Mechanisms of axonal dysfunction in diabetes mellitus

This thesis explores the pathophysiology of axonal dysfunction in diabetes, utilizing excitability techniques which provide information on axonal ion channel function in human subjects. The rationale was that excitability studies may be useful to determine the mechanisms underlying axonal dysfunction in diabetic peripheral neuropathy (DPN) and that it may serve as a biomarker of incipient neuropathy and possibly as a means of monitoring treatment efficacy.Excitability studies were initially undertaken in 54 patients with type 2 diabetes (T2DM), and demonstrated a relationship between neuropathy-specific-quality-of-life and excitability markers that reflect activity of persistent Na+ conductances. These changes occurred concurrently with progressive axonal depolarization with increasing neuropathy severity. Further studies were then undertaken to explore these mechanisms in type 1 diabetes (T1DM). Assessment of sensory and motor excitability in 30 patients suggested membrane depolarization in sensory and motor axons. Mathematical modelling demonstrated that these changes were due to reduced nodal Na+ and K+ conductances and abnormal Na+/K+pump activity. Having demonstrated prominent changes in axonal function in T1DM, studies were conducted to explore the basis for these changes. The possibility that different forms of insulin administration may have differing effects on axonal function was considered. Axonal function was assessed in two separate cohorts of T1DM patients: those treated with continuous subcutaneous insulin infusion (CSII) and a second cohort who received multiple daily insulin injections (MDII). The studies demonstrated abnormalities of axonal function in MDII-treated patients. In contrast, CSII-treated patients had normal axonal function. The final series of studies explored the effect of glycaemic variability on axonal function in T1DM. The relationship between glycaemic variability and axonal excitability was assessed in 12 T1DM patients, using a continuous glucose monitoring system. Patients were studied at three different glucose ranges and glycaemic variability was separately measured over a 48-hour period at the time of testing. The studies demonstrated that acute glucose level did not correlate with axonal dysfunction. However, glycaemic variability was strongly correlated with neurophysiological parameters, suggesting that it is an important determinant of axonal dysfunction in T1DM

Chronic Kidney Disease Has No Impact on Tear Film Substance P Concentration in Type 2 Diabetes

Purpose: The study aimed to ascertain the potential effects of chronic kidney disease (CKD) on substance P concentration in the tear film of people with type 2 diabetes. Methods: Participants were classified into two groups: type 2 diabetes with concurrent chronic kidney disease (T2DM–CKD (n = 25)) and type 2 diabetes without chronic kidney disease (T2DM–no CKD (n = 25)). Ocular surface discomfort assessment, flush tear collection, in-vivo corneal confocal microscopy, and peripheral neuropathy assessment were conducted. Enzyme-linked immunosorbent assays were utilized to ascertain the levels of tear film substance P in collected flush tears. Correlation analysis, hierarchical multiple linear regression analysis, and t-tests or Mann–Whitney U tests were used in the analysis of data for two-group comparisons. Results: There was no substantial difference between the T2DM–CKD and T2DM–no CKD groups for tear film substance P concentration (4.4 (0.2–50.4) and 5.9 (0.2–47.2) ng/mL, respectively; p = 0.54). No difference was observed in tear film substance P concentration between the low-severity peripheral neuropathy and high-severity peripheral neuropathy groups (4.4 (0.2–50.4) and 3.3 (0.3–40.7) ng/mL, respectively; p = 0.80). Corneal nerve fiber length (9.8 ± 4.6 and 12.4 ± 3.8 mm/mm2, respectively; p = 0.04) and corneal nerve fiber density (14.7 ± 8.5 and 21.1 ± 7.0 no/mm2, respectively; p 2, respectively; p = 0.04) and corneal nerve fiber length (12.9 ± 4.2 and 9.7 ± 3.8 mm/mm2, respectively; p = 0.03) between the low- and high-severity peripheral neuropathy groups. Conclusion: In conclusion, no significant difference in tear film substance P concentration was observed between type 2 diabetes with and without CKD. Corneal nerve loss, however, was more significant in type 2 diabetes with chronic kidney disease compared to type 2 diabetes alone, indicating that corneal nerve morphological measures could serve greater utility as a tool to detect neuropathy and nephropathy-related corneal nerve changes

Chronic Kidney Disease Has No Impact on Tear Film Substance P Concentration in Type 2 Diabetes

Purpose: The study aimed to ascertain the potential effects of chronic kidney disease (CKD) on substance P concentration in the tear film of people with type 2 diabetes. Methods: Participants were classified into two groups: type 2 diabetes with concurrent chronic kidney disease (T2DM–CKD (n = 25)) and type 2 diabetes without chronic kidney disease (T2DM–no CKD (n = 25)). Ocular surface discomfort assessment, flush tear collection, in-vivo corneal confocal microscopy, and peripheral neuropathy assessment were conducted. Enzyme-linked immunosorbent assays were utilized to ascertain the levels of tear film substance P in collected flush tears. Correlation analysis, hierarchical multiple linear regression analysis, and t-tests or Mann–Whitney U tests were used in the analysis of data for two-group comparisons. Results: There was no substantial difference between the T2DM–CKD and T2DM–no CKD groups for tear film substance P concentration (4.4 (0.2–50.4) and 5.9 (0.2–47.2) ng/mL, respectively; p = 0.54). No difference was observed in tear film substance P concentration between the low-severity peripheral neuropathy and high-severity peripheral neuropathy groups (4.4 (0.2–50.4) and 3.3 (0.3–40.7) ng/mL, respectively; p = 0.80). Corneal nerve fiber length (9.8 ± 4.6 and 12.4 ± 3.8 mm/mm2, respectively; p = 0.04) and corneal nerve fiber density (14.7 ± 8.5 and 21.1 ± 7.0 no/mm2, respectively; p \u3c 0.01) were reduced significantly in the T2DM–CKD group compared to the T2DM–no CKD group. There were significant differences in corneal nerve fiber density (21.0 ± 8.1 and 15.8 ± 7.7 no/mm2, respectively; p = 0.04) and corneal nerve fiber length (12.9 ± 4.2 and 9.7 ± 3.8 mm/mm2, respectively; p = 0.03) between the low- and high-severity peripheral neuropathy groups. Conclusion: In conclusion, no significant difference in tear film substance P concentration was observed between type 2 diabetes with and without CKD. Corneal nerve loss, however, was more significant in type 2 diabetes with chronic kidney disease compared to type 2 diabetes alone, indicating that corneal nerve morphological measures could serve greater utility as a tool to detect neuropathy and nephropathy-related corneal nerve changes

[In Press] The effectiveness of activity pacing interventions for people with chronic fatigue syndrome : a systematic review and meta-analysis

Purpose: To investigate whether activity pacing interventions (alone or in conjunction with other evidence-based interventions) improve fatigue, physical function, psychological distress, depression, and anxiety in people with chronic fatigue syndrome (CFS). Materials and methods: Seven databases were searched until 13 August 2022 for randomised controlled trials that included activity pacing interventions for CFS and a validated measure of fatigue. Secondary outcomes were physical function, psychological distress, depression, and anxiety. Two reviewers independently screened studies by title, abstract and full text. Methodological quality was evaluated using the PEDro scale. Random-effects meta-analyses were performed in R. Results: 6390 articles were screened, with 14 included. Good overall study quality was supported by PEDro scale ratings. Activity pacing interventions were effective (Hedges’ g (95% CI)) at reducing fatigue (–0.52 (–0.73 to -0.32)), psychological distress (–0.37 (–0.51 to -0.24)) and depression (–0.29 (–0.49 to -0.09)) and improving physical function (mean difference 7.18 (3.17–11.18)) when compared to no treatment/ usual care. The extent of improvement was greater for interventions that encouraged graded escalation of physical activities and cognitive activities. Conclusion: Activity pacing interventions are effective in reducing fatigue and psychological distress and improving physical function in CFS, particularly when people are encouraged to gradually increase activities

Impact of SGLT2 Inhibitors on Corneal Nerve Morphology and Dendritic Cell Density in Type 2 Diabetes

Purpose: This study aims to determine the effects of SGLT2 inhibitors on corneal dendritic cell density and corneal nerve measures in type 2 diabetes. Methods: Corneal dendritic cell densities and nerve parameters were measured in people with type 2 diabetes treated with SGLT2 inhibitors (T2DM-SGLT2i) [n = 23] and those not treated with SGLT2 inhibitors (T2DM-no SGLT2i) [n = 23], along with 24 age and sex-matched healthy controls. Results: There was a reduction in all corneal nerve parameters in type 2 diabetes groups compared to healthy controls (All parameters: p \u3c 0.05). No significant differences in corneal nerve parameters were observed between T2DM-SGLT2i and T2DM-no SGLT2i groups (All parameters: p \u3e 0.05). Central corneal dendritic cells were significantly reduced [mature (p = 0.03), immature (p = 0.06) and total (p = 0.002)] in the T2DM-SGLT2i group compared to the T2DM-no SGLT2i group. Significantly, higher mature (p = 0.04), immature (p = 0.004), total (p = 0.002) dendritic cell densities in the T2DM-no SGLT2i group were observed compared to the healthy controls. In the inferior whorl, no significant difference in immature (p = 0.27) and total dendritic cell densities (p = 0.16) between T2DM-SGLT2i and T2DM-no SGLT2i were observed except mature dendritic cell density (p = 0.018). No differences in total dendritic cell density were observed in the central (p \u3e 0.09) and inferior whorl (p = 0.88) between T2DM-SGLT2i and healthy controls. Conclusion: The present study showed a reduced dendritic cell density in people with type 2 diabetes taking SGLT2 inhibitors compared to those not taking these medications

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

Axonal excitability parameters in patients vs controls.

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

Clinical characteristics of the patient cohort.

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