Why does diabetic peripheral neuropathy hurt in some people but not in others?
Aims: To investigate whether thalamic structure, neuronal function, and bioenergetic status differ between people with type 2 diabetes (T2D) and painful or painless diabetic peripheral neuropathy (DPN).
Methods: This cross-sectional study included 49 participants: 18 with T2D and painful DPN, 11 with T2D and painless DPN, nine with T2D without DPN, and 11 healthy controls (HC). All participants underwent detailed clinical, neurological and neurophysiological phenotyping, structural brain MRI, and two complementary magnetic resonance spectroscopy (MRS) techniques to assess thalamic neuronal (1H-MRS) and bioenergetic profiles (31P-MRS).
Results: Thalamic volume did not differ between groups. In contrast, measures of neuronal function and bioenergetic status differed significantly. The N-acetylaspartate-to-choline ratio (NAA:Cho), a measure of neuronal function, was lowest in participants with painless DPN, while levels in those with painful DPN were equivalent to HC. The inorganic phosphate-to-ATP ratio (Pi:ATP), reflecting thalamic bioenergetics, was highest in painless DPN. Again, participants with painful DPN had Pi:ATP values similar to HC. Within the painful DPN group, pain intensity correlated with thalamic Pi:ATP, and NAA:Cho significantly correlated with Pi:ATP across the whole cohort.
Conclusions: Painful and painless DPN were associated with distinct thalamic neuronal/bioenergetic profiles despite similar thalamic volumes. The findings suggest that relatively preserved thalamic neuronal and bioenergetic function may be involved in the perception of neuropathic pain, whereas painless DPN may be characterized by greater thalamic dysfunction.
Comments. This study combines structural MRI with two complementary MRS techniques, allowing thalamic structure, neuronal function, and bioenergetic status to be assessed in the same participants. The inclusion of four well-characterized groups is an important strength, particularly because the groups did not differ substantially in important demographic and metabolic characteristics, and objective neuropathy severity was broadly similar in participants with painful and painless DPN. The observation that thalamic volume was unchanged while neuronal and bioenergetic profiles differed also illustrates the potential added value of MRS over conventional structural imaging. Limitations include the relatively small sample size, particularly for subgroup and correlation analyses. In addition, 11 participants were excluded from the 1H-MRS analysis because adequate spectra could not be obtained, further reducing statistical power. The modest sample size also limited adjustment for potentially relevant confounders such as BMI and HbA1c. The cross-sectional design does not allow conclusions about the temporal direction or causality of the observed associations. As noted by the authors, the findings should therefore be considered exploratory and require confirmation in larger longitudinal studies. Despite these limitations, the study provides interesting findings with potential clinical relevance, as a better understanding of the mechanisms underlying the altered thalamic neuronal and bioenergetic profiles observed in painless DPN could help identify targets for disease-modifying therapies.
Astrid Wiggers
Reference. Sloan G, Anton A, Teh K, Caunt S, Thomas A, Wilkinson I, Selvarajah D, Tesfaye S. Thalamic neuronal and bioenergetic function in painful diabetic peripheral neuropathy: a dual magnetic resonance spectroscopy study. Diabetologia. 2026 Sep 10. doi: 10.1007/s00125-026-06846-8. Epub ahead of print. PMID: 42720751.
