The Relationship between Dyslipidemia and Acute Axonal Function in Type 2 Diabetes Mellitus In Vivo.

OBJECTIVES:Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus. Treatment largely consists of symptom alleviation and there is a need to identify therapeutic targets for prevention and treatment of DPN. The objective of this study was to utilise novel neurophysiological techniques to investigate axonal function in patients with type 2 diabetes and to prospectively determine their relationship to serum lipids in type 2 diabetic patients. METHODS:Seventy-one patients with type 2 diabetes were consecutively recruited and tested. All patients underwent thorough clinical neurological assessments including nerve conduction studies, and median motor axonal excitability studies. Studies were also undertaken in age matched normal control subjects(n = 42). Biochemical studies, including serum lipid levels were obtained in all patients. Patient excitability data was compared to control data and linear regression analysis was performed to determine the relationship between serum triglycerides and low density lipoproteins and excitability parameters typically abnormal in type 2 diabetic patients. RESULTS:Patient mean age was 64.2±2.3 years, mean glycosylated haemoglobin (HbA1c%) was 7.8±0.3%, mean triglyceride concentration was 1.6±0.1 mmol/L and mean cholesterol concentration was 4.1±0.2mmol/L. Compared to age matched controls, median motor axonal excitability studies indicated axonal dysfunction in type 2 diabetic patients as a whole (T2DM) and in a subgroup of the patients without DPN (T2DM-NN). These included reduced percentage threshold change during threshold electrotonus at 10-20ms depolarising currents (TEd10-20ms)(controls 68.4±0.8, T2DM63.9±0.8, T2DM-NN64.8±1.6%,P<0.05) and superexcitability during the recovery cycle (controls-22.5±0.9, T2DM-17.5±0.8, T2DM-NN-17.3±1.6%,P<0.05). Linear regression analysis revealed no associations between changes in axonal function and either serum triglyceride or low density lipoprotein concentration when adjusted for renal function, a separate risk factor for neuropathy development. Our findings indicate that acutely, serum lipids do not exert an acute effect on axonal function in type 2 diabetic patients: TEd(10-20ms)(1.2(-1.4,3.8);P = 0.4) and superexcitability (2.4(-0.05, 4.8);P = 0.06). CONCLUSIONS:These findings suggest that serum triglyceride levels are not related to axonal function in type 2 diabetic patients. Additional pathogenic mechanisms may play a more substantial role in axonal dysfunction prior to DPN development

Progression of axonal excitability abnormalities with increasing clinical severity of diabetic peripheral neuropathy

Objective: Diabetic peripheral neuropathy (DPN) is a frequent complication for persons with type 2 diabetes. Previous studies have failed to demonstrate any significant impact of treatment for DPN. The present study assessed the role of axonal ion channel dysfunction in DPN and explored the hypothesis that there may be a progressive change in ion channel abnormalities that varied with disease stage. Methods: Neurophysiological studies were conducted using axonal excitability techniques, a clinical method of assessing ion channel dysfunction. Studies were conducted in 178 persons with type 2 diabetes, with participants allocated into four groups according to clinical severity of neuropathy, assessed using the Total Neuropathy Grade. Results: Analysis of excitability data demonstrated a progressive and stepwise reduction in two parameters that are related to the activity of Kv1.1 channels, namely superexcitability and depolarizing threshold electrotonus at 10–20 ms (p \u3c 0.001), and mathematical modelling of axonal excitability findings supported progressive upregulation of Kv1.1 conductances with increasing greater disease severity. Conclusion: The findings are consistent with a progressive upregulation of juxtaparanodal Kv1.1 conductances with increasing clinical severity of diabetic peripheral neuropathy. Significance: From a translational perspective, the study suggests that blockade of Kv1.1 channels using 4-aminopyridine derivatives such as fampridine may be a potential treatment for DPN

Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy

Aims/hypothesis: Diabetic peripheral neuropathy (DPN) is a highly prevalent cause of physical disability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes and animal studies have shown that glucagon-like peptide-1 (GLP-1) receptors are present in the central and peripheral nervous systems. This study investigated whether GLP-1 RAs can improve nerve structure. Methods: Nerve structure was assessed using peripheral nerve ultrasonography and measurement of tibial nerve cross-sectional area, in conjunction with validated neuropathy symptom scores and nerve conduction studies. A total of 22 consecutively recruited participants with type 2 diabetes were assessed before and 1 month after commencing GLP-1 RA therapy (semaglutide or dulaglutide). Results: There was a pathological increase in nerve size before treatment in 81.8% of the cohort (n=22). At 1 month of follow-up, there was an improvement in nerve size in 86% of participants (p\u3c0.05), with 32% returning to normal nerve morphology. A 3 month follow-up study (n=14) demonstrated further improvement in nerve size in 93% of participants, accompanied by reduced severity of neuropathy (p\u3c0.05) and improved sural sensory nerve conduction amplitude (p\u3c0.05). Conclusions/interpretation: This study demonstrates the efficacy of GLP-1 RAs in improving neuropathy outcomes, evidenced by improvements in mainly structural and morphological measures and supported by electrophysiological and clinical endpoints. Future studies, incorporating quantitative sensory testing and measurement of intraepidermal nerve fibre density, are needed to investigate the benefits for small fibre function and structure. Graphical Abstract: [Figure not available: see fulltext.]

Linear Regression model between serum LDL and excitability parameters typically abnormal in type 2 diabetic patients.

<p>Linear Regression model between serum LDL and excitability parameters typically abnormal in type 2 diabetic patients.</p

Clinical characteristics of the patient cohort.

<p>Clinical characteristics of the patient cohort.</p

Axonal excitability parameters in patients vs controls.

<p>Axonal excitability parameters in patients vs controls.</p

Linear Regression model between serum triglycerides and excitability parameters typically abnormal in type 2 diabetic patients.

<p>Linear Regression model between serum triglycerides and excitability parameters typically abnormal in type 2 diabetic patients.</p

Mean threshold electrotonus and recovery cycle plots from type 2 diabetic patients without neuropathy compared to matched normal controls.

<p>Type 2 diabetic patients (block lines) exhibited less threshold change during both threshold electrotonus (a) and the recovery cycle (b) compared to control subjects (dashed lines). Threshold electrotonus parameters are expressed as percentage threshold change during and after subthreshold depolarising and hyperpolarising currents up to 100ms whilst the recovery cycle is given as percentage threshold change at varying intervals after a supramaximal impulse. Significance is indicated by: *P<0.05, **P<0.005 and ***P<0.0005.</p