Autonomic neuropathy in diabetes mellitus

Alberto Verrotti, Giovanni Prezioso, Raffaella Scattoni, Francesco Chiarelli, Alberto Verrotti, Giovanni Prezioso, Raffaella Scattoni, Francesco Chiarelli

Abstract

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The reported prevalence of DAN varies widely depending on inconsistent definition, different diagnostic method, different patient cohorts studied. The pathogenesis is still unclear and probably multifactorial. Once DAN becomes clinically evident, no form of therapy has been identified, which can effectively stop or reverse it. Prevention strategies are based on strict glycemic control with intensive insulin treatment, multifactorial intervention, and lifestyle modification including control of hypertension, dyslipidemia, stop smoking, weight loss, and adequate physical exercise. The present review summarizes the latest knowledge regarding clinical presentation, epidemiology, pathogenesis, and management of DAN, with some mention to childhood and adolescent population.

Keywords: advanced glycation end-products; autonomic nervous system; cardiovascular autonomic neuropathy; diabetes mellitus; diabetic autonomic neuropathy; hyperglycemia; inflammation; oxidative stress.

Figures

Figure 1
Figure 1
Pathogenesis of DAN: the role of hyperglycemia as the cause of inflammation and oxidative stress.

References

    1. Said G. Diabetic neuropathy. Handb Clin Neurol (2013) 115:579–89.10.1016/B978-0-444-52902-2.00033-3
    1. Pasnoor M, Dimachkie MM, Kluding P, Barohn RJ. Diabetic neuropathy part 1: overview and symmetric phenotypes. Neurol Clin (2013) 31:425–45.10.1016/j.ncl.2013.02.004
    1. Boulton AJ, Gries FA, e Jervell JA. Guidelines for diagnosis and outpatient management of diabetic peripheral neuropathy. European association for the study of diabetes, neurodiab. Diabetes Metab (1998) 15(6):508–14.
    1. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American diabetes association. Diabetes Care (2005) 28:956–6210.2337/diacare.28.4.956
    1. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care (2010) 33:2285–93.10.2337/dc10-1303
    1. Trotta D, Verrotti A, Salladini C, Chiarelli F. Diabetic neuropathy in children and adolescents. Pediatr Diabetes (2004) 5(1):44–5710.1111/j.1399-543X.2004.00041.x
    1. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care (2003) 26(5):1553–79.10.2337/diacare.26.5.1553
    1. Vinik AI, Maser RE, Ziegler D. Autonomic imbalance: prophet of doom or scope for hope? Diabet Med (2011) 28:643–51.10.1111/j.1464-5491.2010.03184.x
    1. Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW, et al. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care (1984) 7:447–53.10.2337/diacare.7.5.447
    1. Said G, Bigo A, Améri A, Gayno JP, Elgrably F, Chanson P, et al. Uncommon early-onset neuropathy in diabetic patients. J Neurol (1998) 245:61–8.10.1007/s004150050179
    1. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care (1985) 8:491–8.10.2337/diacare.8.5.491
    1. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care (2010) 33:434–4110.2337/dc09-1294
    1. Boysen A, Lewin MAG, Hecker W, Leichter HE. Autonomic function testing in children. Pediatr Diabetes (2007) 8:261–410.1111/j.1399-5448.2007.00254.x
    1. Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes (2014) 5:17–3910.4239/wjd.v5.i1.17
    1. Krause M, Rüdiger H, Bald M, Näke A, Paditz E. Autonomic blood pressure control in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes (2009) 10:255–63.10.1111/j.1399-5448.2008.00447.x
    1. Tang ZH, Zeng F, Li Z, Zhou L. Association and predictive value analysis for resting heart rate and diabetes mellitus on cardiovascular autonomic neuropathy in general population. J Diabetes Res (2014) 2014:215473.10.1155/2014/215473
    1. Pavy-Le Traon A, Fontaine S, Tap G, Guidolin B, Senard JM, Hanaire H. Cardiovascular autonomic neuropathy and other complications in type 1 diabetes. Clin Auton Res (2010) 20:153–60.10.1007/s10286-010-0062-x
    1. Antonelli Incalzi R, Fuso L, Pitocco D, Basso S, Trové A, Longobardi A, et al. Decline of neuroadrenergic bronchial innervation and respiratory function in type 1 diabetes mellitus: a longitudinal study. Diabetes Metab Res Rev (2007) 23:311–6.10.1002/dmrr.688
    1. Tantucci C, Scionti L, Bottini P, Dottorini ML, Puxeddu E, Casucci G, et al. Influence of autonomic neuropathy of different severities on the hypercapnic drive to breathing in diabetic patients. Chest (1997) 112:145–53.10.1378/chest.112.1.145
    1. Ludka O, Konecny T, Somers V. Sleep apnea, cardiac arrhythmias, and sudden death. Tex Heart Inst J (2011) 38:340–3.
    1. Fujihara K, Kodama S, Horikawa C, Yoshizawa S, Sugawara A, Hirasawa R, et al. The relationship between diabetic neuropathy and sleep apnea syndrome: a meta-analysis. Sleep Disord (2013) 2013:150371.10.1155/2013/150371
    1. Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil (2007) 19:951–6010.1111/j.1365-2982.2007.01023.x
    1. Chang J, Rayner CK, Jones KL, Horowitz M. Diabetic gastroparesis-backwards and forwards. J Gastroenterol Hepatol (2011) 26(Suppl 1):46–57.10.1111/j.1440-1746.2010.06573.x
    1. Rutherford D, Collier A. Sexual dysfunction in women with diabetes mellitus. Gynecol Endocrinol (2005) 21:189–92.10.1080/09513590400021110
    1. Enzlin P, Mathieu C, Vanderschueren D, Demyttenaere K. Diabetes mellitus and female sexuality: a review of 25 years’ research. Diabet Med (1998) 15:809–15.10.1002/(SICI)1096-9136(199810)15:10<809::AID-DIA689>;2-Z
    1. Thorve VS, Kshirsagar AD, Vyawahare NS, Joshi VS, Ingale KG, Mohite RJ. Diabetes-induced erectile dysfunction: epidemiology, pathophysiology and management. J Diabetes Complications (2011) 25:129–36.10.1016/j.jdiacomp.2010.03.003
    1. Tang M, Donaghue KC, Cho YH, Craig ME. Autonomic neuropathy in young people with type 1 diabetes: a systematic review. Pediatr Diabetes (2013) 14:239–48.10.1111/pedi.12039
    1. Tentolouris N, Marinou K, Kokotis P, Karanti A, Diakoumopoulou E, Katsilambros N. Sudomotor dysfunction is associated with foot ulceration in diabetes. Diabet Med (2009) 26:302–510.1111/j.1464-5491.2009.02677.x
    1. Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic neuropathy. Endocrinol Metab Clin North Am (2013) 42:747–87.10.1016/j.ecl.2013.06.001
    1. Vinik AI, Erbas T. Diabetic autonomic neuropathy. Handb Clin Neurol (2013) 117:279–94.10.1016/B978-0-444-53491-0.00022-5
    1. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al. On behalf of the Toronto consensus panel on diabetic neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev (2011) 27:639–5310.1002/dmrr.1239
    1. Verrotti A, Loiacono G, Mohn A, Chiarelli F. New insights in diabetic autonomic neuropathy in children and adolescents. Eur J Endocrinol (2009) 161:811–8.10.1530/EJE-09-0710
    1. Karayannis G, Giamouzis G, Cokkinos DV, Skoularigis J, Triposkiadis F. Diabetic cardiovascular autonomic neuropathy: clinical implications. Expert Rev Cardiovasc Ther (2012) 10:747–65.10.1586/erc.12.53
    1. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care (2003) 26:1895–901.10.2337/diacare.26.6.1895
    1. Neil HA, Thompson AV, John S, McCarthy ST, Mann JI. Diabetic autonomic neuropathy: the prevalence of impaired heart rate variability in a geographically define population. Diabet Med (1989) 6:20–4.10.1111/j.1464-5491.1989.tb01133.x
    1. Ziegler D, Gries FA, Spüler M, Lessmann F. The epidemiology of diabetic neuropathy. diabetic cardiovascular autonomic neuropathy multicenter study group. J Diabetes Complications (1992) 6:49–5710.1016/1056-8727(92)90049-Q
    1. O’Brien IA, O’Hare JP, Lewin IG, Corrall RJ. The prevalence of autonomic neuropathy in insulin-dependent diabetes mellitus: a controlled study based on heart rate variability. Q J Med (1986) 61:957–67.
    1. Verrotti A, Chiarelli F, Blasetti A, Morgese G. Autonomic neuropathy in diabetic children. J Paediatr Child Health (1995) 31:545–8.10.1111/j.1440-1754.1995.tb00881.x
    1. Solders G, Thalme B, Aguirre-Aquino M, Brandt L, Berg U, Persson A. Nerve conduction and autonomic nerve function in diabetic children. A 10-year follow-up study. Acta Paediatr (1997) 86:361–6.10.1111/j.1651-2227.1997.tb09023.x
    1. Karavanaki K, Baum JD. Coexistence of impaired indices of autonomic neuropathy and diabetic nephropathy in a cohort of children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab (2003) 16:79–90.10.1515/JPEM.2003.16.1.79
    1. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the diabetes control and complications trial (DCCT). Diabetologia (1998) 41:416–23.10.1007/s001250050924
    1. Ziegler D, Gries FA, Mühlen H, Rathmann W, Spüler M, Lessmann F. Prevalence and clinical correlates of cardiovascular autonomic and peripheral diabetic neuropathy in patients attending diabetes centers. The Diacan Multicenter Study Group. Diabete Metab (1993) 19:143–51.
    1. Valensi P, Pariès J, Attali JR. French group for research and study of diabetic neuropathy. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications – the French multicenter study. Metabolism (2003) 52:815–20.10.1016/S0026-0495(03)00095-7
    1. Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weigand SD, O’Brien PC, et al. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care (2004) 27:2942–7.10.2337/diacare.27.12.2942
    1. Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the diabetes control and complications trial/epidemiology of diabetes interventions and complications study (DCCT/EDIC). Circulation (2009) 119:2886–93.10.1161/CIRCULATIONAHA.108.837369
    1. Vinik AI, Freeman R, Erbas T. Diabetic autonomic neuropathy. Semin Neurol (2003) 23:365–72.10.1055/s-2004-817720
    1. de M Bandeira S, da Fonseca LJ, da S Guedes G, Rabelo LA, Goulart MO. Vasconcelos SM. Oxidative stress as an underlying contributor in the development of chronic complications in diabetes mellitus. Int J Mol Sci (2013) 14:3265–84.10.3390/ijms14023265
    1. Hoeldtke RD, Bryner KD, VanDyke K. Oxidative stress and autonomic nerve function in early type 1 diabetes. Clin Auton Res (2011) 21:19–28.10.1007/s10286-010-0084-4
    1. Ziegler D, Buchholz S, Sohr C, Nourooz-Zadeh J, Roden M. Oxidative stress predicts progression of peripheral and cardiac autonomic nerve dysfunction over 6 years in diabetic patients. Acta Diabetol (2014).10.1007/s00592-014-0601-3
    1. Sandireddy R, Yerra VG, Areti A, Komirishetty P, Kumar A. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int J Endocrinol (2014) 2014:674987.10.1155/2014/674987
    1. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev (2013) 93:137–8810.1152/physrev.00045.2011
    1. Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, et al. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A (2009) 106:20021–6.10.1073/pnas.0905686106
    1. Vinik AI. The conductor of the autonomic orchestra. Front Endocrinol (2012) 3:71.10.3389/fendo.2012.00071
    1. Dasu MR, Ramirez S, Isseroff RR. Toll-like receptors and diabetes: a therapeutic perspective. Clin Sci (2012) 122:203–14.10.1042/CS20110357
    1. Theilade S, Lyngbaek S, Hansen TW, Eugen-Olsen J, Fenger M, Rossing P, et al. Soluble urokinase plasminogen activator receptor levels are elevated and associated with complications in patients with type 1 diabetes. J Intern Med (2014).10.1111/joim.12269
    1. Cameron NE, Dines KC, Cotter MA. The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats. Diabetologia (1994) 37:1209–15.10.1007/BF00399794
    1. März P, Cheng JG, Gadient RA, Patterson PH, Stoyan T, Otten U, et al. Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci U S A (1998) 95:3251–6.10.1073/pnas.95.6.3251
    1. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA (2001) 286:327–34.10.1001/jama.286.3.327
    1. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature (2006) 440:1217–21.10.1038/nature04672
    1. Conti G, Scarpini E, Baron P, Livraghi S, Tiriticco M, Bianchi R, et al. 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 (2002) 195:35–40.10.1016/S0022-510X(01)00684-0
    1. Navarro-González JF, Mora-Fernández C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol (2008) 19:433–42.10.1681/ASN.2007091048
    1. Lieb DC, Parson HK, Mamikunian G, Vinik AI. Cardiac autonomic imbalance in newly diagnosed and established diabetes is associated with markers of adipose tissue inflammation. Exp Diabetes Res (2012) 2012:878760.10.1155/2012/878760
    1. Ejskjaer N, Arif S, Dodds W, Zanone MM, Vergani D, Watkins PJ, et al. Prevalence of autoantibodies to autonomic nervous tissue structures in Type 1 diabetes mellitus. Diabet Med (1999) 16:544–9.10.1046/j.1464-5491.1999.00092.x
    1. Muhr D, Mollenhauer U, Ziegler AG, Haslbeck M, Standl E, Schnell O. Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy. Diabetes Care (1997) 20:1009–12.10.2337/diacare.20.6.1009
    1. Granberg V, Ejskjaer N, Peakman M, Sundkvist G. Autoantibodies to autonomic nerves associated with cardiac and peripheral autonomic neuropathy. Diabetes Care (2005) 28:1959–64.10.2337/diacare.28.8.1959
    1. Skärstrand H, Dahlin LB, Lernmark A, Vaziri-Sani F. Neuropeptide Y autoantibodies in patients with long-term type 1 and type 2 diabetes and neuropathy. J Diabetes Complications (2013) 27:609–17.10.1016/j.jdiacomp.2013.06.007
    1. Kempler P, Tesfaye S, Chaturvedi N, Stevens LK, Webb DJ, Eaton S, et al. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM complications study. Diabet Med (2002) 19:900–9.10.1046/j.1464-5491.2002.00821.x
    1. Nasr N, Czosnyka M, Arevalo F, Hanaire H, Guidolin B, Larrue V. Autonomic neuropathy is associated with impairment of dynamic cerebral autoregulation in type 1 diabetes. Auton Neurosci (2011) 160:59–63.10.1016/j.autneu.2010.10.001
    1. Kasznicki J, Kosmalski M, Sliwinska A, Mrowicka M, Stanczyk M, Majsterek I, et al. Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy. Mol Biol Rep (2012) 39:8669–78.10.1007/s11033-012-1722-9
    1. Schmidt RE, Dorsey DA, Beaudet LN, Plurad SB, Parvin CA, Ohara S. Effect of IGF-I and neurotrophin-3 on gracile neuroaxonal dystrophy in diabetic and aging rats. Brain Res (2000) 876:88–94.10.1016/S0006-8993(00)02602-0
    1. Dasu MR, Jialal I. Effect of IGF-I and neurotrophin-3 on gracile neuroaxonal dystrophy in diabetic and aging rats. Am J Physiol Endocrinol Metab (2011) 300:E145–54.10.1152/ajpendo.00490.2010
    1. Goncalves AC, Tank J, Diedrich A, Hilzendeger A, Plehm R, Bader M. Diabetic hypertensive leptin receptor-deficient db/db mice develop cardioregulatory autonomic dysfunction. Hypertension (2009) 53:387–92.10.1161/HYPERTENSIONAHA.108.124776
    1. Ekberg K, Brismar T, Johansson BL, Lindström P, Juntti-Berggren L, Norrby A, et al. C-Peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care (2007) 30:71–6.10.2337/dc06-1274
    1. Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res (2012) 5:463–78.10.1007/s12265-012-9367-6
    1. Riihimaa PH, Suominen K, Tolonen U, Jäntti V, Knip M, Tapanainen P. Peripheral nerve function is increasingly impaired during puberty in adolescents with type 1 diabetes. Diabetes Care (2001) 24:1087–92.10.2337/diacare.24.6.1087
    1. Acerini CL, Williams RM, Dunger DB. Metabolic impact of puberty on the course of type 1 diabetes. Diabetes Metab (2001) 27:S19–25.
    1. Fleischer J. Diabetic autonomic imbalance and glycemic variability. J Diabetes Sci Technol (2012) 6:1207–15.10.1177/193229681200600526
    1. The Diabetes Control and Complications Trial Research Group. 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 (1993) 329:977–86.10.1056/NEJM199309303291401
    1. Albers JW, Kenny DJ, Brown M, Greene D, Cleary PA, Lachin JM, et al. Effect of intensive diabetes treatment on nerve conduction in the diabetes control and complications trial. Ann Neurol (1995) 38:869–80.
    1. Martin CL, Albers JW, Pop-Busui R. DCCT/EDIC research group. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care (2014) 37:31–810.2337/dc13-2114
    1. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA (2002) 287:2563–9.10.1001/jama.287.19.2563
    1. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA (2003) 290:2159–67.10.1001/jama.290.16.2159
    1. LeRoith D, Fonseca V, Vinik A. Metabolic memory in diabetes – focus on insulin. Diabetes Metab Res Rev (2005) 21:85–9010.1002/dmrr.530
    1. Stevens MJ, Raffel DM, Allman KC, Schwaiger M, Wieland DM. Regression and progression of cardiac sympathetic dysinnervation complicating diabetes: an assessment by C-11 hydroxyephedrine and positron emission tomography. Metabolism (1999) 48:92–101.10.1016/S0026-0495(99)90016-1
    1. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, et al. EURODIAB prospective complications study group. Vascular risk factors and diabetic neuropathy. N Engl J Med (2005) 352:341–50.10.1056/NEJMoa032782
    1. Azad N, Emanuele NV, Abraira C, Henderson WG, Colwell J, Levin SR, et al. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). J Diabetes Complications (1999) 13:307–13.10.1016/S1056-8727(99)00062-8
    1. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. VADT investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med (2009) 360:129–39.10.1056/NEJMoa0808431
    1. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr, Bigger JT, Buse JB, et al. Action to control cardiovascular risk in diabetes study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med (2008) 358:2545–59.10.1056/NEJMoa0802743
    1. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Advance collaborative group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med (2008) 358:2560–7210.1056/NEJMoa0802987
    1. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med (2003) 348:383–93.10.1056/NEJMoa021778
    1. Carnethon MR, Prineas RJ, Temprosa M, Zhang ZM, Uwaifo G, Molitch ME. The association among autonomic nervous system function, incident diabetes, and intervention arm in the diabetes prevention program. Diabetes prevention program research group. Diabetes Care (2006) 29:914–9.10.2337/diacare.29.04.06.dc05-1729
    1. Maser RE, Lenhard MJ. An overview of the effect of weight loss on cardiovascular autonomic function. Curr Diabetes Rev (2007) 3:204–11.10.2174/157339907781368931
    1. Voulgari C, Pagoni S, Vinik A, Poirier P. Exercise improves cardiac autonomic function in obesity and diabetes. Metabolism (2013) 62:609–21.10.1016/j.metabol.2012.09.005
    1. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev (2012) 6:CD007543.10.1002/14651858.CD007543.pub2
    1. Lee SS, Han HS, Kim H. A 5-yr follow-up nerve conduction study for the detection of subclinical diabetic neuropathy in children with newly diagnosed insulin-dependent diabetes mellitus. Pediatr Diabetes (2010) 11:521–8.10.1111/j.1399-5448.2009.00636.x
    1. Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care (2010) 33:156–61.10.2337/dc09-0606
    1. Ekberg K, Johansson BL. Effect of C-peptide on diabetic neuropathy in patients with type 1 diabetes. Exp Diabetes Res (2008) 2008:457912.10.1155/2008/457912

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