A cross-sectional study investigating the neurotrophic effect of GLP-1ra treatment on small fibre neuropathy in type 2 diabetes

Diabetic neuropathy is a debilitating complication of diabetes mellitus. However, strategies for preventing diabetic neuropathy, other than glycaemic control, remain poorly developed. One promising therapeutic target is the use of glucagon-like peptide-1 receptor analogues (GLP-1-ras), which exhibit neuroprotective effects in rodent and human neuronal models. This is a proof-of-concept study on the potential neuroprotective effects of Liraglutide, a GLP-1-ra with an exceptional homology of Liraglutide to human GLP-1. The study investigates healthy controls, patients with type-2 diabetes who are not on Liraglutide, and patients with type-2 diabetes commencing Liraglutide treatment as part of their routine clinical care. The participants had biochemical markers recorded, large-fibre tests, and small-fibre tests at baseline and at a 6-month follow up to see whether changes occurred in their nerve structure and function. However, none of the measured characteristics changed significantly between baseline and follow up in any of the groups (p ≥ 0.09 in all cases). Therefore, there were no significant differences in the changes in clinical characteristics, including small nerve-fibre indices, over time between the groups (p ≥ 0.36 in all cases). Further analysis of correlations between neuropathic indicators and confounding clinical characteristics, and the changes in those variables over the study, revealed no trends to hint at an effect of Liraglutide on nerve structure or function. The lack of evidence for a neurotrophic effect of Liraglutide in humans with type-2 diabetes is consistent with recent results on the effect of Liraglutide, and another GLP-1-ra, Exenatide, on patients with type-1 diabetes. This mounting evidence from human patients contrasts with promising results from rodent and human neuronal models, highlighting uncertainty regarding the precise mechanism of action of GLP-1s in neural regulation in each case. Future work should focus on identifying the specific mechanisms of action so that optimal GLP-1 therapies can be administered in a targeted manner.