Discussion
T2D, peripheral nerve damage, neuropathic pain, neuropathy, diabetes mellitus, fascicular nerve lesions, pain, weight loss, DSPN, diabetes
POSITIVE, NEUROPATHY, DISEASE, DIABETES MELLITUS, PERIPHERAL NERVE DAMAGE, HEAT, TYPE 2 DIABETES, PATHOPHYSIOLOGY, DIABETES
This study explored in a randomized controlled setting the clinical effects of periodic fasting on somatosensory nerve function in individuals with T2D. We found at the end of study no changes in clinical neuropathy scores within the study groups, especially no worsening of somatosensory nerve function after improvement of glycemic control under periodic fasting. Moreover, we found a decrease in motor NCV of N. tibialis in the M-Diet group and an increase in N. tibialis CMAP in the FMD group. The participants of the M-Diet group had a decrease in heat pain threshold. MRN analysis confirmed the correlation between fascicular nerve lesions of the sciatic nerve and clinical neuropathy scores and no changes between the groups were observed after intervention.Pathophysiology of DSPN remains still debatable and multiple factors can contribute to its clinical presentation of most commonly “stocking and glove” pattern (Studies investigating the effect of lifestyle intervention either with a diet or a physical intervention in DSPN that have been previously reported, are done in few controlled studies and not widely agreeing on the best readouts (Of note, our study compared the effects of weekly administration of FMD with those of a Mediterranean diet. In this way the diet protocol could be standardized to some extent also for the control group, since the diet protocol was tightly regulated for the intervention group. This approach avoided substantial differences in food intake between the participants of the control group, maintaining nutritional homogeneity within the group. Mediterranean diet has been shown to be beneficial for glycemic control in type 2 diabetes patients (Despite a significant weight loss after intervention in the FMD group, when adjusting the statistical analysis for weight loss we found no changes in the reported neuropathy outcomes, suggesting that weight loss alone is not sufficient to modify neuropathy outcomes in this study setting. Positive associations between chronic caloric restriction with weight-loss and thermal nociception have been previously described in animal models with mice exhibiting higher hot-plate latencies after tail-amputation on caloric restriction (40% reduction of caloric intake over 100 weeks) in comparison to ad libitum fed controls. Possible mechanisms involved changes of analgesia-regulating hormones such as glucocorticoids, opioid receptors and adrenocortical hormones modified by short-term food deprivation (The rising incidence of DSPN with longer disease duration of diabetes is naturally associated with ageing process. Caloric restriction as a therapeutic approach to neuropathic pain induced by peripheral nerve damage in elderly mice (12 months old) has been shown to increase mechanical threshold reflecting clinical improvement (Although previous studies have demonstrated excellent interobserver agreement for neuropathy assessment (MRN can visualize and characterize peripheral nerve structures including internal fascicular patterns. MRN analysis was offered to all study participants, however as an optional test. The major reasons for not conducting an MRN analysis were non-consenting (n=7 in the control group and n=9 in the FMD group) and restrictions due to Covid-19 pandemic (n=1 in the control group and n=1 in the FMD group). Although we could not perform MRN in all study participants, we could still confirm the correlation between fascicular nerve lesions of the sciatic nerve and clinical neuropathy scores as previously reported (Noteworthy our study has several limitations. The intervention duration of six months is relatively short for investigating the course of DSPN and limits possible effects of periodic fasting on delaying progression rather than reversing positive symptoms or improving functionality. Previous studies have shown increase of cutaneous nerve density after one year of diet intervention in patients with diabetes mellitus (As a conclusion our study shows that six-month periodic fasting was safe and had no deleterious effects on the clinical course of DSPN in type 2 diabetes patients. Taken together, fasting and diet intervention remain intriguing therapeutic approaches for DSPN with a still unfulfilled need on investigating fasting effects in big cohort studies, with long study intervention and in severe forms of DSPN.