Journal of Molecular Neuroscience

, Volume 56, Issue 3, pp 681–687 | Cite as

Insulin-like Growth Factor 1 Differentially Affects Lithium Sensitivity of Lymphoblastoid Cell Lines from Lithium Responder and Non-responder Bipolar Disorder Patients

  • Elena MilanesiEmail author
  • Adva Hadar
  • Elisabetta Maffioletti
  • Haim Werner
  • Noam Shomron
  • Massimo Gennarelli
  • Thomas G. Schulze
  • Marta Costa
  • Maria Del Zompo
  • Alessio SquassinaEmail author
  • David GurwitzEmail author


Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about 50–60 % of patients do not respond sufficiently to chronic treatment. Insulin-like growth factor 1 (IGF1) has been identified as a candidate gene for BD susceptibility, and its low expression has been suggested as a putative biomarker for lithium unresponsiveness. In this study, we examined the in vitro effects of insulin-like growth factor 1 (IGF-1) on lithium sensitivity in lymphoblastoid cell lines (LCLs) from lithium responder (R) and non-responder (NR) bipolar patients. Moreover, we evaluated levels of microRNA let-7c, a small RNA predicted to target IGF1. We found that exogenous IGF-1 added to serum-free media increased lithium sensitivity selectively in LCLs from NR BD patients. However, no significant differences were observed when comparing let-7c expression in LCLs from R vs. NR BD patients. Our data support a key role for IGF-1 in lithium resistance/response in the treatment of bipolar disorder.


Insulin-like growth factor 1 (IGF-1) Somatomedin C Let-7c Lithium Bipolar disorder Lymphoblastoid cell lines (LCLs) 



Bipolar disorder


Insulin-like growth factor 1


Lymphoblastoid cell lines






IGF-1 receptor


Insulin receptor


Receptor-related protein 1


Insulin-like growth factor binding protein 2




Insulin-like growth factor binding protein 1


Insulin-like growth factor binding protein 3


Quantitative real-time-PCR



The authors thank the patients involved in the study for the generous collaboration. This study was supported by the US Israel Binational Science Foundation (BSF) Grant No. 2013223 (to DG). DG is supported by the Shalom and Varda Yoran Institute for Human Genome Research at Tel Aviv University. Elena Milanesi is a post-doctoral fellow supported by the Shabbetai Donnolo Fellowships between Italy and Israel. MG and Elisabetta Maffioletti are supported by grants from the Italian Ministry of Health (Ricerca Corrente). AS is a post-doctoral fellow funded by a grant from the Sardinia Regional Government (P.O.R. Sardegna F.S.E. Operational Program of the Autonomous Region of Sardinia, European Social Fund 2007-2013–Axis IV Human Resources, Objective l.3, Line of Activity l.3.1.).

Supplementary material

12031_2015_523_MOESM1_ESM.docx (63 kb)
Fig. S1 (A) Growth inhibition (%) induced by 10 μM paroxetine (72 h) in media containing 10 % FBS or 4 % Biogro-2. Bars indicate the average ± SD of the growth inhibition of three replicates. (B) Average of growth inhibition induced by 10 μM paroxetine in 4 % Biogro-2 and 10 % FBS media. Bars indicate the average ± SD of the growth inhibition. (DOCX 63 kb)
12031_2015_523_MOESM2_ESM.docx (23 kb)
Fig. S2 Effect of 10 % FBS on lithium sensitivity, Bars indicate the average of Delta 1 ± SD in R and NR BD patients. (DOCX 22 kb)
12031_2015_523_MOESM3_ESM.docx (40 kb)
Fig. S3 Relative expression levels of IGF-1. Relative expression levels were measured by means of the comparative Ct method (ΔΔ Ct) using GAPDH as endogenous control. Fold change of the difference between R and NR was calculated with 2 − ΔΔCt equation. Differences between R and NR were analyzed with the Mann–Whitney U test. (For more details see Squassina et al., 2013) (DOCX 40 kb)
12031_2015_523_MOESM4_ESM.docx (22 kb)
Fig. S4 Expression of let-7c in LCLs from 10 healthy controls, 10 R BD and 10 NR BD patients. U6 assay was used as endogenous control. Bars represent the fold difference compared with healthy controls ± SD. (DOCX 21 kb)


  1. Åberg MAI, Åberg ND, Hedba H et al (2000) Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. Endocrinology 20:2896–2903Google Scholar
  2. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355PubMedCrossRefGoogle Scholar
  3. Bezchlibnyk YB, Xu L, Wang J-F, Young LT (2007) Decreased expression of insulin-like growth factor binding protein 2 in the prefrontal cortex of subjects with bipolar disorder and its regulation by lithium treatment. Brain Res 1147:213–217. doi: 10.1016/j.brainres.2007.01.147 PubMedCrossRefGoogle Scholar
  4. Carro E, Trejo JL, Busiguina S, Torres-aleman I (2001) Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci 21:5678–5684PubMedGoogle Scholar
  5. Corrada D, Viti F, Merelli I et al (2011) myMIR: a genome-wide microRNA targets identification and annotation tool. Brief Bioinform 12:588–600. doi: 10.1093/bib/bbr062 PubMedCrossRefGoogle Scholar
  6. Grof P, Ph D, Duffy A et al (2002) Is response to prophylactic lithium a familial trait? J Clin Psychiatry 63:942–947PubMedCrossRefGoogle Scholar
  7. Honegger A, Humbel RE (1986) Insulin-like growth factors I and II in fetal and adult bovine serum. Purification, primary structures, and immunological cross-reactivities. J Biol Chem 261:569–575PubMedGoogle Scholar
  8. Hornstein E, Shomron N (2006) Canalization of development by microRNAs. Nat Genet 38(Suppl):S20–S24. doi: 10.1038/ng1803 PubMedCrossRefGoogle Scholar
  9. Kim Y-K, Na K-S, Hwang J-A et al (2013) High insulin-like growth factor-1 in patients with bipolar I disorder: a trait marker? J Affect Disord 151:738–743. doi: 10.1016/j.jad.2013.07.041 PubMedCrossRefGoogle Scholar
  10. Liu X, Zhang T, He S et al (2014) Elevated serum levels of FGF-2, NGF and IGF-1 in patients with manic episode of bipolar disorder. Psychiatry Res 218:54–60. doi: 10.1016/j.psychres.2014.03.042 PubMedCrossRefGoogle Scholar
  11. Maffioletti E, Tardito D, Gennarelli M, Bocchio-Chiavetto L (2014) Micro spies from the brain to the periphery: new clues from studies on microRNAs in neuropsychiatric disorders. Front Cell Neurosci 8:75. doi: 10.3389/fncel.2014.00075 PubMedCentralPubMedCrossRefGoogle Scholar
  12. Manchia M, Adli M, Akula N et al (2013) Assessment of response to lithium maintenance treatment in bipolar disorder: a Consortium on Lithium Genetics (ConLiGen) Report. PLoS One 8(6):e65636PubMedCentralPubMedCrossRefGoogle Scholar
  13. Martin EC, Bratton MR, Zhu Y et al (2012) Insulin-like growth factor-1 signaling regulates miRNA expression in MCF-7 breast cancer cell line. PLoS One 7:e49067. doi: 10.1371/journal.pone.0049067 PubMedCentralPubMedCrossRefGoogle Scholar
  14. Merikangas KR, Akiskal HS, Angst J et al (2007) Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 64:543–552. doi: 10.1001/archpsyc.64.5.543 PubMedCentralPubMedCrossRefGoogle Scholar
  15. Morag A, Kirchheiner J, Rehavi M, Gurwitz D (2010) Human lymphoblastoid cell line panels: novel tools for assessing shared drug pathways. Pharmacogenomics 11:327–340PubMedCrossRefGoogle Scholar
  16. Morag A, Pasmanik-Chor M, Oron-Karni V (2011) Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics 171–184Google Scholar
  17. Orengo AM, Di Carlo E, Comes A et al (2014) Tumor cells engineered with IL-12 and IL-15 genes induce protective antibody responses in nude mice. J Immunol 171:569–575. doi: 10.4049/jimmunol.171.2.569 CrossRefGoogle Scholar
  18. Oved K, Morag A, Pasmanik-Chor M et al (2013) Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants. Transl Psychiatry 3:e313. doi: 10.1038/tp.2013.86 PubMedCentralPubMedCrossRefGoogle Scholar
  19. Palomino A, González-pinto A, Martinez-cengotitabengoa M et al (2013) Progress in neuro-psychopharmacology & biological psychiatry relationship between negative symptoms and plasma levels of insulin-like growth factor 1 in first-episode schizophrenia and bipolar disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 44:29–33. doi: 10.1016/j.pnpbp.2013.01.008 PubMedCrossRefGoogle Scholar
  20. Pereira ACP, McQuillin A, Puri V et al (2011) Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 156:177–187. doi: 10.1002/ajmg.b.31153 PubMedCrossRefGoogle Scholar
  21. Roush S, Slack FJ (2008) The let-7 family of microRNAs. Trends Cell Biol 18:505–516. doi: 10.1016/j.tcb.2008.07.007 PubMedCrossRefGoogle Scholar
  22. Rukov JL, Shomron N (2011) MicroRNA pharmacogenomics: post-transcriptional regulation of drug response. Trends Mol Med 17:412–423. doi: 10.1016/j.molmed.2011.04.003 PubMedCrossRefGoogle Scholar
  23. Sarkissyan S, Sarkissyan M, Wu Y et al (2014) IGF-1 regulates Cyr61 induced breast cancer cell proliferation and invasion. PLoS One 9:e103534. doi: 10.1371/journal.pone.0103534 PubMedCentralPubMedCrossRefGoogle Scholar
  24. Sciacca L, Le Moli R, Vigneri R (2012) Insulin analogs and cancer. Front Endocrinol (Lausanne) 3:21. doi: 10.3389/fendo.2012.00021 Google Scholar
  25. Singh B, Armstrong DT (1997) Insulin-like growth factor-1, a component of serum that enables porcine cumulus cells to expand in response to follicle-stimulating hormone in vitro. Biol Reprod 1375:1370–1375CrossRefGoogle Scholar
  26. Squassina A, Manchia M, Borg J et al (2011) Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. Pharmacogenomics 12:1559–1569PubMedCrossRefGoogle Scholar
  27. Squassina A, Costa M, Congiu D et al (2013) Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients. Pharmacol Res 73:1–7. doi: 10.1016/j.phrs.2013.04.004 PubMedCrossRefGoogle Scholar
  28. Werner H, Leroith D (2014) Insulin and insulin-like growth factor receptors in the brain: Physiological and pathological aspects. Eur Neuropsychopharmacol 1–7. doi:  10.1016/j.euroneuro.2014.01.020
  29. Wulczyn FG, Smirnova L, Rybak A et al (2007) Post-transcriptional regulation of the let-7 microRNA during neural cell specification. FASEB J 21:415–426. doi: 10.1096/fj.06-6130com PubMedCrossRefGoogle Scholar
  30. Yildiz A, Vieta E, Leucht S, Baldessarini RJ (2011) Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology 36:375–389. doi: 10.1038/npp.2010.192 PubMedCentralPubMedCrossRefGoogle Scholar
  31. Zhou R, Yuan P, Wang Y et al (2009) NIH Public Access 34:1395–1405. doi: 10.1038/npp.2008.131.Evidence Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Elena Milanesi
    • 1
    • 2
    Email author
  • Adva Hadar
    • 1
  • Elisabetta Maffioletti
    • 3
  • Haim Werner
    • 1
  • Noam Shomron
    • 2
    • 4
  • Massimo Gennarelli
    • 3
    • 5
  • Thomas G. Schulze
    • 6
  • Marta Costa
    • 7
  • Maria Del Zompo
    • 7
    • 8
  • Alessio Squassina
    • 7
    Email author
  • David Gurwitz
    • 1
    • 4
    Email author
  1. 1.Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.Department of Cell and Developmental Biology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Genetic UnitIRCCS Istituto Centro San Giovanni di Dio FatebenefratelliBresciaItaly
  4. 4.Sagol School of NeuroscienceTel Aviv UniversityTel AvivIsrael
  5. 5.Departement of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  6. 6.Institute of Psychiatric Phenomics and GenomicsLudwig-Maximilians-UniversityMunichGermany
  7. 7.Section of Neuroscience and Clinical Pharmacology, Department of Biomedical SciencesUniversity of CagliariCagliariItaly
  8. 8.Unit of Clinical Pharmacology of the University Hospital of CagliariCagliariItaly

Personalised recommendations