Diabetic peripheral neuropathy from head to toe: looking for different brain metabolic profiles in type 1 diabetes

Aims: To study brain metabolic profiles in type 1 diabetes (T1D) and the possible associations with disease characteristics and different neuropathic phenotypes.

Methods: Sixty T1D adults (age 51.9 years, duration 28.9 years) and 20 healthy controls were enrolled (Methods of Early Detection of diabetic peripheral Neuropathy Study - MEDON, NCT04078516). T1D group included 20 patients with painful diabetic peripheral neuropathy (DPN), 20 with painless DPN and 20 without DPN. DPN was diagnosed based on vibration perception threshold above 25 V while painful DPN according to DN4 ≥4. Proton magnetic resonance (3 T) spectroscopy measurements [N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC)] were obtained in ratios to creatine (cre) from the parietal region, anterior cingulate cortex and thalamus. The ratio between mI/cre and NAA/cre was calculated to get the mI/NAA ratio, a measurement providing information on the relationship between reduced axonal integrity and increased gliosis (Llufriu S et al JAMA Neurol. 2014;71:840-7).

Results: Patients with T1D presented decreased parietal NAA/cre compared to healthy controls (1.41 ± 0.12 vs. 1.55 ± 0.13, p < 0.001) Reduced NAA/cre was associated with more severe DPN (p = 0.04). Moreover, there were increased mI/cre in T1D group compared to controls (parietal: 0.62 ± 0.08 vs. 0.57 ± 0.07, p = 0.02; cingulate: 0.65 ± 0.08 vs. 0.60 ± 0.08, p = 0.03) and the increase in parietal mI/cre levels was associated with higher HbA1c (p = 0.02).  Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre.

Conclusions: Different key brain regions presented distinct changes in metabolic profile related to specific diabetic neuropathy phenotypes.

Comments. Cerebral metabolite levels have been shown to be altered in patients with T1D and some brain areas (parietal cortex and thalamus) confirmed their importance in DPN (Selvarajah D et al Diabetes Care. 2023;46:777-785). In particular the Autors described the increase of mI/NAA ratio in all the studied regions, which could indicate a combination of astrogliosis (increased mI/cre) and axonal damage (decreased NAA/cre) already demonstrated in neurodegenerative diseases (Llufriu S et al JAMA Neurol. 2014;71:840-7; Waragai M et al J Alzheimers Dis. 2017;60:1411-1427). Furthermore, increased parietal GPC/cre (reflecting cellular membrane damage and glial proliferation) was present in DPN subgroups. Finally, increased thalamic glu/cre was found in presence of painful DPN and this shift in the thalamic region could be a key point to understand the development of the neuropathic pain.  Searching for phenotype-specific correlates of DPN would allow us to determine pathophysiological mechanisms underlying the different symptoms to identify new potential treatment targets.

Marika Menduni

Reference. Hansen TM, Croosu SS, Røikjer J, Mørch CD, Ejskjaer N, Frøkjær JB. Neuropathic phenotypes of type 1 diabetes are related to different signatures of magnetic resonance spectroscopy-assessed brain metabolites. Clin Neurophysiol. 2024 Jul 16;166:11-19. doi: 10.1016/j.clinph.2024.06.017. Epub ahead of print. PMID: 39084155.

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