Not all variability is equal: long-term GV impacts axons, short-term GV impacts myelin in T2D

Aims: To investigate the effects of short and long-term glycaemic variability (GV) on peripheral nerve function in individuals with type 2 diabetes (T2D).

Methods: A retrospective cross-sectional study included 230 individuals with T2D who had been under continuous outpatient care for at least 5 years with serial HbA1C measurements prior to undergoing continuous glucose monitoring (CGM) with FreeStyle Libre Pro.  Short-term GV was assessed using CGM-derived standard deviation of glucose levels and time-in-range (TIR). Long-term GV was evaluated using visit-to-visit variability in HbA1c, including 4 complementary metrics: 1. Standard deviation (SD-HbA1c) – quantifies absolute variability; 2. Coefficient of variation (CV-HbA1c) – normalises variability to mean; 3. HbA1c variability score (HVS-HbA1c) – emphasises fluctuation between consecutive values; 4. Average real variability of HbA1c (ARV-HbA1c) – reflects the mean absolute difference between successive HbA1c values. DPNCheck™ was used to measure sural nerve action potential (SNAP) amplitude and sensory conduction velocity (SCV).

Results: Short-term GV metrics were significantly associated with SCV; however, these associations were attenuated after adjusting for mean HbA1c. Conversely, long-term GV metrics, particularly SD-HbA1c, CV-HbA1c, and ARV-HbA1c were strongly associated with reduced SNAP amplitude, and these associations remained significant after adjustment for 5-year mean HbA1c. Notably, short-term GV retained an independent association with SCV only in individuals with HbA1c ≤6.9% (52 mmol/mol), suggesting a limited but distinct impact in well-controlled patients.

Conclusions: Short and long term GV have different impact on peripheral nerve function, with short term GV having an effect on SCV and long-term on SNAP amplitude.

Comments: The findings suggest that long-term glycaemic instability may contribute to the pathogenesis of diabetic polyneuropathy (DPN) through mechanisms independent of mean glycaemic levels. While SCV is a marker of myelin integrity, SNAP amplitude reflects axonal function supporting the hypothesis that sustained glucose fluctuations may lead to progressive axonal injury.

This study reinforces the importance of targeting long-term GV reduction, potentially through lifestyle consistency and tailored pharmacotherapy as a strategy to mitigate DPN progression in T2D. Elevated long-term GV has been associated with poor lifestyle habits, suboptimal treatment adherence, and greater comorbidity burden. Additionally, it may reflect the presence of comorbidities or adverse health states that contribute to poor clinical outcomes. The pathophysiological mechanisms linking long-term GV to complications remain incompletely understood but likely involve sustained metabolic stress, including chronic oxidative stress, low-grade inflammation, and the phenomenon of metabolic memory. These factors impair axonal repair and promote degeneration, contributing to the development of DPN.

The use of multiple GV metrics over five years, coupled with CGM-derived short-term data, represents a major strength. As CGM use becomes more widespread in T2D, there is a growing need to better interpret GV data to inform complication risk. One limitation of the current study is the reliance on serial HbA1c to characterize long-term GV. HbA1c does not capture intra-day fluctuations in glucose levels. Nonetheless, the inclusion of multiple validated HbA1c-based variability metrics offers a comprehensive view of long-term glycaemic instability. Future research should explore the use of extended CGM monitoring to assess long-term GV with greater granularity, incorporating additional metrics that better reflect the full spectrum of glycaemic excursions. This could lead to improved understanding of the role of GV in DPN progression and inform more targeted therapeutic strategies.

Shazli Azmi

Reference: Iwamoto T, Morita M, Hidaka S, Sada K, Iwamoto M, Shibata H. Differential impact of short-term and long-term glycemic variability on peripheral nerve function in type 2 diabetes: A 5-year cohort study. J Diabetes Complications. 2025 Aug;39(8):109081. doi: 10.1016/j.jdiacomp.2025.109081. Epub 2025 May 16. PMID: 40440925.

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