Glucose Control and Diabetic Neuropathy: Lessons from Recent Large Clinical Trials
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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.
KeywordsDistal symmetrical sensorimotor polyneuropathy Cardiovascular autonomic neuropathy Clinical trials Glucose control Diabetic neuropathy
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).
Compliance with Ethics Guidelines
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 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. 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.Google Scholar
- 12.DCCT: Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38:869–80.Google Scholar
- 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.PubMedCentralPubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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;352:837–53Google 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.PubMedCentralPubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCentralPubMedCrossRefGoogle Scholar
- 37.Smith AG, Singleton JR. Diabetic neuropathy. Continuum (Minneap Minn). 2012;18:60–84.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;41:416–23Google Scholar
- 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.PubMedCentralPubMedCrossRefGoogle 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.PubMedCentralPubMedCrossRefGoogle 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.Google Scholar
- 50.DCCT: Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563–9.Google Scholar
- 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.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.PubMedCrossRefGoogle 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.PubMedCentralPubMedCrossRefGoogle 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.CrossRefGoogle Scholar