By Andrew Feldman, MD, MEd
Synopsis: The authors conducted a prospective observational study comparing the effect of early diagnosed, well-controlled type 2 diabetes on peripheral nerve function. Overall, they found similar rates of decline in nerve function in people with well-controlled diabetes compared to age- and sex-matched individuals with normal glucose tolerance. Given the similar decline in nerve function, the authors concluded that the course of diabetic sensorimotor neuropathy is influenced primarily by nerve function at the time of diagnosis and age-related physiological decline.
Source: Strom A, Strassburger K, Ziegler D, et al; GDS Group. Changes over 10 years in peripheral nerve function in people with well-controlled type 2 diabetes and those with normal glucose tolerance. Neurology. 2025;104(12):e213780.
Diabetic neuropathy, occurring over time in up to half of all individuals with diabetes, has risen in incidence and prevalence with the increase in diabetes worldwide. Diabetic neuropathy most commonly presents as a length-dependent, symmetric process, which the authors refer to as diabetic sensorimotor polyneuropathy (DSPN). This can present as numbness, paresthesias, weakness, and neuropathic pain in a “stocking-glove” distribution. Risk factors for DSPN include increased duration of disease and higher levels of hemoglobin A1c (HbA1c). Chronic hyperglycemia preferentially targets sensory axons and autonomic fibers and, later in the disease course, motor axons. Schwann cells also are impaired by hyperglycemia, causing a mixed axonal and demyelinating pattern found on nerve conduction studies.1
Given the known association with hyperglycemia and DSPN, the authors sought to better understand the disease progression of type 2 diabetes (DM2) through the effect of early diagnosed, well-controlled DM2. They conducted a prospective observational study of 52 individuals with DM2 matched for sex and age with 52 individuals with normal glucose tolerance (NGT) and compared peripheral nerve function at baseline and at five-year follow-up. They also studied the peripheral nerve function of 141 individuals with DM2.
Peripheral nerve function was assessed based on electrophysiologic testing, quantitative sensory testing (QST), and clinical neuropathy assessment. Electrophysiologic testing included motor nerve conduction velocity (MNCV) of the peroneal nerve, sensory nerve conduction velocity (SNCV) of the sural nerve, and sensory nerve action potential (SNAP) of the sural nerve at 33°C to 34°C using surface electrodes. QST included vibration perception threshold (VPT) at the right medial malleolus and thermal detection thresholds (TDTs) to warm and cold stimuli at the dorsum of the foot. Clinical assessment was based on the Neuropathy Disability Score (NDS) and the Neuropathy Symptom Score (NSS).
Finally, the authors analyzed laboratory values, including plasma glucose, HbA1c, M-value, high-sensitivity C-reactive protein (hsCRP), cholesterol, serum triglycerides, and creatinine.
The authors found that over five years, there was an increase in VPT and a decrease in MNCV in the DM2 group. In the NGT group, there was an increase in VPT, a decrease in MNCV, and an increase in NDS. There were no significant changes in sural SNAP, SNCV, or TDT for cold or warm stimuli in either group. Multivariate analyses of covariance revealed no significant difference between the two groups in any of the nerve indices after adjusting for corresponding baseline values, height, body mass index, and matching.
In the group of DM2 individuals with 10-year follow-up, the authors found that, at five years, there was a decline in MNCV and sural SNAP, while VPT increased compared to baseline. At 10 years, all indices of peripheral nerve function had declined from baseline. There was no significant difference in the rate of decline in the time periods from baseline to five years and five years to 10 years. The authors created a tool to predict median annual decline of MNCV and SNCV and found that the decline seen in these patients was similar to the expected decline, accounting for individual risk factors and physiologic aging-related decline.
This study found that the decline in nerve function between patients with well-controlled DM2 and normal glucose tolerance was similar. Therefore, the authors attribute DSPN in patients with well-controlled DM2 to the nerve damage that occurred during prediabetes and the period of undiagnosed DM2. They suggest peripheral nerve dysfunction is determined by nerve function levels at diagnosis and aging-related physiologic deterioration, rather than by disease progression.
Commentary
One important consideration for this study was the lack of hyperglycemia in the patients in the diabetic groups. The HbA1c for the 52 individuals in the group with DM2 was 6.2% at baseline and 6.8% at five years compared with 5.3% at baseline and follow-up in the NGT group. The median HbA1c in DM2 individuals with a 10-year follow-up was 6.2% at baseline, 6.6% at five years, and 6.9% at 10 years. In their most recent 2025 guidelines, the American Diabetes Association (ADA) characterizes prediabetes as an HbA1c 5.7% to 6.4%, while diabetes is diagnosed at an HbA1c ≥ 6.5%.2 It is important to recognize that the median baseline patient in the DM2 groups had prediabetes, and the follow-up groups contained a mix of prediabetic and diabetic patients.
Although the authors aimed to study the effect of early diagnosed, well-controlled diabetes, many of the patients included lacked sufficient exposure to hyperglycemia to be characterized as diabetic. A future study should aim to restrict eligibility to patients within the ADA categorizations to more accurately assess nerve function in patients with prediabetes and well-controlled diabetes.
Another important consideration is the indices used for nerve function. In the DM2 group with 10-year follow-up, the median values of the nerve conduction studies of the peroneal MNCV were 46.0 m/s and 42.0 m/s, the sural SNCV were 46.3 m/s and 42.0 m/s, and the sural SNAP were 8.2 μV and 6.4 μV at baseline and at 10 years, respectively. In the five-year cross-matched study, the DM2 group had peroneal MNCVs of 45.0 m/s and 44.0 m/s, sural SNCV of 46.0 m/s and 46.0, and sural SNAP of 6.9 μV and 7.1 μV at baseline and five years, respectively. These values are all considered within the normal limit of accepted standards for nerve conduction studies.3
The physiologic significance of the slight decrease in the nerve indices of the DM2 group at 10 years is unclear, since, clinically, it would not be considered significant or consistent with a diagnosis of DSPN. The authors’ choice of the sural nerve is apt, since DSPN most commonly presents as a lengthwise process that initially targets sensory nerves. A lower extremity sensory nerve, such as the sural nerve, is susceptible to the effects of hyperglycemia and should remain present with increased age in a healthy adult.
Future studies should continue to use nerve conduction studies to analyze nerve function but also could consider assessing small fiber nerve function by analyzing epidermal nerve fiber density via skin biopsy at proximal and distal locations in the lower extremities.
Andrew Feldman, MD, MEd, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.
References
- Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41.
- American Diabetes Association Professional Practice Committee. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes — 2025. Diabetes Care. 2025;48(1 Suppl 1):S27-S49.
- Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders. 4th ed. Elsevier; 2020.
The authors conducted a prospective observational study comparing the effect of early diagnosed, well-controlled type 2 diabetes on peripheral nerve function. Overall, they found similar rates of decline in nerve function in people with well-controlled diabetes compared to age- and sex-matched individuals with normal glucose tolerance. Given the similar decline in nerve function, the authors concluded that the course of diabetic sensorimotor neuropathy is influenced primarily by nerve function at the time of diagnosis and age-related physiological decline.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content