modeling. Genome Res 8: 348–353.    
  • 61. Pierce SB, Costa M, Wisotzkey R, et al. (2001) Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev 15: 672–686.
  • 62. Li W, Kennedy SG, Ruvkun G (2003) daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev 17: 844–858.
  • 63. Husson SJ, Mertens I, Janssen T, et al. (2007) Neuropeptidergic signaling in the nematode Caenorhabditis elegans. Prog Neurobiol 82: 33–55.    
  • 64. Kawano T, Ito Y, Ishiguro M, et al. (2000) Molecular cloning and characterization of a new insulin/IGF-like peptide of the nematode Caenorhabditis elegans. Biochem Biophys Res Commun 273: 431–436.    
  • 65. Matsunaga Y, Gengyo-Ando K, Mitani S, et al. (2012) Physiological function, expression pattern, and transcriptional regulation of a Caenorhabditis elegans insulin-like peptide, INS-18. Biochem Biophys Res Commun 423: 478–483.    
  • 66. Wang X, Wang X, Wang D, et al. (2010) [Expression changes of age-related genes in different aging stages of Caenorhabiditis elegans and the regulating effects of Chuanxiong extract]. China J Chin Mater Med 35: 1599–1602.
  • 67. Kawano T, Nagatomo R, Kimura Y, et al. (2006) Disruption of ins-11, a Caenorhabditis elegans insulin-like gene, and phenotypic analyses of the gene-disrupted animal. Biosci Biotechnol Biochem 70: 3084–3087.    
  • 68. Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382: 536–539.    
  • 69. Paradis S, Ailion M, Toker A, et al. (1999) A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev 13: 1438–1452.    
  • 70. Paradis S, Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12: 2488–2498.    
  • 71. Ogg S, Paradis S, Gottlieb S, et al. (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389: 994–999.    
  • 72. Henderson ST, Johnson TE (2001) daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 11: 1975–1980.    
  • 73. Lee RY, Hench J, Ruvkun G (2001) Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol 11: 1950–1957.
  • 74. Malone EA, Inoue T, Thomas JH (1996) Genetic analysis of the roles of daf-28 and age-1 in regulating Caenorhabditis elegans dauer formation. Genetics 143: 1193–1205.
  • 75. Murphy CT, Mccarroll SA, Bargmann CI, et al. (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424: 277–283.    
  • 76. Matsunaga Y, Nakajima K, Gengyo-Ando K, et al. (2012) A Caenorhabditis elegans insulin-like peptide, INS-17: Its physiological function and expression pattern. Biosci Biotechnol Biochem 76: 2168–2172.    
  • 77. Matsunaga Y, Matsukawa T, Iwasaki T, et al. (2018) Comparison of physiological functions of antagonistic insulin-like peptides, INS-23 and INS-18, in Caenorhabditis elegans. Biosci Biotechnol Biochem 82: 90–96.    
  • 78. Cornils A, Gloeck M, Chen Z, et al. (2011) Specific insulin-like peptides encode sensory information to regulate distinct developmental processes. Development 138: 1183–1193.    
  • 79. Murphy CT, Lee SJ, Kenyon C (2007) Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc Natl Acad Sci U S A 104: 19046–19050.    
  • 80. Tomioka M, Adachi T, Suzuki H, et al. (2006) The insulin/PI 3-kinase pathway regulates salt chemotaxis learning in Caenorhabditis elegans. Neuron 51: 613–625.    
  • 81. Kodama E, Kuhara A, Mohri-Shiomi A, et al. (2006) Insulin-like signaling and the neural circuit for integrative behavior in C. elegans. Genes Dev 20: 2955–2960.    
  • 82. Lin CH, Tomioka M, Pereira S, et al. (2010) Insulin signaling plays a dual role in Caenorhabditis elegans memory acquisition and memory retrieval. J Neurosci 30: 8001–8011.    
  • 83. Chen Z, Hendricks M, Cornils A, et al. (2013) Two insulin-like peptides antagonistically regulate aversive olfactory learning in C. elegans. Neuron 77: 572–585.    
  • 84. Michaelson D, Korta DZ, Capua Y, et al. (2010) Insulin signaling promotes germline proliferation in C. elegans. Development 137: 671–680.
  • 85. Ritter AD, Shen Y, Fuxman BJ, et al. (2013) Complex expression dynamics and robustness in C. elegans insulin networks. Genome Res 23: 954–965.
  • 86. Matsunaga Y, Iwasaki T, Kawano T (2017) Diverse insulin-like peptides in Caenorhabditis elegans. Int Biol Rev , 1.
  • 87. Hua QX, Nakagawa SH, Wilken J, et al. (2003) A divergent INS protein in Caenorhabditis elegans structurally resembles human insulin and activates the human insulin receptor. Genes Dev 17: 826–831.    
  • 88. Kao G, Nordenson C, Still M, et al. (2007) ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells. Cell 128: 577–587.    
  • 89. Matsunaga Y, Honda Y, Honda S, et al. (2016) Diapause is associated with a change in the polarity of secretion of insulin-like peptides. Nat Commun 7: 10573.    
  • 90. Clark ME, Kelner GS, Turbeville LA, et al. (2000) ADAMTS9, a novel member of the ADAM-TS/ metallospondin gene family. Genomics 67: 343–350.    
  • 91. Somerville RP, Longpre JM, Jungers KA, et al. (2003) Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem 278: 9503–9513.    
  • 92. Yoshina S, Mitani S (2015) Loss of C. elegans GON-1, an ADAMTS9 Homolog, Decreases Secretion Resulting in Altered Lifespan and Dauer Formation. PLoS One 10: e0133966.
  • 93. Suckale J, Solimena M (2010) The insulin secretory granule as a signaling hub. Trends Endocrin Met 21: 599–609.    
  • 94. Drucker DJ, Philippe J, Mojsov S, et al. (1987) Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A 84: 3434–3438.    
  • 95. Fehmann HC, Habener JF (1992) Galanin inhibits proinsulin gene expression stimulated by the insulinotropic hormone glucagon-like peptide-I (7-37) in mouse insulinoma beta TC-1 cells. Endocrinology 130: 2890–2896.    
  • 96. Koranyi L, James DE, Kraegen EW, et al. (1992) Feedback inhibition of insulin gene expression by insulin. J Clin Invest 89: 432–436.    
  • 97. Shaw WM, Luo S, Landis J, et al. (2007) The C. elegans TGF-beta Dauer pathway regulates longevity via insulin signaling. Curr Biol 17: 1635–1645.
  • 98. Hung WL, Wang Y, Chitturi J, et al. (2014) A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication. Development 141: 1767–1779.    
  • 99. Liu T, Zimmerman KK, Patterson GI (2004) Regulation of signaling genes by TGFbeta during entry into dauer diapause in C. elegans. BMC Dev Biol 4: 11.    
  • 100. Narasimhan SD, Yen K, Bansal A, et al. (2011) PDP-1 links the TGF-beta and IIS pathways to regulate longevity, development, and metabolism. PLoS Genet 7: e1001377.    
  • 101. Dlakic M (2002) A new family of putative insulin receptor-like proteins in C. elegans. Curr Biol 12: R155–R157.    
  • 102. Tomioka M, Naito Y, Kuroyanagi H, et al. (2016) Splicing factors control C. elegans behavioural learning in a single neuron by producing DAF-2c receptor. Nat Commun 7: 11645.
  • 103. Bulger DA, Fukushige T, Yun S, et al. (2017) Caenorhabditis elegans DAF-2 as a model for human insulin receptoropathies. G3 Genesgenetics 7: 257–268.    


Reader Comments

your name: *   your email: *  

© 2018 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved