Impact of GLP-1 Receptor Agonists on Axonal Function in Diabetic Peripheral Neuropathy

Academic Background

Diabetic Peripheral Neuropathy (DPN) is one of the most common complications in patients with type 2 diabetes worldwide, affecting approximately 50% of diabetic patients. The main symptoms of DPN include neuropathic pain, numbness, and in severe cases, muscle weakness and atrophy. Although current treatments for DPN primarily focus on symptom relief, there is no effective therapy to reverse or halt the progression of nerve damage. In recent years, Glucagon-Like Peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have garnered significant attention due to their multiple roles in diabetes treatment, such as promoting insulin secretion, reducing glucagon release, and aiding weight loss. Additionally, studies have found that GLP-1 receptors are expressed in the peripheral nervous system, suggesting that GLP-1RAs may have potential therapeutic effects on DPN.

This study aims to investigate the impact of GLP-1RAs on axonal function in DPN patients, particularly through neurophysiological techniques (such as axonal excitability testing) and mathematical modeling, to uncover the potential mechanisms by which GLP-1RAs improve DPN.

Source of the Paper

This paper was co-authored by Roshan Dhanapalaratnam, Tushar Issar, Ann M. Poynten, Kerry-Lee Milner, Natalie C. G. Kwai, and Arun V. Krishnan. The authors are affiliated with the University of New South Wales (UNSW Sydney), Prince of Wales Hospital, and the University of Wollongong in Australia. The study was first published on November 25, 2024, in the Journal of Neurophysiology, with the DOI 10.1152/jn.00228.2024.

Research Process

Study Participants and Design

This study recruited 14 patients with type 2 diabetes who were prescribed GLP-1RAs (such as semaglutide or dulaglutide) as part of their clinical treatment. Additionally, data from 10 patients who had previously received exenatide therapy were included to enhance the statistical power of the analysis. All participants underwent clinical assessments, nerve conduction studies, and axonal excitability testing at baseline and 3 months after initiating GLP-1RA therapy.

Experimental Methods

1. Clinical Assessment: The severity of neuropathy was assessed using the Total Neuropathy Score (TNS). The TNS includes sensory and motor symptoms, pinprick sensation, vibration sense, muscle strength examination, deep tendon reflexes, and nerve conduction tests (such as sural sensory nerve action potential and tibial motor nerve action potential).

2. Nerve Conduction Studies: The amplitude of sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs) was recorded by stimulating the sural and tibial nerves to evaluate nerve conduction function.

3. Axonal Excitability Testing: Axonal excitability testing was performed on the median nerve of the upper limb using QTrac software and the TROND protocol. The tests included strength-duration relationship, threshold electrotonus, and recovery cycle parameters to assess the function of voltage-gated ion channels and the Na⁺/K⁺-ATPase pump on the axonal membrane.

4. Mathematical Modeling: The Bostock model was used to analyze axonal excitability data, simulating changes in parameters such as Na⁺ and K⁺ channel permeability and Na⁺/K⁺-ATPase current to explain the mechanisms by which GLP-1RA therapy improves axonal function.

Data Analysis

All data were analyzed using SPSS 26.0. Paired sample t-tests were used to compare changes before and after treatment, while ANOVA and Dunnett post-hoc analyses were used to compare results between the disease group and controls. Additionally, multiple regression analysis was performed to assess the impact of changes in HbA1c and BMI on axonal excitability outcomes.

Key Findings

1. Improvement in Clinical Scores: After 3 months of GLP-1RA therapy, patients showed a significant reduction in TNS (baseline TNS 3.7±4.5, post-treatment TNS 2.3±3.4, p=0.005), indicating improvement in neuropathy symptoms.

2. Improvement in Nerve Conduction Function: The amplitude of sural SNAPs significantly increased after treatment (baseline 11.9±8.5 μV, post-treatment 14.2±9.2 μV, p=0.013), while no significant change was observed in tibial CMAP amplitude (p=0.511).

3. Changes in Axonal Excitability: After GLP-1RA therapy, axonal excitability parameters indicated improvements in Na⁺/K⁺-ATPase pump function and Na⁺ permeability. Specifically, depolarizing threshold electrotonus at 10-20 ms significantly increased (baseline 67.22±4.63%, post-treatment 69.13±6.07%, p=0.019), along with increases in S2 accommodation and subexcitability.

4. Support from Mathematical Modeling: Mathematical modeling revealed that after GLP-1RA therapy, the reduction in Na⁺ permeability of the axonal membrane was less severe, and Na⁺/K⁺-ATPase current increased, further supporting the mechanism by which GLP-1RAs reverse axonal dysfunction by improving Na⁺/K⁺-ATPase pump function.

Conclusions and Significance

This study demonstrates that GLP-1RA therapy significantly improves clinical scores, nerve conduction function, and axonal excitability in DPN patients. Through mathematical modeling, the study reveals that GLP-1RAs reverse axonal dysfunction by enhancing Na⁺/K⁺-ATPase pump function and improving Na⁺ permeability. These findings provide important scientific evidence for the potential use of GLP-1RAs in treating DPN and suggest that GLP-1RAs may have the potential to reverse nerve damage.

Research Highlights

1. Key Finding: GLP-1RA therapy significantly improves axonal function in DPN patients, marking the first time that the therapeutic mechanism of GLP-1RAs in DPN has been revealed through axonal excitability testing and mathematical modeling.

2. Innovative Methods: The study employed advanced axonal excitability testing and the Bostock mathematical model, enabling in-depth analysis of changes in ion channel and pump function on the axonal membrane, providing new insights into the pathological mechanisms of DPN.

3. Clinical Significance: GLP-1RAs not only improve glycemic control and weight in diabetic patients but may also offer additional clinical benefits for DPN patients by improving axonal function.

Other Valuable Information

The study also found that the improvement in axonal function with GLP-1RA therapy was independent of changes in HbA1c and BMI, suggesting that the therapeutic effects of GLP-1RAs on DPN may be independent of their metabolic effects. This finding opens new avenues for further research into the neuroprotective effects of GLP-1RAs.

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Through this study, the potential of GLP-1RAs in the treatment of diabetic peripheral neuropathy has been further validated. Future long-term studies may be needed to assess their sustained effects and clinical application value.