Nerve function varies with hemoglobin A1c in controls and type 2 diabetes,☆☆,☆☆☆

https://doi.org/10.1016/j.jdiacomp.2017.12.007Get rights and content

Abstract

Aims

To determine the cross-sectional threshold at which hemoglobin A1c (HbA1c) is associated with polyneuropathy in healthy controls, and the values associated with the most pronounced decline in nerve function in patients with diabetes.

Methods

We used data from a cross-sectional cohort study of healthy controls and type 2 diabetes patients assessed between November 2010 and May 2013. Healthy controls and patients with diabetes were compared at different HbA1c ranges: <5.5%, 5.5–5.9%, and 6–6.4% for controls, and 6.5–7.4% and >7.5% for patients with diabetes.

Results

The total cohort included 53 controls and 164 patients with diabetes. Subclinical small nerve fiber impairments were observed in controls at HbA1c levels of 5.5–6%, compared with HbA1c <5.5%, for example: lower Laser Doppler flare imaging area of 2.8 ± 1.4 versus 3.9 ± 2 mm2. The most prominent decline in both small and large nerve fiber function was seen with less impaired glycemic control and shorter duration of diabetes, i.e. at HbA1c levels of 6.5–7.4%, compared with >7.5%.

Conclusions

These findings underscore the importance of early treatment at the prediabetes and early diabetes stages to prevent nerve fiber decline that is likely irreversible.

Introduction

The most common complication of diabetes mellitus (DM) is sensorimotor polyneuropathy (DSP),1 occurring in at least 50% of patients who have had DM for 25 years.2,3 As DM is pandemic, DSP constitutes the most common polyneuropathy worldwide,4., 5., 6. and is characterized by progressive and irreversible nerve fiber loss, that leads to considerable morbidity and mortality.7 Due to the lack of disease modifying treatments to stop or reverse nerve damage, prevention is a key component in diabetes care,8 since tight glycemic control has been shown to arrest development and progression of DSP.9,10 Furthermore, there are reports that earlier stages of glucose dysregulation (prediabetes) are associated with polyneuropathy,11., 12., 13. affecting mainly the small nerve fibers,11,14., 15., 16. although this association is not universally accepted.17., 18., 19., 20.

Since the main goal in treating DSP is to stop development and progression, it is necessary to understand when impairments of small and large nerve fibers begin, and the stage associated with the most accelerated nerve fiber loss in patients with diabetes. This will enable the application of appropriate and timely interventions. In the current study, we aimed to determine the onset of nerve impairments, and the stage of accelerated nerve function decline, using various ranges of hemoglobin A1c (HbA1c) levels in healthy controls and a spectrum of type 2 DM (T2DM) patients.

Section snippets

Methods

The study cohort consisted of controls without and patients with type T2DM recruited between November 2010 and May 2013 from the Diabetes and Endocrinology Clinic and the Diabetic Neuropathy Clinic at Toronto General Hospital, as part of cross-sectional cohort studies funded by the Canadian Diabetes Association (now Diabetes Canada) (operating grant OG-3–10–3123-BP) and the JDRF (operating grant 17–2008-715).21,22 The Research Ethics Board of the University Health Network approved the current

Results

The total cohort included 53 controls and 223 patients with type 2 diabetes. Controls with prediabetes (HbA1c: 6–6.4%) were older, and had higher blood pressure values compared with controls with lower HbA1c levels. T2DM patients with higher HbA1c values (≥7.5%) were younger, and had a longer duration of diabetes (Table 1).

Controls with higher HbA1c values of 5.5–5.9% compared with values < 5.5%, had worse small nerve fiber measures and faster heart rates, with similar large nerve fiber

Discussion

Our study results show that the onset of small nerve fiber impairments in healthy controls starts at HbA1c levels of 5.5–6% without any clinical evidence of polyneuropathy or diabetes. This was demonstrated by specialized small nerve fiber tests, and by a faster heart rate, suggesting early autonomic involvement.33 The observation that DSP has a predilection for small nerve fibers at early stages, has been described previously.11,13., 14., 15., 16. However, in our study of healthy controls,

Author contributions

Researched data: Alon Abraham, Carolina Barnett, Hans D. Katzberg Study design: Alon Abraham, Erik Lovblom, Bruce Perkins.

Wrote manuscript: Alon Abraham, Vera Bril.

Reviewed/edited manuscript: all authors.

Acknowledgement

Vera Bril takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

Funding

Canadian Diabetes Association (operating grant OG-3–10–3123-BP) and JDRF Grant 17-2008-715.

References (38)

  • J. George et al.

    Causes of polyneuropathy in the elderly

    Age Ageing

    (1986)
  • A.I. Vinik

    Diabetic neuropathy: pathogenesis and therapy

    Am J Med

    (1999)
  • R. Pop-Busui et al.

    Diabetic neuropathy: a position statement by the American diabetes association

    Diabetes Care

    (2017)
  • T.D. Control et al.

    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)
  • 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)
  • N. Papanas et al.

    Neuropathy in prediabetes: does the clock start ticking early?

    Nat Rev Endocrinol

    (2011)
  • A.G. Smith et al.

    Impaired glucose tolerance and neuropathy

    Neurologist

    (2008)
  • K. Farhad et al.

    Causes of neuropathy in patients referred as “idiopathic neuropathy”

    Muscle Nerve

    (2016)
  • S. Divisova et al.

    Prediabetes/early diabetes-associated neuropathy predominantly involves sensory small fibres

    J Peripher Nerv Syst

    (2012)
  • Cited by (0)

    Alon Abraham, Erik Lovblom and Carolina Barnett have no conflicts of interest to declare.

    Hans Katzberg has received research grants and speaker support from Grifols; research grants, advisory board honoraria, and speaker support from CSL Behring; and speaker/travel support from Genzyme Canada.

    ☆☆

    Bruce A Perkins serves as an advisor to Neurometrix Inc.

    ☆☆☆

    Vera Bril has been a consultant for Bionevia, CSL, Dainnipon Sumitomo, Eisai, Grifols, Lilly Octapharma, UCB, Alexion, Octapharma, UCB, Alexion and Pfizer, and has received research support from all the companies listed in her disclosure.

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