Frontiers in Biology

, Volume 13, Issue 2, pp 137–144 | Cite as

Insulin inhibits the JNK mediated cell death via upregulation of AKT expression in Schwann cells grown in hyperglycemia

  • Mallahalli S. Manu
  • Kuruvanthe S. Rachana
  • Gopal M. Advirao
Research Article



Schwann cells (SCs) are the glial cells of the peripheral nervous system, which forms a thick insulating structure around the axons. Hyperglycemia is known physiologic conditions in both type I and type II diabetes which causes diabetic neuropathy. But the SC possesses insulin receptors even though glucose uptake is independent of insulin. Since the insulin level is highly altered in diabetes, it is of greater importance to evaluate their role in the Schwann cell survival and death.


Schwann cells were isolated from neonatal pups and grown with and without insulin in hyperglycemic medium to mimic diabetic condition for 24 and 48 h. We studied the cell viability using 3 (4,5-dimethylthiazol-2-yl) 2,5- diphenyltetrazolium bromide (MTT) and mitochondrial membrane potential (MMP) assay at different time interval on SCs. We also studied the protein and gene expression of Protein Kinase B (AKT) and Jun N-terminal kinase (JNK), which are greatly involved in cell survival and cell death respectively.


The result shows that, high glucose levels for 48 h decrease the SC viability. Hyperglycemic condition induces the SC death by increasing the JNK expression which in turn reduces the MMP of glial cells. However, insulin administration for SCs grown in high glucose condition can reduce the JNK expression by activating AKT signaling pathway.


These observations demonstrate that the proper insulin balance is required for Schwann cells survival in hyperglycemic condition. Therefore, altered insulin signaling can be one of the reasons for demyelination of peripheral neurons in diabetic neuropathy.


insulin schwann cells apoptosis JNK AKT diabetic peripheral neuropathy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



MSM was supported by Junior Research Fellowship by Department of Science and Technology (DST). We thank Rohit Kumar H. G. and Kiran Kumar H. N. for critical reading and support. This work was supported by grant (SERB No: SB/SO/AS-119/2012) from Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India (New Delhi).


  1. Barr R K, Ramirez M J (2006). c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s Disease. Front Pharmacol, 6: 1–12Google Scholar
  2. Bhatheja K, Field J (2006). Schwann cells: origins and role in axonal maintenance and regeneration. Int J Biochem Cell Biol, 38(12): 1995–1999CrossRefPubMedGoogle Scholar
  3. Brockes J P, Fields K L, Raff M C (1979). Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve. Brain Res, 165(1): 105–118PubMedGoogle Scholar
  4. Cai X X, Luo E, Yuan Q (2010). Interaction between Schwann cells and osteoblasts in vitro. Int J Oral Sci, 2(2): 74–81CrossRefPubMedPubMedCentralGoogle Scholar
  5. Campana W M, Darin S J, O’Brien J S (1999). Phosphatidylinositol 3-kinase and Akt protein kinase mediate IGF-I-and prosaptide-induced survival in Schwann cells. J Neurosci Res, 57(3): 332–341CrossRefPubMedGoogle Scholar
  6. Delaney C L, Cheng H L, Feldman E L (1999). Insulin-like growth factor-I prevents caspase-mediated apoptosis in Schwann cells. J Neurobiol, 41(4): 540–548CrossRefPubMedGoogle Scholar
  7. Denarier E, Forghani R, Farhadi H F, Dib S, Dionne N, Friedman H C, Lepage P, Hudson T J, Drouin R, Peterson A (2005). Functional organization of a Schwann cell enhancer. J Neurosci, 25(48): 11210–11217CrossRefPubMedGoogle Scholar
  8. Dhanasekaran D N, Reddy E P (2008). JNK signaling in apoptosis. Oncogene, 27(48): 6245–6251CrossRefPubMedPubMedCentralGoogle Scholar
  9. Jessen K R, Mirsky R (2005). The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci, 6(9): 671–682CrossRefPubMedGoogle Scholar
  10. Kristiansen M, Hughes R, Patel P, Jacques T S, Clark A R, Ham J (2010). Mkp1 is a c-Jun target gene that antagonizes JNK-dependent apoptosis in sympathetic neurons. J Neurosci, 30(32): 10820–10832CrossRefPubMedPubMedCentralGoogle Scholar
  11. Manning B D, Cantley L C (2007). AKT/PKB signaling: navigating downstream. Cell, 129(7): 1261–1274CrossRefPubMedPubMedCentralGoogle Scholar
  12. Manu M S, Rachana K S, Advirao G M (2017). Altered expression of IRS2 and GRB2 in demyelination of peripheral neurons: Implications in diabetic neuropathy. Neuropeptides, 62: 71–79CrossRefPubMedGoogle Scholar
  13. Morrison R S, Kinoshita Y, Johnson M D, Ghatan S, Ho J T, Garden G (2002). Neuronal survival and cell death signaling pathways. Adv Exp Med Biol, 513: 41–86CrossRefPubMedGoogle Scholar
  14. Nakao J, Shinoda J, Nakai Y, Murase S, Uyemura K (1997). Apoptosis regulates the number of Schwann cells at the premyelinating stage. J Neurochem, 68(5): 1853–1862CrossRefPubMedGoogle Scholar
  15. Okuno S, Saito A, Hayashi T, Chan P H (2004). The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci, 24(36): 7879–7887CrossRefPubMedGoogle Scholar
  16. Rachana K S, Manu M S, Advirao G M (2016). Insulin influenced expression of myelin proteins in diabetic peripheral neuropathy. Neurosci Lett, 629: 110–115CrossRefPubMedGoogle Scholar
  17. RohitKumar H G, Asha K R, Raghavan S C, Advi Rao G M (2015). DNA intercalative 4-butylaminopyrimido[4′,5′:4,5]thieno(2,3-b)quinoline induces cell cycle arrest and apoptosis in leukemia cells. Cancer Chemother Pharmacol, 75(6): 1121–1133CrossRefPubMedGoogle Scholar
  18. Russell JW, Sullivan K A, Windebank A J, Herrmann D N, Feldman E L (1999). Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis, 6(5): 347–363CrossRefPubMedGoogle Scholar
  19. Shettar A, Muttagi G (2012). Developmental regulation of insulin receptor gene in sciatic nerves and role of insulin on glycoprotein P0 in the Schwann cells. Peptides, 36(1): 46–53CrossRefPubMedGoogle Scholar
  20. Shetter A R, Muttagi G, Bhadravathi C, Sagar K (2011). Expression and localization of insulin receptors in dissociated primary cultures of rat Schwann cells, Cell Biol Int, 35:299–304CrossRefPubMedGoogle Scholar
  21. Uranga R M, Katz S, Salvador G A (2013). Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress. J Biol Chem, 288(27): 19773–19784CrossRefPubMedPubMedCentralGoogle Scholar
  22. Vincent A M, Russell JW, Low P, Feldman E L (2004). Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev, 25(4): 612–628CrossRefPubMedGoogle Scholar
  23. Yarza R, Vela S, Solas M, Ramirez M J (2016). c-Jun N-terminal Kinase (JNK) Signaling as a Therapeutic Target for Alzheimer’s Disease. Front Pharmacol, 6: 321CrossRefPubMedPubMedCentralGoogle Scholar
  24. Zhang L, Yu C, Vasquez F E, Galeva N, Onyango I, Swerdlow R H, Dobrowsky R T (2010). Hyperglycemia alters the schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production. J Proteome Res, 9(1): 458–471CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Mallahalli S. Manu
    • 1
  • Kuruvanthe S. Rachana
    • 1
  • Gopal M. Advirao
    • 1
  1. 1.Department of BiochemistryDavangere UniversityDavangereIndia

Personalised recommendations