ABSTRACT
Adenylyl cyclases (ACs) are a group of enzymes that convert adenosine-5'-triphosphate (ATP) to cyclic adenosine 3',5' monophosphate (cAMP), a vital and ubiquitous signalling molecule in cellular responses to hormones and neurotransmitters. There are nine transmembrane (tmAC) forms, which have been widely studied; however, the tenth, soluble AC (sAC) is less extensively characterised. The eye is one of the most metabolically active sites in the body, where sAC has been found in abundance, making it a target for novel therapeutics and biomarking. In the cornea, AC plays a role in endothelial cell function, which is vital in maintaining stromal dehydration, and therefore, clarity. In the retina, AC has been implicated in axon cell growth and survival. As these cells are irreversibly damaged in glaucoma and injury, this molecule may provide focus for future therapies. Another potential area for glaucoma management is the source of aqueous humour production, the ciliary body, where AC has also been identified. Furthering the understanding of lacrimal gland function is vital in managing dry eye disease, a common and debilitating condition. sAC has been linked to tear production and could serve as a therapeutic target. Overall, ACs are an exciting area of study in ocular health, offering multiple avenues for future medical therapies and diagnostics. This review paper explores the diverse roles of ACs in the eye and their potential as targets for innovative treatments.
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Purpose: The aim of this study is to transform optical coherence tomography angiography (OCTA) scans into innovative OCTA graphs, serving as novel biomarkers representing the macular vasculature. Patients and Methods: The study included 90 healthy subjects and 39 subjects with various abnormalities (29 with diabetic retinopathy, 5 with age-related macular degeneration, and 5 with choroid neovascularization). OCTA 5µm macular coronal views (MCVs) were generated for each subject, followed by blood vessel segmentation and skeleton processing. Subsequently, the blood vessel density index, blood vessel skeleton index, and blood vessel tortuosity index were computed. The graphs of each metric were plotted against the axial axes of the OCTA B-scan, representing the integrity of vasculature at successive 5µm macular depths. Results: The results revealed two significant findings. First, the B-scans from OCTA can be transformed into OCTA graphs, yielding three specific OCTA graphs in this study. These graphs provide new biomarkers for assessing the integrity of deep vascular complex (DVC) and superficial vascular complex (SVC) within the macula. Second, a statistically significant difference was observed between normal (n=90) and abnormal (n=39) subjects, with a t-test p-value significantly lower than 0.001. The Mann-Whitney u-test also yielded significant difference but only between the 90 normal and 29 DR subjects. Conclusion: The novel OCTA graphs offer a unique representation of the macula's SVC and DVC, suggesting their potential in aiding physicians in the diagnosis of eye health within OCTA clinics. Further research is warranted to finalize the shape of these newly derived OCTA graphs and establish their clinical relevance and utility.
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Introduction: Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes, imposing a significant burden on individuals and healthcare systems worldwide. This study presents a comprehensive analysis of the global research landscape in DN, aiming to provide scientists, funders, and decision-makers with valuable insights into the current state of research and future directions. Methods: Through a systematic review of published articles, key trends in DN research, including epidemiology, diagnosis, treatment strategies, and gaps in knowledge, are identified and discussed. Results: The analysis reveals an increasing prevalence of DN alongside the rising incidence of diabetes, emphasizing the urgent need for effective prevention and management strategies. Furthermore, the study highlights the geographical imbalance in research activity, with a majority of studies originating from high-income countries. Discussion: This study underscores the importance of fostering international collaboration to address the global impact of DN. Key challenges and limitations in DN research are also discussed, including the need for standardized diagnostic criteria, reliable biomarkers, and innovative treatment approaches. By addressing these gaps, promoting collaboration, and increasing research funding, we can pave the way for advancements in DN research and ultimately improve the lives of individuals affected by this debilitating condition.
Subject(s)
Diabetes Mellitus , Diabetic Neuropathies , Humans , Diabetic Neuropathies/diagnosis , Diabetic Neuropathies/epidemiology , Diabetic Neuropathies/etiology , Forecasting , PrevalenceABSTRACT
Objective: Screening for diabetic peripheral neuropathy (DPN) is essential for early detection and timely intervention. Quantitative assessment of small nerve fiber damage is key to the early diagnosis and assessment of its progression. Corneal confocal microscopy (CCM) is a non-invasive, in-vivo diagnostic technique that provides an accurate surrogate biomarker for small-fiber neuropathy. In this novel study for the first time, we introduced CCM to primary care as a screening tool for DPN alongside retinopathy screening to assess the level of neuropathy in this novel cohort. Research design and methods: 450 consecutive subjects with type 1 or type 2 diabetes attending for annual eye screening in primary care optometry settings underwent assessment with CCM to establish the prevalence of sub-clinical diabetic peripheral neuropathy. Subjects underwent assessment for neurological and ocular symptoms of diabetes and a history of diabetic foot disease, neuropathy and diabetic retinopathy (DR). Results: CCM examination was completed successfully in 427 (94.9%) subjects, 22% of whom had neuropathy according to Diabetic Neuropathy Symptom (DNS) score. The prevalence of sub-clinical neuropathy as defined by abnormal corneal nerve fiber length (CNFL) was 12.9%. In the subjects with a short duration of type 2 diabetes, 9.2% had abnormal CNFL. CCM showed significant abnormalities in corneal nerve parameters in this cohort of subjects with reduction of corneal nerve fiber density (CNFD, p<0.001), CNFL (p<0.001) and corneal nerve branch density (CNBD, p<0.001) compared to healthy subjects. In subjects who had no evidence of DR (67% of all subjects), 12.0% had abnormal CNFL. Conclusions: CCM may be a sensitive biomarker for early detection and screening of DPN in primary care alongside retinopathy screening.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Neuropathies , Diabetic Retinopathy , Humans , Biomarkers , Cornea/diagnostic imaging , Diabetes Mellitus, Type 2/complications , Diabetic Neuropathies/diagnosis , Diabetic Neuropathies/epidemiology , Diabetic Retinopathy/diagnosis , Diabetic Retinopathy/epidemiology , Early Diagnosis , Feasibility Studies , Microscopy, Confocal/methods , Primary Health CareABSTRACT
Aim: Diabetic retinopathy (DR) is widely considered the earliest and most common microvascular complication of diabetes. However, recent studies have shown that retinal nerve fiber layer and corneal nerve abnormalities may be present in diabetic patients without retinopathy. This preliminary study aimed to establish if structural and functional changes in the nerve fiber layer of the retina and cornea occur in patients with type 1 diabetes (T1DM) without retinopathy. Methods: Twenty patients with T1DM, without clinical evidence of retinopathy (Age: 47.0 ± 2.5 years; Duration diabetes: 27.0 ± 3 years) and 15 age-matched healthy control subjects underwent detailed medical neurological examinations. Ophthalmic examinations using Spectral Domain Optical coherence tomography (SD-OCT), Standard Automated Perimetry (SAP), Flicker Defined Form High Edge Perimetry (FDF), Corneal Confocal Microscopy (CCM) and Non-contact corneal Aesthesiometry (NCCA) were performed to quantify the structure and function of the nerves in the retina and cornea, respectively. Results: At the structural level, retinal nerve fiber layer thickness (RNFL) was significantly reduced in the superior nasal (p=0.001) and inferior temporal (p=0.004) sectors, in diabetic patients. Retinal ganglion layer function was reduced in the patient group when assessed using Flicker Defined Form Perimetry (FDF), but this was not significant. The function of the cornea assessed by corneal sensitivity, using a non-contact corneal aesthesiometer (NCCA), was significantly reduced (p=0.001). Structural assessment of corneal nerves using corneal confocal microscopy (CCM) showed reduction at corneal nerve fiber density (CNFD) (p=0.01), branch density (CNBD) (p=0.006) and length (CNFL) (p=0.01) in patients with diabetes. Compared to control subjects, the percentage of abnormality in patients with T1DM for RNFL was 32% while the FDF was abnormal in 61% of patients. Corneal abnormality was observed in 47% for NCCA, 28% for CNFD, and 17% for CNFL. There was no correlation between neuronal damage in the retina and cornea. Conclusions: Neuronal abnormalities were observed in both the retina and cornea of diabetic patients without evidence of retinopathy. The prevalence of structural and functional changes was higher in the retina compared to the cornea. This preliminary study suggests that structural neuronal changes may occur in parallel and correlate with functional changes. The assessment of corneal and retinal nerve structure may be clinically useful for detecting and monitoring the earliest stages of diabetic microvascular abnormalities.
Subject(s)
Corneal Diseases , Diabetes Mellitus, Type 1 , Diabetic Retinopathy , Humans , Adult , Middle Aged , Diabetic Retinopathy/diagnosis , Diabetic Retinopathy/etiology , Diabetes Mellitus, Type 1/complications , Nerve Fibers , Cornea , Retina/diagnostic imaging , Corneal Diseases/diagnosis , Corneal Diseases/etiologyABSTRACT
OBJECTIVE: In vivo corneal confocal microscopy (CCM) is a novel, rapid, and non-invasive technique that identifies early small fiber damage and can predict the progression and development of clinical neuropathy in adults with type 1 diabetes. However, its usefulness in children is not well established. This study compared corneal confocal microscopy with neuropathic symptoms, signs, and objective measures of neuropathy for the diagnosis of diabetic neuropathy in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 83 children with type 1 diabetes and 83 healthy participants of similar age underwent assessment of neuropathy symptoms, signs, nerve conduction studies, quantitative sensory and autonomic function testing, and in vivo CCM. RESULTS: Only of 3/83 (4%) children with type 1 diabetes had subclinical neuropathy. However, corneal nerve fiber density (p = 0.001), branch density (p = 0.006), fiber length (p = 0.002), tibial motor nerve amplitude and conduction velocity, and sural sensory nerve amplitude and conduction velocity (all p < 0.004) were lower in participants with type 1 diabetes than in the controls. Vibration, cooling, and warm perception thresholds and deep breathing heart rate variability were not found to be different (all p > 0.05) between children with type 1 diabetes and healthy controls. Multivariate regression analysis identified a possible association between body mass index and decreased corneal nerves. CONCLUSIONS: Decreased corneal nerves and abnormal nerve conduction were found in children with type 1 diabetes. CCM may allow rapid objective detection of subclinical diabetic neuropathy in children and adolescents with type 1 diabetes.
Subject(s)
Diabetes Mellitus, Type 1 , Diabetic Neuropathies , Adult , Humans , Child , Adolescent , Diabetic Neuropathies/diagnosis , Nerve Fibers , Cornea/innervation , Neural ConductionABSTRACT
A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.
Subject(s)
Auditory Pathways , Cochlear Nucleus , Hair Cells, Auditory , LIM-Homeodomain Proteins , Neurogenesis , Spiral Ganglion , Transcription Factors , Animals , Auditory Pathways/embryology , Cochlea/embryology , Cochlea/innervation , Cochlear Nucleus/embryology , Hair Cells, Auditory/physiology , LIM-Homeodomain Proteins/genetics , LIM-Homeodomain Proteins/physiology , Mice , Neurogenesis/genetics , Spiral Ganglion/enzymology , Transcription Factors/genetics , Transcription Factors/physiologyABSTRACT
Aims: This three-year follow-up study aimed to elucidate whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) have any protection against diabetic neuropathy and nephropathy in patients with type 2 diabetes via reducing variability in glycemia and extraglycemic factors or their averages. Methods: Two type 2 diabetic cohorts of 40 and 73 patients treated with or without SGLT2i along with 60 control subjects were recruited. Two diabetic cohorts matched for HbA1c levels and oral hypoglycemic agents other than SGLT2is underwent glycemic control with or without SGLT2is more than two years. The urinary albumin to creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) every 3 months and neuropathy outcome measures and mean Z-score of 8 neurophysiological tests were determined at the baseline and endpoint. Glycemic variability, evaluated by the coefficient of variation of monthly measured HbA1c levels and casual postprandial plasma glucose (CPPG), and coefficient of variation and average of extraglycemic parameters in diabetic cohorts were determined. Results: The glycemic variability and variability of some extraglycemic factors in SGLT2i cohort were smaller than those in non-SGLT2i cohort. However, only smaller coefficient of variation of HbA1c improved some neuropathy outcome measures, and ameliorated eGFR decline. SGLT2i improved the Z-score of neurophysiological tests. The optimized changes in the blood pressure, HDL-cholesterol and uric acid by SGLT2i led to neurological and renal protection. SGLT2i decreased the prevalence of nephropathy significantly and the prevalence of neuropathy insignificantly. Conclusion: Over 3 years period, SGLT2i significantly improved some neuropathy outcome measures, mean Z-score of 8 neurophysiological tests, and attenuated nephropathy in modestly controlled type 2 diabetes by reducing glycemic variability and mean nonglycemic factors of diabetic microvascular complication.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Neuropathies , Kidney Diseases , Sodium-Glucose Transporter 2 Inhibitors , Blood Glucose , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/etiology , Diabetic Neuropathies/prevention & control , Follow-Up Studies , Glycated Hemoglobin , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic useABSTRACT
Neuronal development in the inner ear is initiated by expression of the proneural basic Helix-Loop-Helix (bHLH) transcription factor Neurogenin1 that specifies neuronal precursors in the otocyst. The initial specification of the neuroblasts within the otic epithelium is followed by the expression of an additional bHLH factor, Neurod1. Although NEUROD1 is essential for inner ear neuronal development, the different aspects of the temporal and spatial requirements of NEUROD1 for the inner ear and, mainly, for auditory neuron development are not fully understood. In this study, using Foxg1Cre for the early elimination of Neurod1 in the mouse otocyst, we showed that Neurod1 deletion results in a massive reduction of differentiating neurons in the otic ganglion at E10.5, and in the diminished vestibular and rudimental spiral ganglia at E13.5. Attenuated neuronal development was associated with reduced and disorganized sensory epithelia, formation of ectopic hair cells, and the shortened cochlea in the inner ear. Central projections of inner ear neurons with conditional Neurod1 deletion are reduced, unsegregated, disorganized, and interconnecting the vestibular and auditory systems. In line with decreased afferent input from auditory neurons, the volume of cochlear nuclei was reduced by 60% in Neurod1 mutant mice. Finally, our data demonstrate that early elimination of Neurod1 affects the neuronal lineage potential and alters the generation of inner ear neurons and cochlear afferents with a profound effect on the first auditory nuclei, the cochlear nuclei.
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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by neuronal loss, extracellular amyloid-ß (Aß) plaques, and intracellular neurofibrillary tau tangles. A diagnosis is currently made from the presenting symptoms, and the only definitive diagnosis can be done post-mortem. Over recent years, significant advances have been made in using ocular biomarkers to diagnose various neurodegenerative diseases, including AD. As the eye is an extension of the central nervous system (CNS), reviewing changes in the eye's biology could lead to developing a series of non-invasive, differential diagnostic tests for AD that could be further applied to other diseases. Significant changes have been identified in the retinal nerve fiber layer (RNFL), cornea, ocular vasculature, and retina. In the present paper, we review current research and assess some ocular biomarkers' accuracy and reliability that could potentially be used for diagnostic purposes. Additionally, we review the various imaging techniques used in the measurement of these biomarkers.
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OBJECTIVE: Corneal nerve fiber length (CNFL) has been shown in research studies to identify diabetic peripheral neuropathy (DPN). In this longitudinal diagnostic study, we assessed the ability of CNFL to predict the development of DPN. RESEARCH DESIGN AND METHODS: From a multinational cohort of 998 participants with type 1 and type 2 diabetes, we studied the subset of 261 participants who were free of DPN at baseline and completed at least 4 years of follow-up for incident DPN. The predictive validity of CNFL for the development of DPN was determined using time-dependent receiver operating characteristic (ROC) curves. RESULTS: A total of 203 participants had type 1 and 58 had type 2 diabetes. Mean follow-up time was 5.8 years (interquartile range 4.2-7.0). New-onset DPN occurred in 60 participants (23%; 4.29 events per 100 person-years). Participants who developed DPN were older and had a higher prevalence of type 2 diabetes, higher BMI, and longer duration of diabetes. The baseline electrophysiology and corneal confocal microscopy parameters were in the normal range but were all significantly lower in participants who developed DPN. The time-dependent area under the ROC curve for CNFL ranged between 0.61 and 0.69 for years 1-5 and was 0.80 at year 6. The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70-5.11; P < 0.001) for new-onset DPN. CONCLUSIONS: CNFL showed good predictive validity for identifying patients at higher risk of developing DPN â¼6 years in the future.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Neuropathies , Cornea/diagnostic imaging , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Diabetic Neuropathies/diagnosis , Diabetic Neuropathies/epidemiology , Humans , Microscopy, Confocal , Nerve FibersABSTRACT
The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN's sensitivity and performance.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Neuropathies/diagnosis , Early Diagnosis , Mass Screening/methods , Diabetic Neuropathies/etiology , HumansABSTRACT
Diabetic polyneuropathy (DPN) and endothelial dysfunction are prevalent complications of diabetes mellitus. Currently, there are two non-invasive markers for endothelial dysfunction: flow-mediated dilation and reactive hyperaemia peripheral arterial tonometry (RH-PAT). However, the relationship between diabetic small fibre neuropathy and macroangiopathy remains obscure thus far. Corneal confocal microscopy (CCM) has emerged as a new diagnostic modality to assess DPN, especially of small fibre. To clarify the relationship between diabetic small fibre neuropathy and vascular dysfunction, we aimed to determine the functions of peripheral nerves and blood vessels through clinical tests such as nerve conduction study, coefficient of variation in the R-R interval, CCM, and RH-PAT in 82 patients with type 2 diabetes. Forty healthy control subjects were also included to study corneal nerve parameters. Correlational and multiple linear regression analyses were performed to determine the associations between neuropathy indices and markers for vascular functions. The results revealed that patients with type 2 diabetes had significantly lower values for most variables of CCM than healthy control subjects. RH-PAT solely remained as an explanatory variable significant in multiple regression analysis for several CCM parameters and vice versa. Other vascular markers had no significant multiple regression with any CCM parameters. In conclusion, endothelial dysfunction as revealed by impaired RH-PAT was significantly associated with CCM parameters in patients with type 2 diabetes. This association may indicate that small fibre neuropathy results from impaired endothelial dysfunction in type 2 diabetes. CCM parameters may be considered surrogate markers of autonomic nerve damage, which is related to diabetic endothelial dysfunction. This study is the first to report the relationship between corneal nerve parameter as small fibre neuropathy in patients with type 2 diabetes and RH-PAT as a marker of endothelial dysfunction.
Subject(s)
Cornea/diagnostic imaging , Diabetes Mellitus, Type 2/physiopathology , Diabetic Angiopathies/physiopathology , Endothelium, Vascular/pathology , Small Fiber Neuropathy/physiopathology , Adult , Aged , Biomarkers , Cornea/physiopathology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/complications , Diabetic Neuropathies/complications , Diabetic Neuropathies/physiopathology , Endothelium, Vascular/physiopathology , Female , Humans , Male , Microscopy, Confocal , Middle Aged , Nerve Fibers , Peripheral Nerves/physiopathology , Regression Analysis , Retrospective StudiesABSTRACT
Aims: To establish the sequential changes by glycemic control in the mean thickness, volume and reflectance of the macular photoreceptor layers (MPRLs) and retinal pigment epithelium in patients with type 2 diabetes without diabetic retinopathy. Methods: Thirty-one poorly controlled (HbA1c > 8.0%) patients with type 2 diabetes without diabetic retinopathy undergoing glycemic control and 39 control subjects with normal HbA1c levels (< 5.9%) underwent periodical full medical, neurological and ophthalmological examinations over 2 years. Glycemic variability was evaluated by standard deviation and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose. 3D swept source-optical coherence tomography (OCT) and OCT-Explorer-generated enface thickness, volume and reflectance images for 9 subfields defined by Early Treatment Diabetic Retinopathy Study of 4 MPRLs {outer nuclear layer, ellipsoid zone, photoreceptor outer segment (PROS) and interdigitation zone} and retinal pigment epithelium were acquired every 3 months. Results: Glycemic control sequentially restored the thickness and volume at 6, 4 and 5 subfields of outer nuclear layer, ellipsoid zone and PROS, respectively. The thickness and volume of outer nuclear layer were restored related to the decrease in HbA1c and casual plasma glucose levels, but not related to glycemic variability and neurological tests. The reflectance of MPRLs and retinal pigment epithelium in patients was marginally weaker than controls, and further decreased at 6 or 15 months during glycemic control. The reduction at 6 months coincided with high HbA1c levels. Conclusion: Glycemic control sequentially restored the some MPRL thickness, especially of outer nuclear layer. In contrast, high glucose during glycemic control decreased reflectance and may lead to the development of diabetic retinopathy induced by glycemic control. The repeated OCT examinations can clarify the benefit and hazard of glycemic control to the diabetic retinopathy.
Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/diagnostic imaging , Glycemic Control , Photoreceptor Cells, Vertebrate , Retinal Pigment Epithelium/diagnostic imaging , Diabetic Retinopathy/blood , Diabetic Retinopathy/diagnostic imaging , Female , Fluorescein Angiography , Follow-Up Studies , Humans , Lipids/blood , Male , Middle Aged , Tomography, Optical CoherenceABSTRACT
PURPOSE: Our goal is early detection of neuropathy in patients with type 2 diabetes with or without microalbuminuria in the absence of diabetic retinopathy and peripheral neuropathy by using in vivo corneal confocal microscopy (IVCCM). METHODS: A total of 60 type-2 diabetic patients, assigned to either a diabetes mellitus (DM) with microalbuminuria group (DM/MA+, n=30) or a DM without microalbuminuria group (DM/MA-, n=30), and 30 age-matched control subjects were enrolled in this study. All cases underwent evaluation of blood glucose level, HbA1c, lipid fractions, body mass index (BMI), and corneal sensitivity (CS). Corneal nerve fiber length (NFL), nerve fiber density (NFD), nerve branch density (NBD), and tortuosity coefficient (TC) were quantified by IVCCM. None of the patients had peripheral neuropathy or retinopathy. RESULTS: Compared with the healthy subjects, NFL and NFD were reduced in both diabetic groups (P<0.0001), while NBD was significantly reduced in the DM/MA+ group. Between the diabetic groups, NFL, NFD, and NBD were significantly higher in the DM/MA- group (all P's<0.001). CS was significantly lower in DM/MA+ compared with DM/MA- and controls (both P's<0.0001). NFD and NFL were inversely correlated with age, triglyceride level, and BMI. CONCLUSION: These results indicate that significant damage to small nerves, quantified using IVCCM, can be detected in the absence of retinopathy, peripheral neuropathy or microalbuminuria in type 2 diabetic patients. The severity of corneal nerve involvement may further increase in the presence of nephropathy. This feature may also be valuable for early detection of microvascular complications of DM, allowing for the prevention of progression of life threatening microvascular complications.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Neuropathies , Diabetic Retinopathy , Cornea , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetic Neuropathies/diagnosis , Diabetic Neuropathies/etiology , Diabetic Retinopathy/complications , Diabetic Retinopathy/diagnosis , Diabetic Retinopathy/epidemiology , Humans , Microscopy, Confocal , Nerve FibersABSTRACT
OBJECTIVE: Corneal nerve fiber length (CNFL) represents a biomarker for diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, the prevalence of abnormal change in diabetes, and its associated clinical variables. RESEARCH DESIGN AND METHODS: We examined 590 participants with diabetes (399 with type 1 diabetes [T1D] and 191 with type 2 diabetes [T2D]) and 204 control patients without diabetes with at least 1 year of follow-up and classified them according to rapid corneal nerve fiber loss (RCNFL) if CNFL change was below the 5th percentile of the control patients without diabetes. RESULTS: Control patients without diabetes were 37.9 ± 19.8 years old, had median follow-up of three visits over 3.0 years, and mean annual change in CNFL was -0.1% (90% CI -5.9% to 5.0%). RCNFL was defined by values exceeding the 5th percentile of 6% loss. Participants with T1D were 39.9 ± 18.7 years old, had median follow-up of three visits over 4.4 years, and mean annual change in CNFL was -0.8% (90% CI -14.0% to 9.9%). Participants with T2D were 60.4 ± 8.2 years old, had median follow-up of three visits over 5.3 years, and mean annual change in CNFL was -0.2% (90% CI -14.1% to 14.3%). RCNFL prevalence was 17% overall and was similar by diabetes type (64 T1D [16.0%], 37 T2D [19.4%], P = 0.31). RNCFL was more common in those with baseline DSP (47% vs. 30% in those without baseline DSP, P = 0.001), which was associated with lower peroneal conduction velocity but not with baseline HbA1c or its change over follow-up. CONCLUSIONS: An abnormally rapid loss of CNFL of 6% per year or more occurs in 17% of diabetes patients. RCNFL may identify patients at highest risk for the development and progression of DSP.
Subject(s)
Cornea/innervation , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 2/diagnosis , Diabetic Neuropathies/diagnosis , Nerve Fibers/pathology , Adolescent , Adult , Aged , Biomarkers/analysis , Case-Control Studies , Cell Count , Cornea/diagnostic imaging , Cornea/pathology , Corneal Diseases/diagnosis , Corneal Diseases/etiology , Corneal Diseases/pathology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Diabetic Neuropathies/pathology , Diabetic Neuropathies/physiopathology , Disease Progression , Female , Follow-Up Studies , Humans , Male , Microscopy, Confocal , Middle Aged , Prognosis , Time Factors , Young AdultABSTRACT
Aims: To investigate the impact of thinning at individual grids of macular neuroretinal layers, clinical factors, and inadequate light exposure on the specific components of sleep disorder in patients with type 2 diabetes. Methods: One hundred twenty-four patients with type 2 diabetes without clinical evidences of diabetic retinopathy and neuropathy (HbA1c: 8.3%, diabetes duration; 8.7 years) and 54 age- and sex-matched control subjects (HbA1c: 5.6%) underwent detailed clinical, neurological, and ophthalmological examinations. The sleep disorder was assessed by the Pittsburgh Sleep Quality Index Japanese Version (PSQI-J). The temporal structures of daily life were assessed by the Munich Chronotype Questionnaire Japanese Version. The thickness at nine grids defined by the Early Treatment Diabetic Retinopathy Study of nine macular neuroretinal layers was determined by swept-source optical coherence tomography and OCT-Explorer. The associations between the individual components of sleep disorders and the thickness at each grid of macular neuroretinal layers, clinical factors, or the temporal structures of daily life were examined. Results: The prevalence of the sleep disorder, global score, and four individual PSQI-J scores in patients with type 2 diabetes were higher than control subjects. The thickness of two and five grids of two inner retinal layers and four to seven grids of four outer retinal layers in patients with type 2 diabetes was thinner than those in control subjects. The thickness at one to eight grids of four outer retinal layers in type 2 diabetic patients was inversely associated with global score and five individual scores of sleep disorder. The thinning at one to two grids of the inner plexiform layer was related to three high individual scores of sleep disorder. The inappropriate light exposure was associated with the sleep disorder and altered macular neuroretinal layers. The high HbA1c and LDL-cholesterol levels were related to the high global score and two individual scores of sleep disorder, respectively. Conclusion: In patients with type 2 diabetes, the thinning at grids of the inner plexiform layer and outer retinal layers was associated with the high scores of specific components of the sleep disorder. The sleep disorder was also related to hyperglycemia, dyslipidemia, and inappropriate light exposure.
Subject(s)
Biomarkers/analysis , Diabetes Mellitus, Type 2/physiopathology , Macula Lutea/pathology , Retina/pathology , Retinal Diseases/complications , Sleep Wake Disorders/etiology , Blood Glucose/analysis , Case-Control Studies , Diabetic Neuropathies , Diabetic Retinopathy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Retinal Diseases/pathology , Sleep Wake Disorders/pathologyABSTRACT
OBJECTIVE: To investigate the impact of normalizing HbA1c by extensive HbA1c control (EHC) on neuropathy outcome measures (NOMs), nephropathy, and retinopathy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Detailed clinical and neurological examinations were performed in two cohorts of 38 patients with uncontrolled type 2 diabetes (HbA1c 9.6% [81.4 mmol/mol]) at baseline and after glycemic control (GC) with or without EHC by diet restriction and hypoglycemic agents over 4 years along with 48 control subjects with normal glucose tolerance (NGT) and 34 subjects with impaired glucose tolerance (IGT) only at baseline. EHC patients, control subjects, and subjects with IGT underwent oral glucose tolerance tests. Glycemic variability (GV) was evaluated by SD and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose. RESULTS: In the EHC cohort, HbA1c levels over 4.3 years and the last 2 years improved to 6.1% (43.2 mmol/mol) and 5.8% (39.9 mmol/mol) with 7.3 kg body wt reduction, and 50% and 28.9% of patients returned to IGT and NGT, respectively, at end point. Baseline neurophysiological and corneal nerve fiber (CNF) measures were impaired in patients. Normalized HbA1c with EHC improved neurophysiological and CNF measures to be similar for those for IGT, while GC without EHC (mean HbA1c level 7.0% [53.5 mmol/mol]) improved only vibration perception. The mean normalized HbA1c levels by EHC determined NOM improvements. The high GV and baseline HbA1c levels compromised NOMs. Albumin excretion rate significantly decreased, while retinopathy severity and frequency insignificantly worsened on EHC. CONCLUSIONS: Normalizing HbA1c in type 2 diabetes of short duration improves microvascular complications including neuropathy and nephropathy more effectively than standard GC but not retinopathy.
Subject(s)
Diabetes Mellitus, Type 2/blood , Diabetic Neuropathies/blood , Adult , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetic Neuropathies/drug therapy , Diabetic Retinopathy/blood , Diabetic Retinopathy/drug therapy , Female , Follow-Up Studies , Glucose Intolerance/blood , Glucose Intolerance/drug therapy , Glucose Tolerance Test , Glycated Hemoglobin/metabolism , Humans , Hyperglycemia/blood , Hyperglycemia/drug therapy , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Prospective StudiesABSTRACT
BACKGROUND: Low foot ulcer risk in South Asian, compared with European, people with type 2 diabetes in the UK has been attributed to their lower levels of neuropathy. We have undertaken a detailed study of corneal nerve morphology and neuropathy risk factors, to establish the basis of preserved small nerve fibre function in South Asians versus Europeans. METHODS: In a cross-sectional, population-based study, age- and sex-matched South Asians (n = 77) and Europeans (n = 78) with type 2 diabetes underwent neuropathy assessment using corneal confocal microscopy, symptoms, signs, quantitative sensory testing, electrophysiology and autonomic function testing. Multivariable linear regression analyses determined factors accounting for ethnic differences in small fibre damage. RESULTS: Corneal nerve fibre length (22.0 ± 7.9 vs. 19.3 ± 6.3 mm/mm2 ; P = 0.037), corneal nerve branch density (geometric mean (range): 60.0 (4.7-246.2) vs. 46.0 (3.1-129.2) no./mm2 ; P = 0.021) and heart rate variability (geometric mean (range): 7.9 (1.4-27.7) vs. 6.5 (1.5-22.0); P = 0.044), were significantly higher in South Asians vs. Europeans. All other neuropathy measures did not differ, except for better sural nerve amplitude in South Asians (geometric mean (range): 10.0 (1.3-43.0) vs. 7.2 (1.0-30.0); P = 0.006). Variables with the greatest impact on attenuating the P value for age- and HbA1C -adjusted ethnic difference in corneal nerve fibre length (P = 0.032) were pack-years smoked (P = 0.13), BMI (P = 0.062) and triglyceride levels (P = 0.062). CONCLUSIONS: South Asians have better preserved small nerve fibre integrity than equivalent Europeans; furthermore, classic, modifiable risk factors for coronary heart disease are the main contributors to these ethnic differences. We suggest that improved autonomic neurogenic control of cutaneous blood flow in Asians may contribute to their protection against foot ulcers.
Subject(s)
Asian People/statistics & numerical data , Diabetes Mellitus, Type 2/ethnology , Diabetic Neuropathies/ethnology , Small Fiber Neuropathy/ethnology , White People/statistics & numerical data , Aged , Asia/ethnology , Case-Control Studies , Cornea/innervation , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Diabetic Foot/epidemiology , Diabetic Foot/ethnology , Diabetic Neuropathies/epidemiology , Female , Foot Ulcer/epidemiology , Foot Ulcer/ethnology , Humans , Male , Middle Aged , Small Fiber Neuropathy/complications , Small Fiber Neuropathy/epidemiology , United Kingdom/epidemiologyABSTRACT
AIMS/HYPOTHESIS: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. METHODS: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. RESULTS: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. CONCLUSIONS/INTERPRETATION: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.