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Non-glucose risk factors in the pathogenesis of diabetic peripheral neuropathy

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Abstract

In this review, we consider the diverse risk factors in diabetes patients beyond hyperglycemia that are being recognized as contributors to diabetic peripheral neuropathy (DPN). Interest in such alternative mechanisms has been encouraged by the recognition that neuropathy occurs in subjects with metabolic syndrome and pre-diabetes and by the reporting of several large clinical studies that failed to show reduced prevalence of neuropathy after intensive glucose control in patients with type 2 diabetes. Animal models of obesity, dyslipidemia, hypertension, and other disorders common to both pre-diabetes and diabetes have been used to highlight a number of plausible pathogenic mechanisms that may either damage the nerve independent of hyperglycemia or augment the toxic potential of hyperglycemia. While pathogenic mechanisms stemming from hyperglycemia are likely to be significant contributors to DPN, future therapeutic strategies will require a more nuanced approach that considers a range of concurrent insults derived from the complex pathophysiology of diabetes beyond direct hyperglycemia.

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References

  1. K.A. Head, Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern. Med. Rev. 11(4), 294–329 (2006)

    PubMed  Google Scholar 

  2. J.B. Buse, D.J. Wexler, A. Tsapas, P. Rossing, G. Mingrone, C. Mathieu, D.A. D’Alessio, M.J. Davies, 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the study of diabetes (EASD). Diabetes. Care. 43(2), 487–493 (2020). https://doi.org/10.2337/dci19-0066

    Article  CAS  PubMed  Google Scholar 

  3. M.K. Kim, S.H. Ko, B.Y. Kim, E.S. Kang, J. Noh, S.K. Kim, S.O. Park, K.Y. Hur, S. Chon, M.K. Moon, N.H. Kim, S.Y. Kim, S.Y. Rhee, K.W. Lee, J.H. Kim, E.J. Rhee, S. Chun, S.H. Yu, D.J. Kim, H.S. Kwon, K.S. Park; Committee of Clinical Practice Guidelines, K.D.A., 2019 clinical practice guidelines for type 2 diabetes mellitus in Korea. Diabetes Metab J. 43(4), 398–406 (2019). https://doi.org/10.4093/dmj.2019.0137

    Article  PubMed  PubMed Central  Google Scholar 

  4. C. Diabetes; Complications Trial Research, G., D.M. Nathan, S. Genuth, J. Lachin, P. Cleary, O. Crofford, M. Davis, L. Rand, C. Siebert, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329(14), 977–986 (1993). https://doi.org/10.1056/NEJM199309303291401

    Article  Google Scholar 

  5. D.M. Nathan, P.A. Cleary, J.Y. Backlund, S.M. Genuth, J.M. Lachin, T.J. Orchard, P. Raskin, B. Zinman, C. Diabetes, Complications Trial/Epidemiology of Diabetes, I., Complications Study Research, G.: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353(25), 2643–2653 (2005). https://doi.org/10.1056/NEJMoa052187

    Article  PubMed  Google Scholar 

  6. S. Yagihashi, H. Mizukami, K. Sugimoto, Mechanism of diabetic neuropathy: where are we now and where to go? J. Diabetes Investig. 2(1), 18–32 (2011). https://doi.org/10.1111/j.2040-1124.2010.00070.x

    Article  CAS  PubMed  Google Scholar 

  7. F. Garcia Soriano, L. Virag, P. Jagtap, E. Szabo, J.G. Mabley, L. Liaudet, A. Marton, D.G. Hoyt, K.G. Murthy, A.L. Salzman, G.J. Southan, C. Szabo, Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat. Med. 7(1), 108–113 (2001). https://doi.org/10.1038/83241

    Article  CAS  PubMed  Google Scholar 

  8. R.J. Heine, B. Balkau, A. Ceriello, S. Del Prato, E.S. Horton, M.R. Taskinen, What does postprandial hyperglycaemia mean? Diabet. Med. 21(3), 208–213 (2004)

    Article  CAS  Google Scholar 

  9. A.E. Caballero, S. Arora, R. Saouaf, S.C. Lim, P. Smakowski, J.Y. Park, G.L. King, F.W. LoGerfo, E.S. Horton, A. Veves, Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 48(9), 1856–1862 (1999)

    Article  CAS  Google Scholar 

  10. S. Thrainsdottir, R.A. Malik, L.B. Dahlin, P. Wiksell, K.F. Eriksson, I. Rosen, J. Petersson, D.A. Greene, G. Sundkvist, Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes 52(10), 2615–2622 (2003)

    Article  CAS  Google Scholar 

  11. R. Stavniichuk, V.R. Drel, H. Shevalye, I. Vareniuk, M.J. Stevens, J.L. Nadler, I.G. Obrosova, Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies. Free Radic. Biol. Med. 49(6), 1036–1045 (2010). https://doi.org/10.1016/j.freeradbiomed.2010.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. S. Tesfaye, N. Chaturvedi, S.E. Eaton, J.D. Ward, C. Manes, C. Ionescu-Tirgoviste, D.R. Witte, J.H. Fuller, E.P.C.S. Group, Vascular risk factors and diabetic neuropathy. N. Engl. J. Med. 352(4), 341–350 (2005). https://doi.org/10.1056/NEJMoa032782

    Article  CAS  PubMed  Google Scholar 

  13. R.M. Herman, J.B. Brower, D.G. Stoddard, A.R. Casano, J.H. Targovnik, J.H. Herman, P. Tearse, Prevalence of somatic small fiber neuropathy in obesity. Int. J. Obes. (Lond) 31(2), 226–235 (2007). https://doi.org/10.1038/sj.ijo.0803418

    Article  CAS  Google Scholar 

  14. A.G. Smith, K. Rose, J.R. Singleton, Idiopathic neuropathy patients are at high risk for metabolic syndrome. J. Neurol. Sci. 273(1-2), 25–28 (2008). https://doi.org/10.1016/j.jns.2008.06.005

    Article  PubMed  PubMed Central  Google Scholar 

  15. A.M. Stino, A.G. Smith, Peripheral neuropathy in prediabetes and the metabolic syndrome. J. Diabetes. Investig. 8(5), 646–655 (2017). https://doi.org/10.1111/jdi.12650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. R.R. Holman, S.K. Paul, M.A. Bethel, D.R. Matthews, H.A. Neil, 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359(15), 1577–1589 (2008). https://doi.org/10.1056/NEJMoa0806470

    Article  CAS  PubMed  Google Scholar 

  17. D. Ziegler, N. Papanas, A.I. Vinik, J.E. Shaw, Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol. 126, 3–22 (2014). https://doi.org/10.1016/B978-0-444-53480-4.00001-1

    Article  PubMed  Google Scholar 

  18. N. Papanas, D. Ziegler, Prediabetic neuropathy: does it exist? Curr. Diab. Rep. 12(4), 376–383 (2012). https://doi.org/10.1007/s11892-012-0278-3

    Article  PubMed  Google Scholar 

  19. N. Papanas, A.I. Vinik, D. Ziegler, Neuropathy in prediabetes: does the clock start ticking early? Nat. Rev. Endocrinol. 7(11), 682–690 (2011). https://doi.org/10.1038/nrendo.2011.113

    Article  CAS  PubMed  Google Scholar 

  20. A. Vinik, J. Ullal, H.K. Parson, C.M. Casellini, Diabetic neuropathies: clinical manifestations and current treatment options. Nat. Clin. Pract. Endocrinol. Metab. 2(5), 269–281 (2006). https://doi.org/10.1038/ncpendmet0142

    Article  CAS  PubMed  Google Scholar 

  21. A.I. Vinik, M.L. Nevoret, C. Casellini, H. Parson, Diabetic neuropathy. Endocrinol. Metab. Clin. North Am. 42(4), 747–787 (2013). https://doi.org/10.1016/j.ecl.2013.06.001

    Article  PubMed  Google Scholar 

  22. P.J. O’Connor, F. Ismail-Beigi, Near-normalization of glucose and microvascular diabetes complications: data from ACCORD and ADVANCE. Ther. Adv. Endocrinol. Metab. 2(1), 17–26 (2011). https://doi.org/10.1177/2042018810390545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. C.L. Martin, J.W. Albers, R. Pop-Busui, D.E.R. Group, Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 37(1), 31–38 (2014). https://doi.org/10.2337/dc13-2114

    Article  CAS  PubMed  Google Scholar 

  24. D.S. Younger, G. Rosoklija, A.P. Hays, W. Trojaborg, N. Latov, Diabetic peripheral neuropathy: a clinicopathologic and immunohistochemical analysis of sural nerve biopsies. Muscle Nerve 19(6), 722–727 (1996). https://doi.org/10.1002/(SICI)1097-4598(199606)19:6<722::AID-MUS6>3.0.CO;2-C

  25. J. Satoh, S. Yagihashi, T. Toyota, The possible role of tumor necrosis factor-alpha in diabetic polyneuropathy. Exp. Diabesity Res. 4(2), 65–71 (2003). https://doi.org/10.1155/EDR.2003.65

    Article  PubMed  PubMed Central  Google Scholar 

  26. G. Conti, E. Scarpini, P. Baron, S. Livraghi, M. Tiriticco, R. Bianchi, C. Vedeler, G. Scarlato, Macrophage infiltration and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitant with endoneurial induction of IL-1beta and p75NTR. J. Neurol. Sci. 195(1), 35–40 (2002)

    Article  CAS  Google Scholar 

  27. S. Yagihashi, S. Yamagishi, R. Wada, Pathology and pathogenetic mechanisms of diabetic neuropathy: correlation with clinical signs and symptoms. Diabetes Res. Clin. Pract. 77(Suppl 1), S184–S189 (2007). https://doi.org/10.1016/j.diabres.2007.01.054

    Article  CAS  PubMed  Google Scholar 

  28. G.G. Duncan, F.A. Elliott, T.G. Duncan, J. Schatanoff, Some clinical potentials of chlorophenoxyisobutyrate (Clofibrate) therapy. (Hyperlipidemia-angina pectoris-blood sludging-diabetic neuropathy). Trans. Am. Clin. Climatol. Assoc. 79, 216–228 (1968)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. A.M. Vincent, J.M. Hayes, L.L. McLean, A. Vivekanandan-Giri, S. Pennathur, E.L. Feldman, Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes. 58(10), 2376–2385 (2009). https://doi.org/10.2337/db09-0047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. A. Gordon Smith, J. Robinson Singleton, Idiopathic neuropathy, prediabetes and the metabolic syndrome. J. Neurol. Sci. 242(1-2), 9–14 (2006). https://doi.org/10.1016/j.jns.2005.11.020

    Article  CAS  PubMed  Google Scholar 

  31. P. Fioretto, P.M. Dodson, D. Ziegler, R.S. Rosenson, Residual microvascular risk in diabetes: unmet needs and future directions. Nat. Rev. Endocrinol. 6(1), 19–25 (2010). https://doi.org/10.1038/nrendo.2009.213

    Article  PubMed  Google Scholar 

  32. A.M. Vincent, L.M. Hinder, R. Pop-Busui, E.L. Feldman, Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J. Peripher. Nerv. Syst. 14(4), 257–267 (2009). https://doi.org/10.1111/j.1529-8027.2009.00237.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. E.P. Davidson, L.J. Coppey, A. Holmes, S. Lupachyk, B.L. Dake, C.L. Oltman, R.G. Peterson, M.A. Yorek, Characterization of diabetic neuropathy in the Zucker diabetic Sprague-Dawley rat: a new animal model for type 2 diabetes. J. Diabetes. Res. 2014, 714273 (2014). https://doi.org/10.1155/2014/714273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. B.L. Guilford, D.E. Wright, Chewing the fat: genetic approaches to model dyslipidemia-induced diabetic neuropathy in mice. Exp. Neurol. 248, 504–508 (2013). https://doi.org/10.1016/j.expneurol.2013.07.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. A. Rosales-Hernandez, A. Cheung, P. Podgorny, C. Chan, C. Toth, Absence of clinical relationship between oxidized low density lipoproteins and diabetic peripheral neuropathy: a case control study. Lipids Health Dis. 13, 32 (2014). https://doi.org/10.1186/1476-511X-13-32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. A. Holmes, L.J. Coppey, E.P. Davidson, M.A. Yorek, Rat models of diet-induced obesity and high fat/low dose streptozotocin type 2 diabetes: effect of reversal of high fat diet compared to treatment with enalapril or menhaden oil on glucose utilization and neuropathic endpoints. J. Diabetes Res. 2015, 307285 (2015). https://doi.org/10.1155/2015/307285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Y.R. Cho, J.H. Lim, M.Y. Kim, T.W. Kim, B.Y. Hong, Y.S. Kim, Y.S. Chang, H.W. Kim, C.W. Park, Therapeutic effects of fenofibrate on diabetic peripheral neuropathy by improving endothelial and neural survival in db/db mice. PLoS ONE. 9(1), e83204 (2014). https://doi.org/10.1371/journal.pone.0083204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. A.E. Rumora, M.G. Savelieff, S.A. Sakowski, E.L. Feldman, Disorders of mitochondrial dynamics in peripheral neuropathy: Clues from hereditary neuropathy and diabetes. Int. Rev. Neurobiol. 145, 127–176 (2019). https://doi.org/10.1016/bs.irn.2019.05.002

    Article  CAS  PubMed  Google Scholar 

  39. A.G. Smith, J.R. Singleton, Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. J. Diabetes Compl. 27(5), 436–442 (2013). https://doi.org/10.1016/j.jdiacomp.2013.04.003

    Article  Google Scholar 

  40. E.A. Jarmuzewska, A. Ghidoni, A.A. Mangoni, Hypertension and sensorimotor peripheral neuropathy in type 2 diabetes. Eur. Neurol. 57(2), 91–95 (2007). https://doi.org/10.1159/000098058

    Article  CAS  PubMed  Google Scholar 

  41. J.C. Ansquer, C. Foucher, P. Aubonnet, K. Le Malicot, Fibrates and microvascular complications in diabetes-insight from the FIELD study. Curr. Pharm. Des. 15(5), 537–552 (2009)

    Article  CAS  Google Scholar 

  42. A. Othman, R. Bianchi, I. Alecu, Y. Wei, C. Porretta-Serapiglia, R. Lombardi, A. Chiorazzi, C. Meregalli, N. Oggioni, G. Cavaletti, G. Lauria, A. von Eckardstein, T. Hornemann, Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats. Diabetes. 64(3), 1035–1045 (2015). https://doi.org/10.2337/db14-1325

    Article  CAS  PubMed  Google Scholar 

  43. A. Othman, R. Benghozi, I. Alecu, Y. Wei, E. Niesor, A. von Eckardstein, T. Hornemann, Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy? J. Clin. Lipidol. 9(4), 568–575 (2015). https://doi.org/10.1016/j.jacl.2015.03.011

    Article  PubMed  Google Scholar 

  44. Y.A. Rajabally, R.S. Shah, Dyslipidaemia in chronic acquired distal axonal polyneuropathy. J. Neurol. 258(8), 1431–1436 (2011). https://doi.org/10.1007/s00415-011-5950-z

    Article  CAS  PubMed  Google Scholar 

  45. T.D. Wiggin, K.A. Sullivan, R. Pop-Busui, A. Amato, A.A. Sima, E.L. Feldman, Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes. 58(7), 1634–1640 (2009). https://doi.org/10.2337/db08-1771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. S. Wu, X. Cao, R. He, K. Xiong, Detrimental impact of hyperlipidemia on the peripheral nervous system: a novel target of medical epidemiological and fundamental research study. Neural. Regen. Res. 7(5), 392–399 (2012). https://doi.org/10.3969/j.issn.1673-5374.2012.05.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. F.S. Al-Ani, M.S. Al-Nimer, F.S. Ali, Dyslipidemia as a contributory factor in etiopathogenesis of diabetic neuropathy. Ind. J. Endocrinol. Metab. 15(2), 110–114 (2011). https://doi.org/10.4103/2230-8210.81940

    Article  Google Scholar 

  48. N.J. Stone, J.G. Robinson, A.H. Lichtenstein, C.N. Bairey Merz, C.B. Blum, R.H. Eckel, A.C. Goldberg, D. Gordon, D. Levy, D.M. Lloyd-Jones, P. McBride, J.S. Schwartz, S.T. Shero, S.C. Smith Jr, K. Watson, P.W. Wilson; American College of Cardiology/American Heart Association Task Force on Practice, G., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63(25 Pt B), 2889–2934 (2014). https://doi.org/10.1016/j.jacc.2013.11.002

    Article  PubMed  Google Scholar 

  49. E.J. Stevens, A.L. Carrington, D.R. Tomlinson, Nerve ischaemia in diabetic rats: time-course of development, effect of insulin treatment plus comparison of streptozotocin and BB models. Diabetologia. 37(1), 43–48 (1994)

    Article  CAS  Google Scholar 

  50. T.M. Davis, B.B. Yeap, W.A. Davis, D.G. Bruce, Lipid-lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study. Diabetologia. 51(4), 562–566 (2008). https://doi.org/10.1007/s00125-007-0919-2

    Article  CAS  PubMed  Google Scholar 

  51. D. Tomassoni, E. Traini, L. Vitaioli, F. Amenta, Morphological and conduction changes in the sciatic nerve of spontaneously hypertensive rats. Neurosci. Lett. 362(2), 131–135 (2004). https://doi.org/10.1016/j.neulet.2004.03.014

    Article  CAS  PubMed  Google Scholar 

  52. J.A. Gregory, C.G. Jolivalt, J. Goor, A.P. Mizisin, N.A. Calcutt, Hypertension-induced peripheral neuropathy and the combined effects of hypertension and diabetes on nerve structure and function in rats. Acta Neuropathol. 124(4), 561–573 (2012). https://doi.org/10.1007/s00401-012-1012-6

    Article  PubMed  Google Scholar 

  53. A. De Visser, A. Hemming, C. Yang, S. Zaver, R. Dhaliwal, Z. Jawed, C. Toth, The adjuvant effect of hypertension upon diabetic peripheral neuropathy in experimental type 2 diabetes. Neurobiol Dis. 62, 18–30 (2014). https://doi.org/10.1016/j.nbd.2013.07.019

    Article  CAS  PubMed  Google Scholar 

  54. H. Takata, Y. Takeda, A. Zhu, Y. Cheng, T. Yoneda, M. Demura, K. Yagi, S. Karashima, M. Yamagishi, Protective effects of mineralocorticoid receptor blockade against neuropathy in experimental diabetic rats. Diabetes Obes. Metab. 14(2), 155–162 (2012). https://doi.org/10.1111/j.1463-1326.2011.01499.x

    Article  CAS  PubMed  Google Scholar 

  55. J.W. Mold, S.K. Vesely, B.A. Keyl, J.B. Schenk, M. Roberts, The prevalence, predictors, and consequences of peripheral sensory neuropathy in older patients. J. Am. Board Fam. Pract. 17(5), 309–318 (2004)

    Article  Google Scholar 

  56. D.Y. Cho, J.W. Mold, M. Roberts, Further investigation of the negative association between hypertension and peripheral neuropathy in the elderly: an Oklahoma Physicians Resource/Research Network (OKPRN) Study. J. Am. Board Fam. Med. 19(3), 240–250 (2006)

    Article  Google Scholar 

  57. R.E. Schmidt, D.A. Dorsey, L.N. Beaudet, K.E. Frederick, C.A. Parvin, S.B. Plurad, M.G. Levisetti, Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy. Am. J. Pathol. 163(5), 2077–2091 (2003). https://doi.org/10.1016/S0002-9440(10)63565-1

    Article  PubMed  PubMed Central  Google Scholar 

  58. A.I. Vinik, R. Freeman, T. Erbas, Diabetic autonomic neuropathy. Semin. Neurol. 23(4), 365–372 (2003). https://doi.org/10.1055/s-2004-817720

    Article  PubMed  Google Scholar 

  59. K.C. Tomlinson, S.M. Gardiner, T. Bennett, Blood pressure in streptozotocin-treated Brattleboro and Long-Evans rats. Am. J. Physiol. 258(4 Pt 2), R852–R859 (1990)

    CAS  PubMed  Google Scholar 

  60. L. Edwards, C. Ring, D. McIntyre, J.B. Winer, U. Martin, Cutaneous sensibility and peripheral nerve function in patients with unmedicated essential hypertension. Psychophysiology. 45(1), 141–147 (2008). https://doi.org/10.1111/j.1469-8986.2007.00608.x

    Article  PubMed  Google Scholar 

  61. K.Y. Forrest, R.E. Maser, G. Pambianco, D.J. Becker, T.J. Orchard, Hypertension as a risk factor for diabetic neuropathy: a prospective study. Diabetes. 46(4), 665–670 (1997)

    Article  CAS  Google Scholar 

  62. S.M. Manschot, W.H. Gispen, L.J. Kappelle, G.J. Biessels, Nerve conduction velocity and evoked potential latencies in streptozotocin-diabetic rats: effects of treatment with an angiotensin converting enzyme inhibitor. Diabet. Metab. Res. Rev. 19(6), 469–477 (2003). https://doi.org/10.1002/dmrr.401

    Article  CAS  Google Scholar 

  63. T. Cavusoglu, T. Karadeniz, E. Cagiltay, M. Karadeniz, G. Yigitturk, E. Acikgoz, Y. Uyanikgil, U. Ates, M.I. Tuglu, O. Erbas, The protective effect of losartan on diabetic neuropathy in a diabetic rat model. Exp clin endocrinol diabetes 123(8), 479–484 (2015). https://doi.org/10.1055/s-0035-1550019

    Article  CAS  PubMed  Google Scholar 

  64. E.K. Maxfield, N.E. Cameron, M.A. Cotter, K.C. Dines, Angiotensin II receptor blockade improves nerve function, modulates nerve blood flow and stimulates endoneurial angiogenesis in streptozotocin-diabetic rats and nerve function. Diabetologia. 36(12), 1230–1237 (1993)

    Article  CAS  Google Scholar 

  65. A. Reja, S. Tesfaye, N.D. Harris, J.D. Ward, Is ACE inhibition with lisinopril helpful in diabetic neuropathy? Diabet. Med. 12(4), 307–309 (1995)

    Article  CAS  Google Scholar 

  66. R.A. Malik, S. Williamson, C. Abbott, A.L. Carrington, J. Iqbal, W. Schady, A.J. Boulton, Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet. 352(9145), 1978–1981 (1998). https://doi.org/10.1016/S0140-6736(98)02478-7

    Article  CAS  PubMed  Google Scholar 

  67. J. Elliott, S. Tesfaye, N. Chaturvedi, R.A. Gandhi, L.K. Stevens, C. Emery, J.H. Fuller, E.P.C.S. Group, Large-fiber dysfunction in diabetic peripheral neuropathy is predicted by cardiovascular risk factors. Diabetes Care. 32(10), 1896–1900 (2009). https://doi.org/10.2337/dc09-0554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. A. Harkavyi, P.S. Whitton, Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br. J. Pharmacol. 159(3), 495–501 (2010). https://doi.org/10.1111/j.1476-5381.2009.00486.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. P. Luciani, C. Deledda, S. Benvenuti, I. Cellai, R. Squecco, M. Monici, F. Cialdai, G. Luciani, G. Danza, C. Di Stefano, F. Francini, A. Peri, Differentiating effects of the glucagon-like peptide-1 analogue exendin-4 in a human neuronal cell model. Cell Mol. Life Sci. 67(21), 3711–3723 (2010). https://doi.org/10.1007/s00018-010-0398-3

    Article  CAS  PubMed  Google Scholar 

  70. P. Anagnostis, V.G. Athyros, F. Adamidou, A. Panagiotou, M. Kita, A. Karagiannis, D.P. Mikhailidis, Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabet. Obes. Metab. 13(4), 302–312 (2011). https://doi.org/10.1111/j.1463-1326.2010.01345.x

    Article  CAS  Google Scholar 

  71. T. Perry, D.K. Lahiri, D. Chen, J. Zhou, K.T. Shaw, J.M. Egan, N.H. Greig, A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J. Pharmacol. Exp. Ther. 300(3), 958–966 (2002)

    Article  CAS  Google Scholar 

  72. M.J. During, L. Cao, D.S. Zuzga, J.S. Francis, H.L. Fitzsimons, X. Jiao, R.J. Bland, M. Klugmann, W.A. Banks, D.J. Drucker, C.N. Haile, Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med. 9(9), 1173–1179 (2003). https://doi.org/10.1038/nm919

    Article  CAS  PubMed  Google Scholar 

  73. M. Kan, G. Guo, B. Singh, V. Singh, D.W. Zochodne, Glucagon-like peptide 1, insulin, sensory neurons, and diabetic neuropathy. J. Neuropathol. Exp. Neurol. 71(6), 494–510 (2012). https://doi.org/10.1097/NEN.0b013e3182580673

    Article  CAS  PubMed  Google Scholar 

  74. M. Tsukamoto, N. Niimi, K. Sango, S. Takaku, Y. Kanazawa, K. Utsunomiya, Neurotrophic and neuroprotective properties of exendin-4 in adult rat dorsal root ganglion neurons: involvement of insulin and RhoA. Histochem. Cell Biol. 144(3), 249–259 (2015). https://doi.org/10.1007/s00418-015-1333-3

    Article  CAS  PubMed  Google Scholar 

  75. C.G. Jolivalt, M. Fineman, C.F. Deacon, R.D. Carr, N.A. Calcutt, GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice. Diabetes Obes Metab. 13(11), 990–1000 (2011). https://doi.org/10.1111/j.1463-1326.2011.01431.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. T. Himeno, H. Kamiya, K. Naruse, N. Harada, N. Ozaki, Y. Seino, T. Shibata, M. Kondo, J. Kato, T. Okawa, A. Fukami, Y. Hamada, N. Inagaki, Y. Seino, D.J. Drucker, Y. Oiso, J. Nakamura, Beneficial effects of exendin-4 on experimental polyneuropathy in diabetic mice. Diabetes. 60(9), 2397–2406 (2011). https://doi.org/10.2337/db10-1462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. R. Bianchi, I. Cervellini, C. Porretta-Serapiglia, N. Oggioni, B. Burkey, P. Ghezzi, G. Cavaletti, G. Lauria, Beneficial effects of PKF275-055, a novel, selective, orally bioavailable, long-acting dipeptidyl peptidase IV inhibitor in streptozotocin-induced diabetic peripheral neuropathy. J. Pharmacol. Exp. Ther. 340(1), 64–72 (2012). https://doi.org/10.1124/jpet.111.181529

    Article  CAS  PubMed  Google Scholar 

  78. C. Holscher, Insulin, incretins and other growth factors as potential novel treatments for Alzheimer’s and Parkinson’s diseases. Biochem. Soc. Trans. 42(2), 593–599 (2014). https://doi.org/10.1042/BST20140016

    Article  CAS  PubMed  Google Scholar 

  79. H.Y. Jin, W.J. Liu, J.H. Park, H.S. Baek, T.S. Park, Effect of dipeptidyl peptidase-IV (DPP-IV) inhibitor (Vildagliptin) on peripheral nerves in streptozotocin-induced diabetic rats. Arch. Med. Res. 40(7), 536–544 (2009). https://doi.org/10.1016/j.arcmed.2009.09.005

    Article  CAS  PubMed  Google Scholar 

  80. W.J. Liu, H.Y. Jin, K.A. Lee, S.H. Xie, H.S. Baek, T.S. Park, Neuroprotective effect of the glucagon-like peptide-1 receptor agonist, synthetic exendin-4, in streptozotocin-induced diabetic rats. Br J Pharmacol. 164(5), 1410–1420 (2011). https://doi.org/10.1111/j.1476-5381.2011.01272.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. M. Jaiswal, C.L. Martin, M.B. Brown, B. Callaghan, J.W. Albers, E.L. Feldman, R. Pop-Busui. Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study. J. Diabet. Compl. (2015). https://doi.org/10.1016/j.jdiacomp.2015.07.013

  82. M. Dobretsov, D. Romanovsky, J.R. Stimers, Early diabetic neuropathy: triggers and mechanisms. World J. Gastroenterol. 13(2), 175–191 (2007)

    Article  CAS  Google Scholar 

  83. C.R. Pierson, W. Zhang, Y. Murakawa, A.A. Sima, Insulin deficiency rather than hyperglycemia accounts for impaired neurotrophic responses and nerve fiber regeneration in type 1 diabetic neuropathy. J. Neuropathol. Exp. Neurol. 62(3), 260–271 (2003)

    Article  CAS  Google Scholar 

  84. K. Sugimoto, Y. Murakawa, W. Zhang, G. Xu, A.A. Sima, Insulin receptor in rat peripheral nerve: its localization and alternatively spliced isoforms. Diabetes Metab. Res. Rev. 16(5), 354–363 (2000)

    Article  CAS  Google Scholar 

  85. K. Sugimoto, Y. Murakawa, A.A. Sima, Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. J. Peripher. Nerv. Syst. 7(1), 44–53 (2002)

    Article  CAS  Google Scholar 

  86. Y.M. Hoybergs, T.F. Meert, The effect of low-dose insulin on mechanical sensitivity and allodynia in type I diabetes neuropathy. Neurosci. Lett. 417(2), 149–154 (2007). https://doi.org/10.1016/j.neulet.2007.02.087

    Article  CAS  PubMed  Google Scholar 

  87. G.J. Biessels, E.J. Stevens, S.J. Mahmood, W.H. Gispen, D.R. Tomlinson, Insulin partially reverses deficits in peripheral nerve blood flow and conduction in experimental diabetes. J. Neurol. Sci. 140(1-2), 12–20 (1996)

    Article  CAS  Google Scholar 

  88. J. Partanen, L. Niskanen, J. Lehtinen, E. Mervaala, O. Siitonen, M. Uusitupa, Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 333(2), 89–94 (1995). https://doi.org/10.1056/NEJM199507133330203

    Article  CAS  PubMed  Google Scholar 

  89. K. Sugimoto, M. Baba, S. Suzuki, S. Yagihashi, The impact of low-dose insulin on peripheral nerve insulin receptor signaling in streptozotocin-induced diabetic rats. PLoS ONE. 8(8), e74247 (2013). https://doi.org/10.1371/journal.pone.0074247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. D.W. Zochodne, Diabetes and the plasticity of sensory neurons. Neurosci. Lett. 596, 60–65 (2015). https://doi.org/10.1016/j.neulet.2014.11.017

    Article  CAS  PubMed  Google Scholar 

  91. X.H. Bao, V. Wong, Q. Wang, L.C. Low, Prevalence of peripheral neuropathy with insulin-dependent diabetes mellitus. Pediatr. Neurol. 20(3), 204–209 (1999)

    Article  CAS  Google Scholar 

  92. S.H. Kim, C.O. Baek, K.A. Lee, T.S. Park, H.S. Baek, H.Y. Jin, Clinical implication of elevated CA 19-9 level and the relationship with glucose control state in patients with type 2 diabetes. Endocrine. 46(2), 249–255 (2014). https://doi.org/10.1007/s12020-013-0058-0

    Article  CAS  PubMed  Google Scholar 

  93. D.F. Steiner, Evidence for a precursor in the biosynthesis of insulin. Trans. N Y Acad. Sci. 30(1), 60–68 (1967)

    Article  CAS  Google Scholar 

  94. A. Vinik, Physiological and pathophysiological significance of C-peptide actions. Introduction. Exp. Diab. Res. 5(1), 3–5 (2004). https://doi.org/10.1080/15438600490447816

    Article  Google Scholar 

  95. C.E. Hills, N.J. Brunskill, Cellular and physiological effects of C-peptide. Clin Sci (Lond) 116(7), 565–574 (2009). https://doi.org/10.1042/CS20080441

    Article  CAS  Google Scholar 

  96. A.A. Sima, Diabetic neuropathy in type 1 and type 2 diabetes and the effects of C-peptide. J Neurol Sci. 220(1-2), 133–136 (2004). https://doi.org/10.1016/j.jns.2004.03.014

    Article  PubMed  Google Scholar 

  97. K. Ekberg, T. Brismar, B.L. Johansson, B. Jonsson, P. Lindstrom, J. Wahren, Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1 diabetes. Diabetes. 52(2), 536–541 (2003)

    Article  CAS  Google Scholar 

  98. T. Forst, T. Kunt, T. Pohlmann, K. Goitom, M. Engelbach, J. Beyer, A. Pfutzner, Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus. J. Clin. Invest. 101(10), 2036–2041 (1998). https://doi.org/10.1172/JCI2147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. A.O. Shpakov, O.K. Granstrem, [C-peptide physiological effects]. Ross Fiziol Zh Im I M Sechenova. 99(2), 196–211 (2013)

    CAS  PubMed  Google Scholar 

  100. A.A. Sima, New insights into the metabolic and molecular basis for diabetic neuropathy. Cell Mol. Life Sci. 60(11), 2445–2464 (2003). https://doi.org/10.1007/s00018-003-3084-x

    Article  CAS  PubMed  Google Scholar 

  101. A.A. Sima, C-peptide and diabetic neuropathy. Expert Opin. Investig. Drugs. 12(9), 1471–1488 (2003). https://doi.org/10.1517/13543784.12.9.1471

    Article  CAS  PubMed  Google Scholar 

  102. A.A. Sima, W. Zhang, G. Grunberger, Type 1 diabetic neuropathy and C-peptide. Exp. Diabesity Res. 5(1), 65–77 (2004). https://doi.org/10.1080/15438600490424541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. A.A. Sima, W. Zhang, Mechanisms of diabetic neuropathy: axon dysfunction. Handb. Clin. Neurol. 126, 429–442 (2014). https://doi.org/10.1016/B978-0-444-53480-4.00031-X

    Article  PubMed  Google Scholar 

  104. C.W. Grote, D.E. Wright, A role for insulin in diabetic neuropathy. Front. Neurosci. 10, 581 (2016). https://doi.org/10.3389/fnins.2016.00581

    Article  PubMed  PubMed Central  Google Scholar 

  105. S.B. McMahon, J.V. Priestley, Peripheral neuropathies and neurotrophic factors: animal models and clinical perspectives. Curr. Opin. Neurobiol. 5(5), 616–624 (1995)

    Article  CAS  Google Scholar 

  106. V.M. Verge, C.S. Andreassen, T.G. Arnason, H. Andersen, Mechanisms of disease: role of neurotrophins in diabetes and diabetic neuropathy. Handb. Clin. Neurol. 126, 443–460 (2014). https://doi.org/10.1016/B978-0-444-53480-4.00032-1

    Article  PubMed  Google Scholar 

  107. D.R. Tomlinson, P. Fernyhough, L.T. Diemel, Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors. Diabetes. 46(Suppl 2), S43–S49 (1997)

    Article  CAS  Google Scholar 

  108. D.W. Zochodne, Neurotrophins and other growth factors in diabetic neuropathy. Semin. Neurol. 16(2), 153–161 (1996). https://doi.org/10.1055/s-2008-1040971

    Article  CAS  PubMed  Google Scholar 

  109. S.C. Apfel, Neurotrophic factors in the therapy of diabetic neuropathy. Am. J. Med. 107(2B), 34S–42S (1999)

    Article  CAS  Google Scholar 

  110. P. Anand, Neurotrophic factors and their receptors in human sensory neuropathies. Prog. Brain Res. 146, 477–492 (2004). https://doi.org/10.1016/S0079-6123(03)46030-5

    Article  CAS  PubMed  Google Scholar 

  111. G. Pittenger, A. Vinik, Nerve growth factor and diabetic neuropathy. Exp. Diabes. Res. 4(4), 271–285 (2003). https://doi.org/10.1155/EDR.2003.271

    Article  Google Scholar 

  112. S.C. Apfel, J.C. Arezzo, M. Brownlee, H. Federoff, J.A. Kessler, Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res. 634(1), 7–12 (1994)

    Article  CAS  Google Scholar 

  113. R.E. Schmidt, D.A. Dorsey, L.N. Beaudet, C.A. Parvin, E. Escandon, Effect of NGF and neurotrophin-3 treatment on experimental diabetic autonomic neuropathy. J. Neuropathol. Exp. Neurol. 60(3), 263–273 (2001)

    Article  CAS  Google Scholar 

  114. K.A. Elias, M.J. Cronin, T.A. Stewart, R.C. Carlsen, Peripheral neuropathy in transgenic diabetic mice: restoration of C-fiber function with human recombinant nerve growth factor. Diabetes. 47(10), 1637–1642 (1998)

    Article  CAS  Google Scholar 

  115. T.J. Huang, N.M. Sayers, A. Verkhratsky, P. Fernyhough, Neurotrophin-3 prevents mitochondrial dysfunction in sensory neurons of streptozotocin-diabetic rats. Exp. Neurol. 194(1), 279–283 (2005). https://doi.org/10.1016/j.expneurol.2005.03.001

    Article  CAS  PubMed  Google Scholar 

  116. N.A. Calcutt, J.D. Freshwater, A.P. Mizisin, Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia. 47(4), 718–724 (2004). https://doi.org/10.1007/s00125-004-1354-2

    Article  CAS  PubMed  Google Scholar 

  117. K.A. Lee, K.T. Park, H.M. Yu, H.Y. Jin, H.S. Baek, T.S. Park, Effect of granulocyte colony-stimulating factor on the peripheral nerves in streptozotocin-induced diabetic rat. Diabetes Metab. J. 37(4), 286–290 (2013). https://doi.org/10.4093/dmj.2013.37.4.286

    Article  PubMed  PubMed Central  Google Scholar 

  118. R. Levi-Montalcini, P.U. Angeletti, Essential role of the nerve growth factor in the survival and maintenance of dissociated sensory and sympathetic embryonic nerve cells in vitro. Dev. Biol. 6, 653–659 (1963)

    Article  CAS  Google Scholar 

  119. A.I. Vinik, A. Mehrabyan, Diabetic neuropathies. Med. Clin. North Am. 88(4), 947–999 (2004). https://doi.org/10.1016/j.mcna.2004.04.009. xi

    Article  CAS  PubMed  Google Scholar 

  120. L. Li, T. Yu, L. Yu, H. Li, Y. Liu, D. Wang. Exogenous brain-derived neurotrophic factor relieves pain symptoms of diabetic rats by reducing excitability of dorsal root ganglion neurons. Int. J. Neurosci. 1–10 (2015). https://doi.org/10.3109/00207454.2015.1057725

  121. S.R. Chowdhury, A. Saleh, E. Akude, D.R. Smith, D. Morrow, L. Tessler, N.A. Calcutt, P. Fernyhough, Ciliary neurotrophic factor reverses aberrant mitochondrial bioenergetics through the JAK/STAT pathway in cultured sensory neurons derived from streptozotocin-induced diabetic rodents. Cell Mol. Neurobiol. 34(5), 643–649 (2014). https://doi.org/10.1007/s10571-014-0054-9

    Article  CAS  PubMed  Google Scholar 

  122. A. Saleh, Roy Chowdhury, S.K. Smith, D.R. Balakrishnan, S. Tessler, L. Martens, C. Morrow, D. Schartner, E. Frizzi, K.E. Calcutt, N.A. Fernyhough, P.: Ciliary neurotrophic factor activates NF-kappaB to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents. Neuropharmacology. 65, 65–73 (2013). https://doi.org/10.1016/j.neuropharm.2012.09.015

    Article  CAS  PubMed  Google Scholar 

  123. Z. Dang, D. Maselli, G. Spinetti, E. Sangalli, F. Carnelli, F. Rosa, E. Seganfreddo, F. Canal, A. Furlan, A. Paccagnella, E. Paiola, B. Lorusso, C. Specchia, M. Albiero, R. Cappellari, A. Avogaro, A. Falco, F. Quaini, K. Ou, I. Rodriguez-Arabaolaza, C. Emanueli, M. Sambataro, G.P. Fadini, P. Madeddu, Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes. Diabetologia. 58(11), 2653–2662 (2015). https://doi.org/10.1007/s00125-015-3735-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. J.M. Dominguez 2nd, M.A. Yorek, M.B. Grant, Combination therapies prevent the neuropathic, proinflammatory characteristics of bone marrow in streptozotocin-induced diabetic rats. Diabetes. 64(2), 643–653 (2015). https://doi.org/10.2337/db14-0433

    Article  CAS  PubMed  Google Scholar 

  125. S. Takaku, H. Yanagisawa, K. Watabe, H. Horie, T. Kadoya, K. Sakumi, Y. Nakabeppu, F. Poirier, K. Sango, GDNF promotes neurite outgrowth and upregulates galectin-1 through the RET/PI3K signaling in cultured adult rat dorsal root ganglion neurons. Neurochem. Int. 62(3), 330–339 (2013). https://doi.org/10.1016/j.neuint.2013.01.008

    Article  CAS  PubMed  Google Scholar 

  126. M. Tsukamoto, K. Sango, N. Niimi, H. Yanagisawa, K. Watabe, K. Utsunomiya, Upregulation of galectin-3 in immortalized Schwann cells IFRS1 under diabetic conditions. Neurosci Res. 92, 80–85 (2015). https://doi.org/10.1016/j.neures.2014.11.008

    Article  CAS  PubMed  Google Scholar 

  127. Y. Li, N. Tong. Angiotensin-converting enzyme I/D polymorphism and diabetic peripheral neuropathy in type 2 diabetes mellitus: A meta-analysis. J. Renin. Angiotensin. Aldosterone. Syst. (2014). https://doi.org/10.1177/1470320314539828

  128. C. Clair, M.J. Cohen, F. Eichler, K.J. Selby, N.A. Rigotti, The effect of cigarette smoking on diabetic peripheral neuropathy: a systematic review and meta-analysis. J. Gen. Intern. Med. 30(8), 1193–1203 (2015). https://doi.org/10.1007/s11606-015-3354-y

    Article  PubMed  PubMed Central  Google Scholar 

  129. W.S. Lv, W.J. Zhao, S.L. Gong, D.D. Fang, B. Wang, Z.J. Fu, S.L. Yan, Y.G. Wang, Serum 25-hydroxyvitamin D levels and peripheral neuropathy in patients with type 2 diabetes: a systematic review and meta-analysis. J. Endocrinol. Invest. 38(5), 513–518 (2015). https://doi.org/10.1007/s40618-014-0210-6

    Article  CAS  PubMed  Google Scholar 

  130. T. Yu, L. Li, Y. Bi, Z. Liu, H. Liu, Z. Li, Erythropoietin attenuates oxidative stress and apoptosis in Schwann cells isolated from streptozotocin-induced diabetic rats. J. Pharm. Pharmacol. 66(8), 1150–1160 (2014). https://doi.org/10.1111/jphp.12244

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank the Research Institute of Clinical Medicine of Jeonbuk National University—Biomedical Research Institute of Jeonbuk National University Hospital for partly supporting the process of manuscript writing. We also thank Nigel A. Calcutt at UCSD for giving us the concept of non-glucotoxic pathway in DPN.

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  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University-Jeonbuk National University Hospital, Jeonbuk National University, Medical School, Jeonju, South Korea

    Kyung Ae Lee, Tae Sun Park & Heung Yong Jin

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Lee, K.A., Park, T.S. & Jin, H.Y. Non-glucose risk factors in the pathogenesis of diabetic peripheral neuropathy. Endocrine 70, 465–478 (2020). https://doi.org/10.1007/s12020-020-02473-4

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