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Glucose Control and Diabetic Neuropathy: Lessons from Recent Large Clinical Trials

  • Microvascular Complications—Neuropathy (D Ziegler, Section Editor)
  • Published:
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Abstract

Diabetic peripheral and autonomic neuropathies are common complications of diabetes with broad spectrums of clinical manifestations and high morbidity. Studies using various agents to target the pathways implicated in the development and progression of diabetic neuropathy were promising in animal models. In humans, however, randomized controlled studies have failed to show efficacy on objective measures of neuropathy. The complex anatomy of the peripheral and autonomic nervous systems, the multitude of pathogenic mechanisms involved, and the lack of uniformity of neuropathy measures have likely contributed to these failures. To date, tight glycemic control is the only strategy convincingly shown to prevent or delay the development of neuropathy in patients with type 1 diabetes and to slow the progression of neuropathy in some patients with type 2 diabetes. Lessons learned about the role of glycemic control on distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy are discussed in this review.

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References

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  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;28:956–62.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Dyck PJ, Albers JW, Andersen H, Arezzo JC, Biessels GJ, Bril V, Feldman EL, Litchy WJ, O'Brien PC, Russell JW. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev. 2011;27. Discusses updates on diagnostic criteria for severity of diabetic polyneuropathies.

  4. Ziegler D, Mayer P, Muhlen H, Gries FA. The natural history of somatosensory and autonomic nerve dysfunction in relation to glycaemic control during the first 5 years after diagnosis of type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1991;34:822–9.

    Article  CAS  PubMed  Google Scholar 

  5. Maser RE, Steenkiste AR, Dorman JS, Nielsen VK, Bass EB, Manjoo Q, et al. Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes. 1989;38:1456–61.

    Article  CAS  PubMed  Google Scholar 

  6. Adler AI, Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Smith DG. Risk factors for diabetic peripheral sensory neuropathy. Results of the Seattle Prospective Diabetic Foot Study. Diabetes Care. 1997;20:1162–7.

    Article  CAS  PubMed  Google Scholar 

  7. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet. 2005;366:1719–24.

    Article  PubMed  Google Scholar 

  8. Klein R, Klein BE, Moss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996;124:90–6.

    Article  CAS  PubMed  Google Scholar 

  9. Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329:304–9.

    Article  CAS  PubMed  Google Scholar 

  10. Amthor KF, Dahl-Jorgensen K, Berg TJ, Heier MS, Sandvik L, Aagenaes O, et al. The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: the Oslo Study. Diabetologia. 1994;37:579–84.

    Article  CAS  PubMed  Google Scholar 

  11. DCCT: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977–86.

  12. DCCT: Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38:869–80.

  13. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care. 2010;33:1090–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Sands ML, Shetterly SM, Franklin GM, Hamman RF. Incidence of distal symmetric (sensory) neuropathy in NIDDM. The San Luis Valley Diabetes Study. Diabetes Care. 1997;20:322–9.

    Article  CAS  PubMed  Google Scholar 

  15. Chao CC, Hsieh SC, Yang WS, Lin YH, Lin WM, Tai TY, et al. Glycemic control is related to the severity of impaired thermal sensations in type 2 diabetes. Diabetes Metab Res Rev. 2007;23:612–20.

    Article  CAS  PubMed  Google Scholar 

  16. Perkins BA, Dholasania A, Buchanan RA, Bril V. Short-term metabolic change is associated with improvement in measures of diabetic neuropathy: a 1-year placebo cohort analysis. Diabet Med. 2010;27:1271–9.

    Article  CAS  PubMed  Google Scholar 

  17. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin- dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103–17.

    Article  CAS  PubMed  Google Scholar 

  18. UKPDS: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.

    Article  CAS  PubMed  Google Scholar 

  21. Charles M, Ejskjaer N, Witte DR, Borch-Johnsen K, Lauritzen T, Sandbaek A. Prevalence of neuropathy and peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the ADDITION-Denmark study. Diabetes Care. 2011;34:2244–9.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–30.

    Article  PubMed Central  PubMed  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. Pop-Busui R, Lu J, Brooks MM, Albert S, Althouse AD, Escobedo J, et al. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort. Diabetes Care. 2013;36:3208–15. Discusses the BARI 2D trial and its findings.

    Article  CAS  PubMed  Google Scholar 

  25. Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care. 1999;22:99–111.

    Article  Google Scholar 

  26. Martin CL, Albers JW, Pop-Busui R. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:31–8. Discusses neuropathy and related findings in the DCCT.

    Article  CAS  PubMed  Google Scholar 

  27. Pop-Busui R, Herman WH, Feldman EL, Low PA, Martin CL, Cleary PA, et al. DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history. Curr Diab Rep. 2010;10:276–82.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Martin CL, Albers J, Herman WH, Cleary P, Waberski B, Greene DA, et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care. 2006;29:340–4.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Martin CL, Waberski BH, Pop-Busui R, Cleary PA, Catton S, Albers JW, et al. Vibration perception threshold as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: results from the DCCT/EDIC study. Diabetes Care. 2010;33:2635–41.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17:1281–9.

    Article  CAS  PubMed  Google Scholar 

  31. Herman WH, Pop-Busui R, Braffett BH, Martin CL, Cleary PA, Albers JW, et al. Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med. 2012;29:937–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Dyck PJ, Karnes J, O'Brien PC, Swanson CJ. Neuropathy Symptom Profile in health, motor neuron disease, diabetic neuropathy, and amyloidosis. Neurology. 1986;36:1300–8.

    Article  CAS  PubMed  Google Scholar 

  33. Dyck PJ, Karnes JL, O'Brien PC, Litchy WJ, Low PA, Melton 3rd LJ. The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity. Neurology. 1992;42:1164–70.

    Article  CAS  PubMed  Google Scholar 

  34. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341–50.

    Article  CAS  PubMed  Google Scholar 

  35. Dyck PJ, Norell JE, Tritschler H, Schuette K, Samigullin R, Ziegler D, et al. Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity. Diabetes Care. 2007;30:2619–25.

    Article  PubMed  Google Scholar 

  36. Dyck PJ, Overland CJ, Low PA, Litchy WJ, Davies JL, Carter RE, et al. “Unequivocally Abnormal” vs “Usual” Signs and symptoms for proficient diagnosis of diabetic polyneuropathy: Cl vs N Phys Trial. Arch Neurol. 2012;69:1609–14.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Smith AG, Singleton JR. Diabetic neuropathy. Continuum (Minneap Minn). 2012;18:60–84.

    Google Scholar 

  38. Malik R, Veves A, Tesfaye S, Smith G, Cameron N, Zochodne D, et al. Small fiber neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy. Diabetes Metab Res Rev. 2011;27:678–84.

    Article  Google Scholar 

  39. Witte DR, Tesfaye S, Chaturvedi N, Eaton SE, Kempler P, Fuller JH. Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia. 2005;48:164–71.

    Article  CAS  PubMed  Google Scholar 

  40. DCCT: 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

  41. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Low PA, Denq JC, Opfer-Gehrking TL, Dyck PJ, O'Brien PC, Slezak JM. Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Muscle Nerve. 1997;20:1561–8.

    Article  CAS  PubMed  Google Scholar 

  43. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27:639–53.

    Article  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoogwerf BJ, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care. 2010;33:1578–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Pambianco G, Costacou T, Ellis D, Becker DJ, Klein R, Orchard TJ. The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes. 2006;55:1463–9.

    Article  CAS  PubMed  Google Scholar 

  47. Cefalu WT, Ratner RE. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: the “gift” that keeps on giving! Diabetes Care. 2014;37:5–7.

    Article  PubMed  Google Scholar 

  48. Albers JW, Herman WH, Pop-Busui R, Martin CL, Cleary P, Waberski B. Subclinical neuropathy among Diabetes Control and Complications Trial participants without diagnosable neuropathy at trial completion: possible predictors of incident neuropathy? Diabetes Care. 2007;30:2613–8.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med. 2000;342:381–9.

  50. DCCT: Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563–9.

  51. DCCT/EDIC, Writing, 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.

  52. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53.

    Article  PubMed  Google Scholar 

  53. Perkins BA, Orszag A, Ngo M, Ng E, New P, Bril V. Prediction of incident diabetic neuropathy using the monofilament examination: a 4-year prospective study. Diabetes Care. 2010;33:1549–54.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.

    Article  CAS  PubMed  Google Scholar 

  55. Charles M, Fleischer J, Witte DR, Ejskjaer N, Borch-Johnsen K, Lauritzen T, et al. Impact of early detection and treatment of diabetes on the 6-year prevalence of cardiac autonomic neuropathy in people with screen-detected diabetes: ADDITION-Denmark, a cluster-randomised study. Diabetologia. 2013;56:101–8.

    Article  CAS  PubMed  Google Scholar 

  56. Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  CAS  PubMed  Google Scholar 

  57. Calles-Escandon J, Lovato LC, Simons-Morton DG, Kendall DM, Pop-Busui R, Cohen RM, et al. Effect of intensive compared with standard glycemia treatment strategies on mortality by baseline subgroup characteristics: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care. 2010;33:721–7.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;6:CD007543. Discusses how to prevent and treat diabetic neuropathy with enhanced glucose control.

    PubMed Central  PubMed  Google Scholar 

  59. Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:2503–15.

    Article  CAS  PubMed  Google Scholar 

  60. Kempler P, Amarenco G, Freeman R, Frontoni S, Horowitz M, Stevens M, et al. Gastrointestinal autonomic neuropathy, erectile-, bladder- and sudomotor dysfunction in patients with diabetes mellitus: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27:665–77.

    Article  Google Scholar 

  61. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1996;39:1377–84.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  PubMed  Google Scholar 

  63. 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.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

R.P.B. is supported by grants from NIH/NIDDK, NIH/NHLBI (1R01HL102334-01, U01-DK-094176, U01-DK-094157, U01DK098246) and the American Diabetes Association (1-14-MN-02). M.J. is supported by grants from the American Diabetes Association (1-14-MN-02). C.L.M. is supported by grants from the National Institutes of Health/NIDDK (U01-DK-094176, U01-DK-094157, and U01DK098246).

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Conflict of Interest

Lynn Ang, Mamta Jaiswal, Catherine Martin, and Rodica Pop-Busui declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article describes studies with human subjects, and Dr. Pop-Busui participated in some of them. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, 5329 Brehm Tower 1000 Wall Street, Ann Arbor, MI, 48105, USA

    Lynn Ang, Catherine Martin & Rodica Pop-Busui

  2. Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA

    Mamta Jaiswal

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  1. Lynn Ang
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  2. Mamta Jaiswal
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  3. Catherine Martin
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  4. Rodica Pop-Busui
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Correspondence to Rodica Pop-Busui.

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This article is part of the Topical Collection on Microvascular Complications—Neuropathy

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Ang, L., Jaiswal, M., Martin, C. et al. Glucose Control and Diabetic Neuropathy: Lessons from Recent Large Clinical Trials. Curr Diab Rep 14, 528 (2014). https://doi.org/10.1007/s11892-014-0528-7

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