Protection of insulin‑like growth factor 1 on experimental peripheral neuropathy in diabetic mice

Wang,Hua; Zhang,Hao; Cao,Fuming; Lu,Jiaping; Tang,Jin; Li,Huizhi; Zhang,Yiyun; Feng,Bo; Tang,Zhaosheng

doi:10.3892/mmr.2018.9435

Protection of insulin‑like growth factor 1 on experimental peripheral neuropathy in diabetic mice

Authors:
- Hua Wang
- Hao Zhang
- Fuming Cao
- Jiaping Lu
- Jin Tang
- Huizhi Li
- Yiyun Zhang
- Bo Feng
- Zhaosheng Tang
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Affiliations: Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
Published online on: September 3, 2018 https://doi.org/10.3892/mmr.2018.9435
Pages: 4577-4586

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Abstract

The present study investigated whether insulin‑like growth factor‑1 (IGF‑1) exerts a protective effect against neuropathy in diabetic mice and its potential underlying mechanisms. Mice were divided into four groups: Db/m (control), db/db (diabetes), IGF‑1‑treated db/db and IGF‑1‑picropodophyllin (PPP)‑treated db/db. Behavioral studies were conducted using the hot plate and von Frey methods at 6 weeks of age prior to treatment. The motor nerve conduction velocity (NCV) of the sciatic nerve was measured using a neurophysiological method at 8 weeks of age. The alterations in the expression levels of IGF‑1 receptor (IGF‑1R), c‑Jun N‑terminal kinase (JNK), extracellular signal‑regulated kinase (ERK), p38 and effect of IGF‑1 on the sciatic nerve morphology were observed by western blotting and electron microscopy. Compared with the control group, the diabetes group developed hypoalgesia after 12 weeks, and neurological lesions improved following an intraperitoneal injection of recombinant (r)IGF‑1. The sciatic NCV in the diabetes group was significantly lower compared with the control group. The sciatic NCV improved following rIGF‑1 intervention; however, was impaired following administration of the IGF‑1 receptor antagonist, PPP. The myelin sheath in the sciatic nerve of the diabetes group was significantly more impaired compared with the control group. The myelin sheath in the sciatic nerves of the rIGF‑1‑treated group was significantly improved compared with the diabetes group; whereas, they were significantly impaired following administration of the IGF‑1R inhibitor. In addition, the expression of IGF‑1R, phosphorylated (p)‑JNK and p‑ERK of sciatic nerves in the db/db mice was significantly increased following treatment with IGF‑1. The expression levels of these proteins were significantly lower in the IGF‑1‑PPP group compared with the IGF‑1 group; however, no significant difference was observed in the expression levels of p‑p38 following treatment with IGF‑1. The results of the present study demonstrated that IGF‑1 may improve neuropathy in diabetic mice. This IGF‑1‑induced neurotrophic effect may be associated with the increased phosphorylation levels of JNK and ERK, not p38; however, it was attenuated by administration of an IGF‑1R antagonist.

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1	Xu Y, Wang L, He J, Bi Y, Li M, Wang T, Wang L, Jiang Y, Dai M, Lu J, et al: Prevalence and control of diabetes in Chinese adults. JAMA. 310:948–959. 2013. View Article : Google Scholar : PubMed/NCBI
2	Galuppo M, Giacoppo S, Bramanti P and Mazzon E: Use of natural compounds in the management of diabetic peripheral neuropathy. Molecules. 19:2877–2895. 2014. View Article : Google Scholar : PubMed/NCBI
3	Bongaerts BW, Rathmann W, Kowall B, Herder C, Stöckl D, Meisinger C and Ziegler D: Postchallenge hyperglycemia is positively associated with diabetic polyneuropathy: The KORA F4 study. Diabetes Care. 35:1891–1893. 2012. View Article : Google Scholar : PubMed/NCBI
4	Duby JJ, Campbell RK, Setter SM, White JR and Rasmussen KA: Diabetic neuropathy: An intensive review. Am J Health Syst Pharm. 61:160–173; quiz 175–176. 2004.PubMed/NCBI
5	Morrison JF, Shehab S, Sheen R, Dhanasekaran S, Shaffiullah M and Mensah-Brown E: Sensory and autonomic nerve changes in the monosodium glutamate-treated rat: A model of type II diabetes. Exp Physiol. 93:213–222. 2008. View Article : Google Scholar : PubMed/NCBI
6	Beiswenger KK, Calcutt NA and Mizisin AP: Epidermal nerve fiber quantification in the assessment of diabetic neuropathy. Acta Histochem. 110:351–362. 2008. View Article : Google Scholar : PubMed/NCBI
7	Grisold A, Callaghan BC and Feldman EL: Mediators of diabetic neuropathy: Is hyperglycemia the only culprit? Curr Opin Endocrinol Diabetes Obes. 24:103–111. 2017. View Article : Google Scholar : PubMed/NCBI
8	Román-Pintos LM, Villegas-Rivera G, Rodríguez-Carrizalez AD, Miranda-Díaz AG and Cardona-Muñoz EG: Diabetic polyneuropathy in Type 2 diabetes mellitus: Inflammation, oxidative stress and mitochondrial function. J Diabetes Res. 2016:34256172016. View Article : Google Scholar : PubMed/NCBI
9	Chung SS, Ho EC, Lam KS and Chung SK: Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol. 14(8 Suppl 3): S233–S236. 2003. View Article : Google Scholar : PubMed/NCBI
10	Yakar S, Pennisi P, Wu Y, Zhao H and LeRoith D: Clinical relevance of systemic and local IGF-I. Endocr Dev. 9:11–16. 2005. View Article : Google Scholar : PubMed/NCBI
11	Hao CN, Geng YJ, Li F, Yang T, Su DF, Duan JL and Li Y: Insulin-like growth factor-1 receptor activation prevents hydrogen peroxide-induced oxidative stress, mitochondrial dysfunction and apoptosis. Apoptosis. 16:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI
12	Puche JE, García-Fernández M, Muntané J, Rioja J, González-Barón S and Castilla Cortazar I: Low doses of insulin-like growth factor-I induce mitochondrial protection in aging rats. Endocrinology. 149:2620–2627. 2008. View Article : Google Scholar : PubMed/NCBI
13	Carro E, Trejo JL, Núñez A and Torres-Aleman I: Brain repair and neuroprotection by serum insulin-like growth factor I. Mol Neurobiol. 27:153–162. 2003. View Article : Google Scholar : PubMed/NCBI
14	Ishii DN: Implication of insulin-like growth factors in the pathogenesis of diabetic neuropathy. Brain Res Brain Res Rev. 20:47–67. 1995. View Article : Google Scholar : PubMed/NCBI
15	Papanas N and Ziegler D: Risk factors and comorbidities in diabetic neuropathy: An update 2015. Rev Diabet Stud. 12:48–62. 2015. View Article : Google Scholar : PubMed/NCBI
16	Menu E, Jernberg-Wiklund H, Stromberg T, De Raeve H, Girnita L, Larsson O, Axelson M, Asosingh K, Nilsson K, Van Camp B and Vanderkerken K: Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: An in vitro and in vivo study in the 5T33MM mouse model. Blood. 107:655–660. 2006. View Article : Google Scholar : PubMed/NCBI
17	Hargreaves K, Dubner R, Brown F, Flores C and Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 32:77–88. 1988. View Article : Google Scholar : PubMed/NCBI
18	Kanazawa Y, Takahashi-Fujigasaki J, Ishizawa S, Takabayashi N, Ishibashi K, Matoba K, Kawanami D, Yokota T, Tajima N and Utsunomiya K: The Rho-kinase inhibitor fasudil restores normal motor nerve conduction velocity in diabetic rats by assuring the proper localization of adhesion-related molecules in myelinating Schwann cells. Exp Neurol. 247:438–446. 2013. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, et al: Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity and treatments. Diabetes Care. 33:2285–2293. 2010. View Article : Google Scholar : PubMed/NCBI
21	Rathur HM and Boulton AJ: The neuropathic diabetic foot. Nat Clin Pract Endocrinol Metab. 3:14–25. 2007. View Article : Google Scholar : PubMed/NCBI
22	Capoluongo E, Pitocco D, Santonocito C, Concolino P, Santini SA, Manto A, Lulli P, Ghirlanda G, Zuppi C and Ameglio F: Association between serum free IGF-I and IGFBP-3 levels in type-I diabetes patients affected with associated autoimmune diseases or diabetic complications. Eur Cytokine Netw. 17:167–174. 2006.PubMed/NCBI
23	Chu Q, Moreland R, Yew NS, Foley J, Ziegler R and Scheule RK: Systemic insulin-like growth factor-1 reverses hypoalgesia and improves mobility in a mouse model of diabetic peripheral neuropathy. Mol Ther. 16:1400–1481. 2008. View Article : Google Scholar : PubMed/NCBI
24	Schmidt RE, Dorsey DA, Beaudet LN, Plurad SB, Parvin CA and Miller MS: Insulin-like growth factor I reverses experimental diabetic autonomic neuropathy. Am J Pathol. 155:1651–1660. 1999. View Article : Google Scholar : PubMed/NCBI
25	Homs J, Pagès G, Ariza L, Casas C, Chillón M, Navarro X and Bosch A: Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy. Mol Ther Methods Clin Dev. 1:72014. View Article : Google Scholar : PubMed/NCBI
26	O'Brien PD, Sakowski SA and Feldman EL: Mouse models of diabetic neuropathy. ILAR J. 54:259–272. 2014. View Article : Google Scholar : PubMed/NCBI
27	Russell JW, Cheng HL and Golovoy D: Insulin-like growth factor-I promotes myelination of peripheral sensory axons. J Neuropathol Exp Neurol. 59:575–584. 2000. View Article : Google Scholar : PubMed/NCBI
28	Delaney CL, Russell JW, Cheng HL and Feldman EL: Insulin-like growth factor-I and over-expression of Bcl-xL prevent glucose-mediated apoptosis in Schwann cells. J Neuropathol Exp Neurol. 60:147–160. 2001. View Article : Google Scholar : PubMed/NCBI
29	Zhuang HX, Snyder CK, Pu SF and Ishii DN: Insulin-like growth factors reverse or arrest diabetic neuropathy: Effects on hyperalgesia and impaired nerve regeneration in rats. Exp Neurol. 140:198–205. 1996. View Article : Google Scholar : PubMed/NCBI
30	Gao WQ, Shinsky N, Ingle G, Beck K, Elias KA and Powell-Braxton L: IGF-I deficient mice show reduced peripheral nerve conduction velocities and decreased axonal diameters and respond to exogenous IGF-I treatment. J Neurobiol. 39:142–152. 1999. View Article : Google Scholar : PubMed/NCBI
31	Rabiee A, Krüger M, Ardenkjær-Larsen J, Kahn CR and Emanuelli B: Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action. Cell Signal. 47:1–15. 2018. View Article : Google Scholar : PubMed/NCBI
32	Zhou YL, Liu SQ, Yuan B and Lu N: The expression of insulin-like growth factor-1 in senior patients with diabetes and dementia. Exp Ther Med. 13:103–106. 2017. View Article : Google Scholar : PubMed/NCBI
33	Pfäffle R, Kiess W and Klammt J: Downstream insulin-like growth factor. Endocr Dev. 23:42–51. 2012. View Article : Google Scholar : PubMed/NCBI
34	Leinninger GM, Backus C, Uhler MD, Lentz SI and Feldman EL: Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. FASEB J. 18:1544–1546. 2004. View Article : Google Scholar : PubMed/NCBI
35	Qi M and Elion EA: MAP kinase pathways. J Cell Sci. 118:3569–3572. 2005. View Article : Google Scholar : PubMed/NCBI
36	Mohammadi R and Saadati A: Influence of insulin-like growth factor I on nerve regeneration using allografts: A sciatic nervemodel. J Craniofac Surg. 25:1510–1515. 2014. View Article : Google Scholar : PubMed/NCBI