Sodium Glucose Cotransporter-2 Inhibitor Protects Against Diabetic Neuropathy and Nephropathy in Modestly Controlled Type 2 Diabetes: Follow-Up Study.

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.

The Impact of Glycemic Control on Retinal Photoreceptor Layers and Retinal Pigment Epithelium in Patients With Type 2 Diabetes Without Diabetic Retinopathy: A Follow-Up Study.

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.

Improvement in Neuropathy Outcomes With Normalizing HbA1c in Patients With Type 2 Diabetes.

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.

The Preferential Impairment of Pupil Constriction Stimulated by Blue Light in Patients with Type 2 Diabetes without Autonomic Neuropathy.

The main aim of the present paper is to examine whether the pupillary light reflex (PLR) mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) is impaired in type 2 diabetic patients. One hundred and three diabetic patients without diabetic autonomic neuropathy (DAN) and 42 age-matched controls underwent a series of detailed neurological examinations. The patients were stratified into three groups: stage I, no neuropathy; stage II, asymptomatic neuropathy; stage III, symptomatic but without DAN. The PLR to 470 and 635 nm light at 20 cd/m2 was recorded. Small fiber neuropathy was assessed by corneal confocal microscopy and quantifying corneal nerve fiber (CNF) morphology. The 470 nm light induced a stronger and faster PLR than did 635 nm light in all subjects. The PLR to both lights was impaired equally across all of the diabetic subgroups. The postillumination pupil response (PIPR) after 470 nm light offset at ≥1.7 sec was attenuated in diabetic patients without differences between subgroups. Receiver operating characteristic analysis revealed that the PIPR mediated by ipRGCs in patients with stage II and stage III neuropathy was different from that of the control subjects. Clinical factors, nerve conduction velocity, and CNF measures were significantly correlated with PLR parameters with 470 nm light. PLR kinetics were more impaired by stimulation with blue light than with red light in diabetic patients without DAN.

The Expanded Bead Size of Corneal C-Nerve Fibers Visualized by Corneal Confocal Microscopy Is Associated with Slow Conduction Velocity of the Peripheral Nerves in Patients with Type 2 Diabetes Mellitus.

This study aims to establish the corneal nerve fiber (CNF) morphological alterations in a large cohort of type 2 diabetic patients and to investigate the association between the bead size, a novel parameter representing composite of accumulated mitochondria, glycogen particles, and vesicles in CNF, and the neurophysiological dysfunctions of the peripheral nerves. 162 type 2 diabetic patients and 45 healthy control subjects were studied in detail with a battery of clinical and neurological examinations and corneal confocal microscopy. Compared with controls, patients had abnormal CNF parameters. In particular the patients had reduced density and length of CNF and beading frequency and increased bead size. Alterations in CNF parameters were significant even in patients without neuropathy. The HbA1c levels were tightly associated with the bead size, which was inversely related to the motor and sensory nerve conduction velocity (NCV) and to the distal latency period of the median nerve positively. The CNF density and length positively correlated with the NCV and amplitude. The hyperglycemia-induced expansion of beads in CNF might be a predictor of slow NCV in peripheral nerves in type 2 diabetic patients.

Elasticity of the tibial nerve assessed by sonoelastography was reduced before the development of neuropathy and further deterioration associated with the severity of neuropathy in patients with type 2 diabetes.

AIMS/INTRODUCTION: To measure the elasticity of the tibial nerve using sonoelastography, and to associate it with diabetic neuropathy severity, the cross-sectional area of the tibial nerve and neurophysiological findings in type 2 diabetic patients. MATERIALS AND METHODS: The elasticity of the tibial nerve was measured as the tibial nerve:acoustic coupler strain ratio using high-resolution ultrasonography in 198 type 2 diabetic patients stratified into subgroups by neuropathy severity, and 29 control participants whose age and sex did not differ from the diabetic subgroups. RESULTS: The elasticity of the tibial nerve in patients without neuropathy (P < 0.001) was reduced compared with controls (0.76 ± 0.023), further decreasing (0.655 ± 0.014 to 0.414 ± 0.018) after developing neuropathy. The cut-off value of elasticity of the tibial nerve that suggested the presence of neuropathy was 0.558. The area under the curve (0.829) was greater than that for the cross-sectional area (0.612). The cross-sectional area of the tibial nerve in diabetic patients without neuropathy (6.11 ± 0.13 mm(2)) was larger than that in controls (4.84 ± 0.16 mm(2)), and increased relative to neuropathy severity (P < 0.0001). The elasticity of the tibial nerve was negatively associated with neuropathy severity (P < 0.0001), cross-sectional area (P = 0.002) and 2000 Hz current perception threshold (P = 0.011), and positively associated with nerve conduction velocities (P < 0.0001). CONCLUSIONS: Determining the elasticity of the tibial nerve in type 2 diabetic patients could reveal early biomechanical changes that were likely caused by thickened fibrous sheaths of peripheral nerves, and might be a novel tool for characterizing diabetic neuropathy.

Morphological changes of the peripheral nerves evaluated by high-resolution ultrasonography are associated with the severity of diabetic neuropathy, but not corneal nerve fiber pathology in patients with type 2 diabetes.

AIMS/INTRODUCTION: To evaluate the morphological changes of the median and posterior tibial nerve using high-resolution ultrasonography, and the corneal C fiber pathology by corneal confocal microscopy in type 2 diabetic patients. MATERIALS AND METHODS: The cross-sectional area, hypoechoic area and maximum thickness of the nerve fascicle of both nerves were measured by high-resolution ultrasonography in 200 type 2 diabetic patients, stratified by the severity of diabetic neuropathy, and in 40 age- and sex-matched controls. These parameters were associated with corneal C fiber pathology visualized by corneal confocal microscopy, neurophysiological tests and severity of diabetic neuropathy. RESULTS: The cross-sectional area, hypoechoic area and maximum thickness of the nerve fascicle of both nerves in patients without diabetic neuropathy were larger than those in control subjects (P < 0.05 to P < 0.001), and further increased relative to the severity of neuropathy (P < 0.0001). All morphological changes of both nerves were negatively associated with motor and sensory nerve conduction velocity (P = 0.01 to P < 0.0001), and directly associated with 2,000-Hz current perception threshold (P = 0.009 to P < 0.001). The significant corneal C fiber pathology occurred before developing the neuropathy, and deteriorated only in patients with the most severe neuropathy. The association between the morphological changes of both nerves and corneal C fiber pathology was poor. CONCLUSIONS: The morphological changes in peripheral nerves of type 2 diabetic patients were found before the onset of neuropathy, and were closely correlated with the severity of diabetic neuropathy, but not with corneal C fiber pathology.

Correlation between sudomotor function, sweat gland duct size and corneal nerve fiber pathology in patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: To study the correlation between sudomotor function, sweat gland duct size and corneal nerve fiber pathology in type 2 diabetes. MATERIALS AND METHODS: Sudomotor function was quantified by Neuropad test, and sweat gland duct and corneal nerve fibers were visualized by confocal microscopy in 78 patients with type 2 diabetes stratified by diabetic neuropathy and 28 control participants. RESULTS: In patients with diabetic neuropathy, sudomotor function, as judged by the time required for complete color change of a Neuropad, was impaired compared with that of controls (P < 0.0001), thereby showing deterioration was related to the severity of diabetic neuropathy (P < 0.0001). Sweat gland ducts were smaller in patients without neuropathy than in controls (P < 0.0001), and further shrinking was seen in patients with severe diabetic neuropathy (P < 0.05). Patients without diabetic neuropathy showed reduced density and length (P < 0.001) of corneal nerve fibers and beading frequency (P < 0.0001), and increased tortuosity (P < 0.0001) compared with controls, and these changes deteriorated in patients with severe diabetic neuropathy. Sudomotor function was negatively associated with corneal nerve fibers (P < 0.002) and branches (P < 0.01), and influenced by the severity of diabetic neuropathy (P < 0.0001); sweat gland duct size correlated with serum triglycerides (P < 0.02), uric acid (P < 0.01), corneal nerve branch (P < 0.03), sudomotor function (P < 0.03) and severity of neuropathy (P < 0.03). CONCLUSIONS: Type 2 diabetic patients had sudomotor dysfunction and smaller sweat gland ducts compared with controls. The stage of diabetic neuropathy and corneal nerve fiber pathology were independent predictors of sudomotor dysfunction, and serum triglycerides, uric acid, corneal nerve branch, stage of diabetic neuropathy and sudomotor function were predictors of sweat gland duct size.

Morphometric features of corneal epithelial basal cells, and their relationship with corneal nerve pathology and clinical factors in patients with type 2 diabetes.

AIMS/INTRODUCTION: We compared the morphometric features of corneal epithelial basal cells between patients with type 2 diabetes mellitus and healthy controls, and analyzed the relationship of these features with corneal nerve fiber pathology and clinical factors in the patients. MATERIALS AND METHODS: Corneal epithelial basal cells and corneal nerve fibers were visualized by corneal confocal microscopy in 75 patients with type 2 diabetes and 42 age-matched controls. Density, area and area variability of corneal epithelial basal cells, as well as the width of the intercellular space between neighboring cells, were evaluated for both groups. RESULTS: Patients showed decreased density (P < 0.02) and area (P < 0.0001), larger area variability (P < 0.0001) and a wider intercellular space (P < 0.0001) compared with controls. Density correlated inversely with area (P < 0.0001), width of intercellular space (P < 0.03) and beading frequency (P < 0.03), whereas it correlated directly with prothrombin time (P < 0.002) and activated partial thromboplastin time (P < 0.03). Area correlated inversely with duration of diabetes (P < 0.05) and coefficient of variation of area (P < 0.01), whereas it correlated directly with beading frequency (P < 0.05). Area variability correlated inversely with area (P < 0.01) and prothrombin time (P < 0.01), whereas it correlated directly with fibrinogen level (P < 0.0001). CONCLUSIONS: Type 2 diabetes induces morphometric changes in corneal epithelial basal cells; this seems to be related to the morbid period of diabetes, beading frequency of corneal nerve fibers and blood coagulation state.

Corneal nerve fiber pathology in Japanese type 1 diabetic patients and its correlation with antecedent glycemic control and blood pressure.

UNLABELLED: Aims/Introduction: Morphological changes to corneal C-fibers in Japanese type 1 diabetic patients were visualized by corneal confocal microscopy (CCM). The effects of prior glycemic control and blood pressure on morphological parameters were clarified. MATERIALS AND METHODS: Corneal nerve fibers were visualized by CCM in 38 Japanese type 1 diabetic patients (14 with and 24 without neuropathy) and 38 controls. Morphological parameters were compared and related to annual mean HbA1c, blood pressure, and serum lipid levels of previous years prior to CCM examination. RESULTS: Compared with controls, diabetic patients had reduced corneal nerve fiber length (CNFL; 9.80 ± 0.38 vs 13.65 ± 0.88 mm/mm(2); P < 0.001), reduced density (CNFD; 25.32 ± 1.04 vs 36.62 ± 2.37/mm(2); P < 0.0005), lower frequency of beading (22.38 ± 0.73 vs 30.44 ± 1.03/0.1 mm; P < 0.0001), and increased tortuosity (3.13 ± 0.09 vs 1.74 ± 0.06; P < 0.0001). These changes were found in patients without neuropathy. There was no difference in nerve branches between controls and diabetic patients. The mean annual HbA1c level for the 7-10 years prior to CCM examination was an independent predictor of reduced CNFL and CNFD; HbA1c levels obtained 1-3 months and 1 year prior to CCM, as well as blood pressure 3, 5, and 6 years prior to CCM, were independent predictors of reduced beading frequency. CONCLUSIONS: Corneal confocal microscopy is a novel, noninvasive technique to evaluate morphological changes of corneal C-fibers in type 1 diabetes. Antecedent hyperglycemia and blood pressure have different time-dependent effects on CNFL and CNFD and the frequency of beading. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00157.x, 2011).