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<0.05), 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<0.05) and improved sural sensory nerve conduction amplitude (p<0.05). 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.

Tear film and ocular surface neuropeptides: Characteristics, synthesis, signaling and implications for ocular surface and systemic diseases.

Ocular surface neuropeptides are vital molecules primarily involved in maintaining ocular surface integrity and homeostasis. They also serve as communication channels between the nervous system and the immune system, maintaining the homeostasis of the ocular surface. Tear film and ocular surface neuropeptides have a role in disease often due to abnormalities in their synthesis (either high or low production), signaling through defective receptors, or both. This creates imbalances in otherwise normal physiological processes. They have been observed to be altered in many ocular surface and systemic diseases including dry eye disease, ocular allergy, keratoconus, LASIK-induced dry eye, pterygium, neurotrophic keratitis, corneal graft rejection, microbial keratitis, headaches and diabetes. This review examines the characteristics of neuropeptides, their synthesis and their signaling through G-protein coupled receptors. The review also explores the types of neuropeptides within the tears and ocular surface, and how they change in ocular and systemic diseases.

Peripheral neuropathy: an important contributor to physical limitation and morbidity in stages 3 and 4 chronic kidney disease.

BACKGROUND: Impaired physical function drives adverse outcomes in chronic kidney disease (CKD). Peripheral neuropathy is highly prevalent in CKD, though its contribution to physical function in CKD patients is unknown. This study examined the relationships between peripheral neuropathy, walking speed and quality of life (QoL) in stages 3 and 4 CKD. METHODS: This was a prospective observational study investigating neuropathy in CKD patients with an estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73 m2. A total of 109 patients were consecutively recruited. The presence and severity of peripheral neuropathy was determined using the total neuropathy score. Walking speed was assessed at both usual and maximal speed, and QoL was assessed using the Short- Form 36 (SF-36) questionnaire. RESULTS: Peripheral neuropathy was highly prevalent: 40% demonstrated mild neuropathy and 37% had moderate-severe neuropathy. Increasing neuropathy severity was the primary predictor of reduced walking speed (R2 = -0.41, P < 0.001) and remained so after multivariable analysis adjustment for diabetes. This association was evident for both usual and maximal walking speeds. Neuropathy correlated significantly with low scores on multiple domains of SF-36 including physical function (r = -0.570, P < 0.001). Subanalysis according to diabetic status revealed a high prevalence of neuropathy both with and without diabetes; relationships to walking speed remained evident in subgroup analysis. However, those with diabetes demonstrated greater severity of neuropathy, slower walking speed and lower scores in QoL. CONCLUSIONS: Moderate to severe peripheral neuropathy was common in stages 3 and 4 CKD, associated with reduced walking speed independent of diabetes status and was correlated with patient-reported QoL. This suggests that neuropathy is an important contributor to declining physical function in CKD irrespective of diabetes status. Targeted diagnosis and management of peripheral neuropathy during CKD progression may improve functional outcomes and QoL.

Diagnostic accuracy of nerve ultrasonography for the detection of peripheral neuropathy in type 2 diabetes.

BACKGROUND AND PURPOSE: Nerve conduction studies (NCS) are the current objective measure for diagnosis of peripheral neuropathy in type 2 diabetes but do not assess nerve structure. This study investigated the utility of peripheral nerve ultrasound as a marker of the presence and severity of peripheral neuropathy in type 2 diabetes. METHODS: A total of 156 patients were recruited, and nerve ultrasound was undertaken on distal tibial and distal median nerves. Neuropathy severity was graded using the modified Toronto Clinical Neuropathy Scale (mTCNS) and Total Neuropathy Score (TNS). Studies were undertaken by a single ultrasonographer blinded to nerve conduction results. RESULTS: A stepwise increase in tibial nerve cross-sectional area (CSA) was noted with increasing TNS grade (p < 0.001) and each mTCNS quartile (p < 0.001). Regression analysis demonstrated a correlation between tibial nerve CSA and neuropathy severity (p < 0.001). Using receiver operator curve analysis, tibial nerve CSA of >12.88 mm yielded a sensitivity of 70.5% and specificity of 85.7% for neuropathy detection. Binary logistic regression revealed that tibial nerve CSA was a predictor of abnormal sural sensory nerve action potential amplitude (odds ratio = 1.239, 95% confidence interval [CI] = 1.142-1.345) and abnormal neuropathy score (odds ratio = 1.537, 95% confidence interval [CI] = 1.286-1.838). CONCLUSIONS: Tibial nerve ultrasound has good specificity and sensitivity for neuropathy diagnosis in type 2 diabetes. The study demonstrates that tibial nerve CSA correlates with neuropathy severity. Future serial studies using both ultrasound and NCS may be useful in determining whether changes in ultrasound occur prior to development of nerve conduction abnormalities and neuropathic symptoms.

Impact of Peripheral and Corneal Neuropathy on Markers of Ocular Surface Discomfort in Diabetic Chronic Kidney Disease.

SIGNIFICANCE: There is a reduction in corneal nerve fiber density and length in type 2 diabetes mellitus with chronic kidney disease compared with type 2 diabetes mellitus alone; however, this difference does not result in worse ocular surface discomfort or dry eye disease. PURPOSE: This study aimed to determine the clinical impact of corneal nerve loss on ocular surface discomfort and markers of ocular surface homeostasis in people with type 2 diabetes mellitus without chronic kidney disease (T2DM-no CKD) and those with type 2 diabetes mellitus with concurrent chronic kidney disease (T2DM-CKD). METHODS: Participants were classified based on estimated glomerular filtration rates into two groups: T2DM-CKD (n = 27) and T2DM-no CKD (n = 28). RESULTS: There was a significant difference between the T2DM-CKD and T2DM-no CKD groups in corneal nerve fiber density (14.9 ± 8.6 and 21.1 ± 7.1 no./mm 2 , respectively; P = .005) and corneal nerve fiber length (10.0 ± 4.6 and 12.3 ± 3.7 mm/mm 2 , respectively; P = .04). Fluorescein tear breakup time was significantly reduced in T2DM-CKD compared with T2DM-no CKD (8.1 ± 4.4 and 10.7 ± 3.8 seconds, respectively; P = .01), whereas ocular surface staining was not significantly different (3.5 ± 1.7 and 2.7 ± 2.3 scores, respectively; P = .12). In terms of ocular surface discomfort, there were no significant differences in the ocular discomfort score scores (12.5 ± 11.1 and 13.6 ± 12.1, respectively; P = .81) and Ocular Pain Assessment Survey scores (3.3 ± 5.4 and 4.3 ± 6.1, respectively; P = .37) between the T2DM-CKD and T2DM-no CKD. CONCLUSIONS: The current study demonstrated that corneal nerve loss is greater in T2DM-CKD than in T2DM-no CKD. However, these changes do not impact ocular surface discomfort or markers of ocular surface homeostasis.

Effect of a Fundamental Motor Skills Intervention on Fundamental Motor Skill and Physical Activity in a Preschool Setting: A Cluster Randomized Controlled Trial.

PURPOSE: To determine the effect of a 12-week fundamental motor skill (FMS) program on FMS and physical activity (PA) on preschool-aged children. METHOD: A cluster randomized controlled trial. The intervention (PhysicaL ActivitY and Fundamental Motor Skills in Pre-schoolers [PLAYFun] Program) was a 12-week games-based program, delivered directly to the children in childcare centers by exercise physiologists. Children in the control arm received the usual preschool curriculum. Outcomes included FMS competence (Test of Gross Motor Development-2) and PA (accelerometer) assessed at baseline, 12 weeks, and 24 weeks (12-wk postintervention). RESULTS: Fifty children (mean age = 4.0 [0.6] y; 54% male) were recruited from 4 childcare centers. Two centers were randomized to PLAYFun and 2 centers were randomized to the waitlist control group. Children attended on average 2.0 (1.0) 40-minute sessions per week. The PLAYFun participants demonstrated significant increases in object control (P < .001) and total FMS (P = .010) competence at week 12, compared with controls in a group × time interaction. Girls, but not boys, in PLAYFun significantly increased moderate to vigorous PA after the intervention (P = .004). These increases were not maintained 12-week postcompletion of PLAYFun. CONCLUSIONS: The PLAYFun Program is effective at improving FMS competence in boys and girls and increasing PA in girls. However, improvements are not maintained when opportunities to practice are not sustained.

Impact of the metabolic syndrome on peripheral nerve structure and function in type 2 diabetes.

BACKGROUND AND PURPOSE: There is a strong association between the metabolic syndrome in diabetes and the development of peripheral neuropathy; however, the pathophysiological mechanisms remain unknown. METHODS: Participants with type 2 diabetes and metabolic syndrome (T2DM/MetS, n = 89) and type 2 diabetes alone (T2DM; n = 59) underwent median nerve ultrasound and excitability studies to assess peripheral nerve structure and function. A subset of T2DM/MetS (n = 24) and T2DM (n = 22) participants underwent confocal microscopy to assess central and inferior whorl corneal nerve structure. Neuropathy severity was assessed using the modified Toronto Clinical Neuropathy Score (mTCNS). Diabetes groups were similar for age, sex distribution, diabetes duration, hemoglobin A1c , insulin treatment, and renal function. Sixty healthy controls similar for age and sex distribution were recruited for comparison. RESULTS: Participants with T2DM/MetS manifested with a greater mTCNS compared to T2DM (p < 0.05). Median nerve cross-sectional area was larger in the T2DM/MetS group compared to the T2DM cohort (p < 0.05). Participants with T2DM/MetS had reductions in central (all p < 0.01) and inferior whorl (all p < 0.05) nerve measures. Compared to T2DM, the T2DM/MetS group demonstrated more severe changes in nerve excitability measures, which was due to reduced sodium channel permeability and sodium-potassium pump function. In comparison, only sodium channel permeability was reduced in the T2DM group. CONCLUSIONS: Compared to participants with type 2 diabetes alone, those with diabetes and metabolic syndrome manifested greater alterations in peripheral nerve structure and function, which may be due to reduced function of the sodium-potassium pump.

Altered peripheral nerve structure and function in latent autoimmune diabetes in adults.

AIM: The present study was undertaken to investigate mechanisms of peripheral nerve dysfunction in latent autoimmune diabetes in adults (LADA). MATERIALS AND METHODS: Participants with LADA (n = 15) underwent median nerve ultrasonography and nerve excitability to examine axonal structure and function, in comparison to cohorts of type 1 diabetes (n = 15), type 2 diabetes (n = 23) and healthy controls (n = 26). The LADA group was matched for diabetes duration, glycaemic control, and neuropathy severity with the type 1 and type 2 diabetes groups. A validated mathematical model of the human axon was utilized to investigate the pathophysiological basis of nerve dysfunction. RESULTS: The most severe changes in nerve structure and function were noted in the LADA group. The LADA cohort demonstrated a significant increase in nerve cross-sectional area compared to type 1 participants and controls. Compared to type 1 and 2 diabetes, measures of threshold electrotonus, which assesses nodal and internodal conductances, were significantly worse in LADA in response to both depolarising currents and hyperpolarising currents. In the recovery cycle, participants with LADA had a significant increase in the relative refractory period. Mathematical modelling of excitability recordings indicated the basis of nerve dysfunction in LADA was different to type 1 and 2 diabetes. CONCLUSIONS: Participants with LADA exhibited more severe changes in nerve function and different underlying pathophysiological mechanisms compared to participants with type 1 or 2 diabetes. Intensive management of risk factors to delay the progression of neuropathy in LADA may be required.

Motor unit number estimation of facial muscles using the M Scan-Fit method.

INTRODUCTION: M Scan-Fit, an automated method for motor unit number estimation (MUNE), was assessed in muscles innervated by the facial nerve. METHODS: Healthy volunteers were recruited. M Scans were recorded twice from nasalis and depressor anguli oris (DAO) muscles, and then fitted to a probabilistic model. RESULTS: Twenty-one subjects were evaluated; 38% were females and 62% were males, with a mean age of 34.71 years. The average number of MUs was 38.57 on both testing occasions (t ≤ 0.0001; P = 1.0) for the nasalis. For the DAO, results were 20.62 MUs for the first and 23.48 for the second (t = -2.12; P = .04). Pearson's interrater correlation coefficients were 0.96 (P < .0001) for nasalis and 0.87 (P ≤ .01) for DAO. Intraclass correlation coefficients were 0.88 (P ≤ .01) for nasalis and 0.39 (P = .37) for DAO. DISCUSSION: M Scan-Fit MUNE is an automated, accurate, reliable method of estimating MU number and size from facial muscles.

Correlation between markers of peripheral nerve function and structure in type 1 diabetes.

BACKGROUND: Clinical and experimental studies in patients with type 1 and type 2 diabetes have demonstrated changes in ion channel function and nerve structure. In this study, we investigated the relationship between axonal dysfunction and morphological change in diabetic polyneuropathy by using neuromuscular ultrasound and nerve excitability techniques. We also explored possible differences in this relationship between type 1 and type 2 diabetes. METHODS: Nerve ultrasound and corresponding motor excitability studies were undertaken in 110 diabetes patients (50 type 1; 60 type 2) and 60 age-matched controls (30 for each group). Neuropathy severity was assessed by using total neuropathy score. Median and tibial nerve cross-sectional areas were measured at nonentrapment sites by using high-resolution linear probe. RESULTS: Median and tibial nerve cross-sectional areas were significantly higher in diabetes patients compared with controls: type 1 (median = 7.6 ± 0.2 mm2 vs 6.3 ± 0.1 mm2 ; tibial = 14.5 ± 0.7 mm2 vs 10.8 ± 0.3 mm2 , P < .05) and type 2 (median = 9.1 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; tibial = 18.5 ± 1.0 mm2 vs 12.8 ± 0.5 mm2 , P < .05). In the type 1 cohort, significant correlations were found between nerve cross-sectional area and excitability parameters including resting current-threshold slope (median: r = 0.523, P < .0001; tibial: r = -0.571, P = .004) and depolarizing threshold electrotonus at 90 to 100 ms (median: 0.424, P < .01; tibial: r = 0.435, P = .030). In contrast, there was no relationship between excitability values and nerve cross-sectional area in the type 2 cohort. CONCLUSIONS: This study has identified correlation between markers of axonal membrane function and structural abnormalities in peripheral nerves of type 1 diabetes patients. The differential relationship in nerve function and structure between type 1 and type 2 diabetes provides clinical evidence that different pathophysiological mechanisms underlie the development of neuropathy in these patient groups.

Altered axonal excitability properties in facial palsy.

INTRODUCTION: Axonal excitability measures give insight into the biophysical properties of peripheral nerve axons. In this study we applied these techniques to the study of facial palsy. METHODS: Thirty patients with established facial palsy due to unresolved Bell's palsy or herpes zoster (>6 months duration), tumor invasion of the facial nerve, or traumatic facial nerve injury were assessed using facial nerve excitability techniques. RESULTS: Full recordings were obtained in 23 patients (15 unrecovered Bell's palsy or herpes zoster, 5 trauma, 3 tumor-related). Compared with normal controls, the facial palsy group demonstrated changes in stimulus response properties, threshold electrotonus, refractoriness, superexcitability, and I/V slope. Depolarizing threshold electrotonus distinguished between viral and non-viral etiologies on subgroup analysis. DISCUSSION: In this cross-sectional study, established facial palsy demonstrated findings similar to those seen in studies of regenerated axons. The improved understanding of underlying axonal characteristics offered by the technique may guide future treatment. Muscle Nerve 57: 268-272, 2018.

Effects of hemodialysis on intraneural blood flow in end-stage kidney disease.

INTRODUCTION: We quantified intraneural blood flow (INBF) in 18 patients with end-stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity, and nerve excitability parameters. METHODS: Sonographic measurements of the median nerve were performed at the same site before and after hemodialysis. INBF was quantified by analyzing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity (MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using Total Neuropathy Score. RESULTS: A total of 39% of ESKD patients had detectable INBF compared with none in the control group (P < 0.0001). Patients with detectable INBF had larger nerves and more severe neuropathy (P < 0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: P < 0.01; MPI: P < 0.01). A significant relationship was found between interdialytic change in INBF and changes in nerve excitability. CONCLUSIONS: Increased INBF is a potential marker for neuropathy severity in ESKD patients. Muscle Nerve 57: 287-293, 2018.

Association between glycemic variability and peripheral nerve dysfunction in type 1 diabetes.

INTRODUCTION: Glycemic variability (GV) may be a novel factor in the pathogenesis of diabetic complications. However, the effect of GV on peripheral nerve function has not been explored systematically. METHODS: The relationship between GV and acute glucose levels on motor and sensory nerve function in 17 patients with type 1 diabetes mellitus (T1DM) was assessed using continuous glucose monitoring and nerve excitability techniques to provide insight into the behavior of axonal voltage-gated ion channels. The mean amplitude of glycemic excursions (MAGE) was calculated to quantify GV. RESULTS: MAGE strongly correlated with excitability markers of altered motor and sensory axonal function, including superexcitability (r = 0.54), S2 accommodation (r = -0.76), minimum current threshold (I/V) slope (r = 0.71), strength duration time constant (r = 0.66), and latency (r = 0.65; P < 0.05). Acute glucose levels did not correlate with markers of axonal function. CONCLUSIONS: These findings suggest that GV may be an important mediator of axonal dysfunction in T1DM and a contributing factor in development of diabetic neuropathy. Muscle Nerve, 2016 Muscle Nerve 54: 967-969, 2016.

Continuous subcutaneous insulin infusion preserves axonal function in type 1 diabetes mellitus.

BACKGROUND: Diabetic peripheral neuropathy is a common and debilitating complication of diabetes mellitus. Although strict glycaemic control may reduce the risk of developing diabetic peripheral neuropathy, the neurological benefits of different insulin regimens remain relatively unknown. METHODS: In the present study, 55 consecutive patients with type 1 diabetes mellitus underwent clinical neurological assessment. Subsequently, 41 non-neuropathic patients, 24 of whom were receiving multiple daily insulin injections (MDII) and 17 receiving continuous subcutaneous insulin infusion (CSII), underwent nerve excitability testing, a technique that assesses axonal ion channel function and membrane potential in human nerves. Treatment groups were matched for glycaemic control, body mass index, disease duration and gender. Neurophysiological parameters were compared between treatment groups and those taken from age and sex-matched normal controls. RESULTS: Prominent differences in axonal function were noted between MDII-treated and CSII-treated patients. Specifically, MDII patients manifested prominent abnormalities when compared with normal controls in threshold electrotonus (TE) parameters including depolarizing TE(10-20ms), undershoot and hyperpolarizing TE (90-100 ms) (P < 0.05). Additionally, recovery cycle parameters superexcitability and subexcitability were also abnormal (P < 0.05). In contrast, axonal function in CSII-treated patients was within normal limits when compared with age-matched controls. The differences between the groups were noted in cross-sectional analysis and remained at longitudinal follow-up. CONCLUSIONS: Axonal function in type 1 diabetes is maintained within normal limits in patients treated with continuous subcutaneous insulin infusion and not with multiple daily insulin injections. This raises the possibility that CSII therapy may have neuroprotective potential in patients with type 1 diabetes.

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 < 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.

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 < 0.05). No significant differences in corneal nerve parameters were observed between T2DM-SGLT2i and T2DM-no SGLT2i groups (All parameters: p > 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 > 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.

Effect of Metformin on Peripheral Nerve Morphology in Type 2 Diabetes: A Cross-Sectional Observational Study.

Diabetic peripheral neuropathy (DPN) affects ∼50% of the 500 million people with type 2 diabetes worldwide and is considered disabling and irreversible. The current study was undertaken to assess the effect of metformin on peripheral neuropathy outcomes in type 2 diabetes. Participants with type 2 diabetes (n = 69) receiving metformin were recruited and underwent clinical assessment, peripheral nerve ultrasonography, nerve conduction studies, and axonal excitability studies. Also concurrently screened were 318 participants who were not on metformin, and 69 were selected as disease control subjects and matched to the metformin participants for age, sex, diabetes duration, BMI, HbA1c, and use of other diabetes therapies. Medical record data over the previous 20 years were analyzed for previous metformin use. Mean tibial nerve cross-sectional area was lower in the metformin group (metformin 14.1 ± 0.7 mm2, nonmetformin 16.2 ± 0.9 mm2, P = 0.038), accompanied by reduction in neuropathy symptom severity (P = 0.021). Axonal excitability studies demonstrated superior axonal function in the metformin group, and mathematical modeling demonstrated that these improvements were mediated by changes in nodal Na+and K+conductances. Metformin treatment is associated with superior nerve structure and clinical and neurophysiological measures. Treatment with metformin may be neuroprotective in DPN.

Axonal dysfunction prior to neuropathy onset in type 1 diabetes.

BACKGROUND: The present study was undertaken to determine whether there were changes evident in axonal membrane function prior to the onset of neuropathy in patients with type 1 and type 2 diabetes. METHODS: From a cohort of 110 consecutive referrals, nerve excitability was investigated in 40 diabetic patients without clinical evidence of neuropathy (20 type 1 diabetic patients and 20 type 2 diabetic patients). Groups were matched for gender, disease duration and HbA(1c). Studies were also undertaken in two control groups, younger controls and older controls, matched for age and gender with the diabetic cohorts. RESULTS: Subjects with type 1 diabetes demonstrated significant nerve excitability abnormalities when compared with younger normal controls. Specifically, type 1 subjects showed a significant reduction at multiple time points in both depolarising and hyperpolarising threshold electrotonus. Additionally, the relative refractory period was prolonged (type 1, 3.19 ms; younger normal controls, 3.0 ms; p < 0.05) and superexcitability was reduced (type 1, -23.12%; younger normal controls, -26.37%; p < 0.05), consistent with axonal membrane depolarisation. Correlations were identified in type 1 patients between disease duration and nerve excitability parameters, including the relative refractory period (r = -0.533, p < 0.05). In contrast, only minor non-specific changes were noted in the type 2 group. DISCUSSION: This study provides clear evidence of altered axonal function in patients with type 1 diabetes in the absence of clinical neuropathy. These findings suggest that altered axonal membrane potential may precede neuropathy onset in type 1 diabetes and as such may indicate a window of opportunity to intervene and potentially reverse axonal membrane dysfunction before the development of irreversible neuropathy.

Conjunctival microcirculation in ocular and systemic microvascular disease.

The conjunctival microcirculation is an accessible complex network of micro vessels whose quantitative assessment can reveal microvascular haemodynamic properties. Currently, algorithms for the measurement of conjunctival haemodynamics use either manual or semi-automated systems, which may provide insight into overall conjunctival health, as well as in ocular and systemic disease. These algorithms include functional slit-lamp biomicroscopy, laser doppler flowmetry, optical coherence tomography angiography, orthogonal polarized spectral imaging, computer-assisted intravitral microscopy, diffuse reflectance spectroscopy and corneal confocal microscopy. Furthermore, several studies have demonstrated a relationship between conjunctival microcirculatory haemodynamics and many diseases such as dry eye disease, Alzheimer's disease, diabetes, hypertension, sepsis, coronary microvascular disease, and sickle cell anaemia. This review aims to describe conjunctival microcirculation, its characteristics, and techniques for its measurement, as well as the association between conjunctival microcirculation and microvascular abnormalities in disease states.

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 < 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.