On the natural course of peripheral nerve dysfunction

Aims: What is the natural course of peripheral nerve function in patients with well-controlled type 2 diabetes (T2D) compared to people with normal glucose tolerance (NGT)?

Methods: This prospective analysis from the German Diabetes Study assessed n=52 T2D patients (known duration <1 year) and n=52 age- and sex-matched NGT individuals with a 5-year follow-up. Additionally, n=141 patients with T2D with 5- and 10-year follow-ups at the time of this analysis were also assessed. Study endpoints were electrophysiological testing for peroneal motor nerve conduction velocity (MNCV), sural sensory NCV (SNCV), and nerve action potential (SNAP); vibration perception threshold (VPT); thermal detection thresholds (TDT); the neuropathy disability (NDS) and symptom scores (NSS).  Diabetic sensorimotor polyneuropathy (DSPN) was defined according to the Toronto consensus criteria.

Results: At 5-year follow-up in NGT, BMI was significantly increased, while total cholesterol and M-value decreased (all P<0.05). During the same period in T2D, triglycerides, HbA1c, and fasting glucose significantly increased, while height and CRP significantly decreased (all P<0.05). Regarding peripheral nerve function at 5-year follow-up, in NGT there was a small but significant reduction in MNCV and cold TDT, with a significant increase in VPT, warm TDT, and NDS (all P<0.05). DSPN was not present amongst NGT at baseline and follow-up (0%). Older baseline age was associated with 5-year VPT in NGT. In T2D, there was a significant decrease in MNCV, with a significant increase in VPT (all P<0.05). Furthermore, in T2D compared to NGT at follow-up, MNCV was significantly lower, while VPT, NDS and NSS were significantly higher (all P<0.05). DSPN complicated 10.7% of the T2D cohort at baseline and 8.5% at follow-up. However, similar 5-year nerve function declines occurred in NGT and T2D after adjustment for baseline values and pairwise matching. In the subgroup of 141 T2D, after 10-years diastolic blood pressure, total cholesterol, M-value, creatinine, CRP, and albuminuria significantly decreased, while triglycerides, HDL, HbA1c, and fasting glucose increased (all P<0.05). Variations were observed over time in smoking and LDL (all P<0.05) and HbA1c. At 5 years compared to baseline MNCV and SNAP significantly decreased, while VPT increased (all P<0.05). At 10 years compared to baseline, all tests worsened (all P<0.05) and compared to 5 years all except for TDT (all P<0.05). Older baseline age was associated with 10-year increased VPT and improved SNAP. DSPN complicated 3.8% at baseline, 1.9% at 5 years, and 8.6% at 10 years.

Conclusions: Deterioration of peripheral nerve function in well-controlled T2D is possibly shaped by nerve function at diagnosis and aging-related changes rather than by diabetes progression.

Comments: In the absence of effective disease modifying treatments for DSPN, glycaemic control and cardiovascular risk factor management are key. However, previous studies employing this approach have demonstrated mixed results suggesting additional contributing factors. This elegant study indicates that in adequately controlled T2D, DSPN within the first decade is related to peripheral nerve status at diagnosis and physiologic aging. Therefore, as the authors note, to restore nerve function both existing nerve damage and aging must be addressed, which is not realistically achievable. Given that T2D may remain undiagnosed for years, identification of high-risk individuals is critical. Although the study used gold standard peripheral nerve functional testing to determine DSPN, a question about small fibre structure still remains. Highly sensitive endpoints of skin biopsy and corneal confocal microscopy can complement our understanding about the onset and severity of peripheral nerve damage, particularly during the earliest stages of hyperglycaemia and aid in designing highly effective prevention strategies.     

Ioannis N. Petropoulos

Reference: Strom A, Strassburger K, Ziegler D, Sipola G, Prystupa K, Wagner R, Roden M, Bönhof GJ; 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 Jun 24;104(12):e213780. doi: 10.1212/WNL.0000000000213780. Epub 2025 May 29. PMID: 40440593; PMCID: PMC12123752.

🔗 https://www.neurology.org/doi/full/10.1212/WNL.0000000000213780