Sustained corneal nerve loss predicts the development of diabetic neuropathy in type 2 diabetes.

Introduction: This study was undertaken to investigate whether sustained rather than a single measure of corneal nerve loss was associated with the onset of diabetic peripheral neuropathy (DPN) and the progression of neuropathic symptoms and deficits in individuals with type 2 diabetes (T2D). Methods: Participants underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function, and corneal confocal microscopy (CCM) at baseline, 1, 2, and 4-7 years. Sustained corneal nerve loss was defined as abnormal corneal nerve fiber density (CNFD, <24 fibers/mm2), corneal nerve branch density (CNBD, <21 branches/mm2), and corneal nerve fiber length (CNFL, <16 mm/mm2) persisting for ≥50% of the study duration. Results: A total of 107 participants with a mean duration of T2D of 13.3 ± 7.3 years, aged 54.8 ± 8.5 years, underwent baseline and follow-up assessments over a median duration of 4 years, ranging from 1 to 7 years. The DPN prevalence at baseline was 18/107 (16.8%), and of the 89 participants without DPN at baseline, 13 (14.6%) developed DPN during follow-up. Approximately half of the cohort had sustained corneal nerve damage, and corneal nerve measures were significantly lower in this group than those without sustained damage (p < 0.0001). Sustained corneal nerve damage was associated with the development of DPN (p < 0.0001), a progressive loss of vibration perception (p ≤ 0.05), an increased incidence of burning pain, numbness, or a combination of both (p = 0.01-0.001), and a borderline association with progressive sudomotor dysfunction (p = 0.07). Sustained abnormal CNFL effectively distinguished between participants who developed DPN and those who did not (AUC: 76.3, 95% CI: 65.9-86.8%, p < 0.0001), while baseline and other sustained measures did not predict DPN onset. Conclusion: Sustained abnormal CCM is associated with more severe corneal nerve damage, DPN development, and the progression of neuropathic symptoms and deficits. Regular CCM monitoring may enable the identification of those at greater risk of developing and worsening DPN who may benefit from more aggressive risk factor reduction.

Corneal confocal microscopy detects early nerve regeneration after pharmacological and surgical interventions: Systematic review and meta-analysis.

Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that enables the identification of corneal nerve fibre degeneration and regeneration. To undertake a systematic review and meta-analysis of studies utilizing CCM to assess for corneal nerve regeneration after pharmacological and surgical interventions in patients with peripheral neuropathy. Databases (EMBASE [Ovid], PubMed, CENTRAL and Web of Science) were searched to summarize the evidence from randomized and non-randomized studies using CCM to detect corneal nerve regeneration after pharmacological and surgical interventions. Data synthesis was undertaken using RevMan web. Eighteen studies including 958 patients were included. CCM identified an early (1-8 months) and longer term (1-5 years) increase in corneal nerve measures in patients with peripheral neuropathy after pharmacological and surgical interventions. This meta-analysis confirms the utility of CCM to identify nerve regeneration following pharmacological and surgical interventions. It could be utilized to show a benefit in clinical trials of disease modifying therapies for peripheral neuropathy.

Where Art Thou O treatment for diabetic neuropathy: the sequel.

INTRODUCTION: Having lived through a pandemic and witnessed how regulatory approval processes can evolve rapidly; it is lamentable how we continue to rely on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN. AREAS COVERED: Small (Aδ and C) fibers are key to the genesis of pain, regulate skin blood flow, and play an integral role in the development of diabetic foot ulceration but continue to be ignored. This article challenges the rationale for the FDA insisting on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN. EXPERT OPINION: Quantitative sensory testing, intraepidermal nerve fiber density, and especially corneal confocal microscopy remain an after-thought, demoted at best to exploratory secondary endpoints in clinical trials of diabetic neuropathy. If pharma are to be given a fighting chance to secure approval for a new therapy for diabetic neuropathy, the FDA needs to reassess the evidence rather than rely on 'opinion' for the most suitable endpoint(s) in clinical trials of diabetic neuropathy.

Longitudinal Studies of Wearables in Patients with Diabetes: Key Issues and Solutions.

Glucose monitoring is key to the management of diabetes mellitus to maintain optimal glucose control whilst avoiding hypoglycemia. Non-invasive continuous glucose monitoring techniques have evolved considerably to replace finger prick testing, but still require sensor insertion. Physiological variables, such as heart rate and pulse pressure, change with blood glucose, especially during hypoglycemia, and could be used to predict hypoglycemia. To validate this approach, clinical studies that contemporaneously acquire physiological and continuous glucose variables are required. In this work, we provide insights from a clinical study undertaken to study the relationship between physiological variables obtained from a number of wearables and glucose levels. The clinical study included three screening tests to assess neuropathy and acquired data using wearable devices from 60 participants for four days. We highlight the challenges and provide recommendations to mitigate issues that may impact the validity of data capture to enable a valid interpretation of the outcomes.

Cardiovascular autonomic neuropathy is associated with increased glycemic variability driven by hyperglycemia rather than hypoglycemia in patients with diabetes.

AIM: Cardiac autonomic neuropathy (CAN) has been suggested to be associated with hypoglycemia and impaired hypoglycemia unawareness. We have assessed the relationship between CAN and extensive measures of glucose variability (GV) in patients with type 1 and type 2 diabetes. METHODS: Participants with diabetes underwent continuous glucose monitoring (CGM) to obtain measures of GV and the extent of hyperglycemia and hypoglycemia and cardiovascular autonomic reflex testing. RESULTS: Of the 40 participants (20 T1DM and 20 T2DM) (aged 40.70 ± 13.73 years, diabetes duration 14.43 ± 7.35 years, HbA1c 8.85 ± 1.70%), 23 (57.5%) had CAN. Despite a lower coefficient of variation (CV) (31.26 ± 11.87 vs. 40.33 ± 11.03, P = 0.018), they had a higher CONGA (8.42 ± 2.58 vs. 6.68 ± 1.88, P = 0.024) with a lower median LBGI (1.60 (range: 0.20-3.50) vs. 4.90 (range: 3.20-7.40), P = 0.010) and percentage median time spent in hypoglycemia (4 (range:4-13) vs. 1 (range:0-5), P = 0.008), compared to those without CAN. The percentage GRADEEuglycemia (3.30 ± 2.78 vs. 5.69 ± 3.09, P = 0.017) and GRADEHypoglycemia (0.3 (range: 0 - 3.80) vs. 1.8 (range: 0.9-6.5), P = 0.036) were significantly lower, while the percentage median GRADEHyperglycemia (95.45 (range:93-98) vs. 91.6 (82.8-95.1), P = 0.013) was significantly higher in participants with CAN compared to those without CAN. CONCLUSION: CAN was associated with increased glycemic variability with less time in euglycemia attributed to a greater time in hyperglycemia but not hypoglycemia.

Continuous glucose monitoring reveals a novel association between duration and severity of hypoglycemia, and small nerve fiber injury in patients with diabetes.

Objective: Continuous glucose monitoring (CGM) has revealed that glycemic variability and low time in range are associated with albuminuria and retinopathy. We have investigated the relationship between glucose metrics derived from CGM and a highly sensitive measure of neuropathy using corneal confocal microscopy in participants with type 1 and type 2 diabetes. Methods: A total of 40 participants with diabetes and 28 healthy controls underwent quantification of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) and inferior whorl length (IWL) and those with diabetes underwent CGM for four consecutive days. Results: CNBD was significantly lower in patients with high glycemic variability (GV) compared to low GV (median (range) (25.0 (19.0-37.5) vs 38.6 (29.2-46.9); P = 0.007); in patients who spent >4% compared to <4% time in level 1 hypoglycemia (54-69 mg/dL) (25.0 (22.9-37.5) vs 37.5 (29.2-46.9); P = 0.045) and in patients who spent >1% compared to <1% time in level 2 hypoglycemia (<54 mg/dL) (25.0 (19.8-41.7) vs 35.4 (28.1-44.8); P = 0.04). Duration in level 1 hypoglycemia correlated with CNBD (r = -0.342, P = 0.031). Duration in level 1 (181-250 mg/dL) and level 2 (>250 mg/dL) hyperglycemia did not correlate with CNFD (P > 0.05), CNBD (P > 0.05), CNFL (P > 0.05) or IWL (P > 0.05). Conclusions: Greater GV and duration in hypoglycemia, rather than hyperglycemia, are associated with nerve fiber loss in diabetes.

Elevated Adipsin and Reduced C5a Levels in the Maternal Serum and Follicular Fluid During Implantation Are Associated With Successful Pregnancy in Obese Women.

Introduction: Complement factors mediate the recruitment and activation of immune cells and are associated with metabolic changes during pregnancy. The aim of this study was to determine whether complement factors in the maternal serum and follicular fluid (FF) are associated with in vitro fertilization (IVF) outcomes in overweight/obese women. Methods: Forty overweight/obese (BMI = 30.8 ± 5.2 kg/m2) female patients, 33.6 ± 6.3 years old, undergoing IVF treatment for unexplained infertility were recruited. Baseline demographic information, including biochemical hormonal, metabolic, and inflammatory markers, and pregnancy outcome, was collected. Levels of 14 complement markers (C2, C4b, C5, C5a, C9, adipsin, mannose-binding lectin, C1q, C3, C3b/iC3b, C4, factor B, factor H, and properdin) were assessed in the serum and FF and compared to IVF outcome, inflammatory, and metabolic markers using multivariate and univariate models. Results: Out of 40 IVF cycles, 14 (35%) resulted in pregnancy. Compared to women with failed pregnancies, women with successful pregnancies had higher levels of adipsin in the serum and FF (p = 0.01) but lower C5a levels (p = 0.05). Serum adipsin levels were positively correlated with circulating levels of vitamin D (R = 0.5, p = 0.02), glucagon (R = 0.4, p = 0.03), leptin (R = 0.4, p = 0.01), resistin (R = 0.4, p = 0.02), and visfatin (R = 0.4, p = 0.02), but negatively correlated with total protein (R = -0.5, p = 0.03). Higher numbers of top-quality embryos were associated with increased levels of C3, properdin, C1q, factors H and B, C4, and adipsin, but with reduced C2 and C5a levels (p ≤ 0.01). Conclusions: Higher adipsin and lower C5a levels in the maternal serum during implantation are potential markers of successful outcome in obese women undergoing IVF-assisted pregnancies.

Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes.

AIMS/INTRODUCTION: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years. MATERIALS AND METHODS: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up. RESULTS: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain. CONCLUSIONS: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss.