Treatment-naive Type Research Articles

Profiles of Peripheral Neuropathy and Risk Factors in People With Treatment-Naive Type 2 Diabetes Mellitus and Prediabetes

Profiles of Peripheral Neuropathy and Risk Factors in People With Treatment-Naive Type 2 Diabetes Mellitus and Prediabetes

The "triple-layer sign": an optical coherence tomography signature for the detection of non-exudative macular neovascularization.

To assess the sensitivity and specificity of the "triple layer sign" (TLS) (retinal pigment epithelium (RPE), neovascular tissue, and Bruch's membrane) on structural optical coherence tomography (OCT) images for the diagnosis of treatment-naïve non-exudative type-1 macular neovascularization (NE-MNV) in age-related macular degeneration (AMD). Cross-sectional study. Two masked retinal experts evaluated the presence of the TLS in eyes with NE-MNV and controls with an RPE elevation without exudation due to other causes than NE-MNV in AMD [e.g., medium-large drusen, cuticular drusen, basal laminar deposits (BlamD)]. 130 eyes of 98 consecutive patients met the study criteria; 40 eyes of 40 patients satisfied the criteria for being included in the NE-MNV secondary to AMD group (27 females, 13 males, with a mean age of 73.8 ± 8.0years), and 90 eyes of 58 patients met the criteria to be included in the control group (31 eyes were included in the medium-to-large drusen sub-group, 32 eyes in the cuticular drusen sub-group, and 27 eyes in the BlamD group. The TLS was observed in 39/40 patients with NE-MNV and 8/90 controls. The sensitivity and specificity of the TLS for the diagnosis of NE-MNV were 97% and 91%, respectively. The TLS on OCT demonstrated high sensitivity and specificity values in detecting treatment-naive type 1 NE-MNV.

Corneal topography and higher-order aberrations in patients with type 2 diabetes mellitus

Background: Changes in blood sugar levels cause alterations in the anterior segment and retina of the eye. This study was aimed at evaluating corneal topography, aberrometry, and corneal asphericity in patients with treatment-naive type 2 diabetes mellitus (T2DM).
 Methods: Participants with treatment-naive T2DM were enrolled in this cross-sectional study. The inclusion criteria were glycated hemoglobin A1c (Hb A1c) greater than or equal to 7.5% and absence of other ocular or systemic diseases. Patients who refused to participate or had a history of topical or systemic steroid use, hyperlipidemia, hypertension, anemia, prior ocular disorder or surgery, diabetic retinopathy, glaucoma, cataract, active ocular inflammatory or infectious disease, or contact lens use were excluded. All participants underwent a comprehensive ophthalmic examination. The Pentacam HR Scheimpflug tomography system (Pentacam High Resolution; Oculus, Wetzlar, Germany) was used to measure the anterior-segment parameters.
 Results: Sixty eyes of 30 patients with a male-to-female ratio of 1:1 were included; the mean (standard deviation [SD]) age and Hb A1c were 51.63 (6.73) years and 8.82% (1.31%), respectively. The mean (SD) values of central corneal thickness, root mean square (RMS) of total aberration, RMS of lower-order aberrations, RMS of higher-order aberrations, spherical aberration, 0° coma, 90° coma, flat anterior keratometry (K), steep anterior K, mean anterior K, anterior topographic astigmatism, flat posterior K, steep posterior K, mean posterior K, posterior topographic astigmatism, anterior corneal asphericity, and posterior corneal asphericity were 540.22 (24.47) µm, 1.72 (0.73) µm, 1.63 (0.73) µm, 0.51 (0.17) µm, + 0.31 (0.09) µm, - 0.06 (0.15) diopters (D), 0.003 (0.21) D, 43.87 (1.49) D, 44.69 (1.50) D, 44.28 (1.44) D, + 0.82 (0.83) D, - 6.25 (0.27) D, - 6.55 (0.31) D, - 6.40 (0.28) D, - 0.30 (0.15) D, - 0.32 (0.12) Q-value, and - 0.47 (0.17) Q-value, respectively.
 Conclusions: We presented the mean values of Pentacam parameters for aberrometry, keratometry, and corneal asphericity in patients with treatment-naive T2DM. These values could serve as a baseline for prospective monitoring of the ocular health status of this cohort and for comparison with future cohorts of patients with well-controlled T2DM. Further studies are required to assess the presence and applicability of ocular changes following intensive blood glucose control in T2DM and further understand the related pathophysiology.

Association of SLC22A1, SLC22A2, SLC47A1, and SLC47A2 Polymorphisms with Metformin Efficacy in Type 2 Diabetic Patients.

Response to metformin, first-line therapy for type 2 diabetes mellitus (T2DM), exists interindividual variation. Considering that transporters belonging to the solute carrier (SLC) superfamily are determinants of metformin pharmacokinetics, we evaluated the effects of promoter variants in organic cation transporter 1 (OCT1) (SLC22A1 rs628031), OCT2 (SLC22A2 rs316019), multidrug and toxin extrusion protein 1 (MATE1) (SLC47A1 rs2289669), and MATE2 (SLC47A2 rs12943590) on the variation in metformin response. The glucose-lowering effects and improvement of insulin resistance of metformin were assessed in newly diagnosed, treatment-naive type 2 diabetic patients of Han nationality in Chaoshan China (n = 93) receiving metformin. Fasting plasma glucose (FPG), fasting insulin (FINS), glycated hemoglobin A1 (HbA1C), homeostasis model assessment-insulin sensitivity (HOMA-IS), and homeostasis model assessment-insulin resistance (HOMA-IR) were the main metformin efficacy measurements. There were significant correlations between both SLC47A1 rs2289669 and SLC47A2 rs12943590 and the efficacy of metformin in individuals with T2DM. In normal weight T2DM patients, significant associations between the AA and GG genotypes of the rs2289669 variant of SLC47A1 and a greater reduction in FINS and HOMA-IR were detected. A significant correlation was observed between the AG genotype of the rs12943590 polymorphism of SLC47A2 and a greater reduction in HOMA-IR. Gene–environment interaction analysis showed that in the FINS interaction model, the second-order of dose30_g-SLC47A2 rs12943590 was statistically significant. The variants of SLC47A1 rs2289669 and SLC47A2 rs12943590 could be predictors of insulin resistance in type 2 diabetic patients treated with metformin. The second-order interaction of dose30_g-SLC47A2 rs12943590 may have a significant effect on FINS in patients with T2DM on metformin treatment. These findings suggest that promoter variants of SLC47A1 and SLC47A2 are important determinants of metformin transport and response in type 2 diabetes mellitus.

Metagenomic analysis reveals crosstalk between gut microbiota and glucose-lowering drugs targeting the gastrointestinal tract in Chinese patients with type 2 diabetes: a 6 month, two-arm randomised trial

Aims/hypothesisThe use of oral glucose-lowering drugs, particularly those designed to target the gut ecosystem, is often observed in association with altered gut microbial composition or functional capacity in individuals with type 2 diabetes. The gut microbiota, in turn, plays crucial roles in the modulation of drug efficacy. We aimed to assess the impacts of acarbose and vildagliptin on human gut microbiota and the relationships between pre-treatment gut microbiota and therapeutic responses.MethodsThis was a randomised, open-labelled, two-arm trial in treatment-naive type 2 diabetes patients conducted in Beijing between December 2016 and December 2017. One hundred participants with overweight/obesity and newly diagnosed type 2 diabetes were recruited from the Pinggu Hospital and randomly assigned to the acarbose (n=50) or vildagliptin (n=50) group using sealed envelopes. The treatment period was 6 months. Blood, faecal samples and visceral fat data from computed tomography images were collected before and after treatments to measure therapeutic outcomes and gut microbiota. Metagenomic datasets from a previous type 2 diabetes cohort receiving acarbose or glipizide for 3 months were downloaded and processed. Statistical analyses were applied to identify the treatment-related changes in clinical variables, gut microbiota and associations.ResultsNinety-two participants were analysed. After 6 months of acarbose (n=44) or vildagliptin (n=48) monotherapy, both groups achieved significant reductions in HbA1c (from 60 to 46 mmol/mol [from 7.65% to 6.40%] in the acarbose group and from 59 to 44 mmol/mol [from 7.55% to 6.20%] in the vildagliptin group) and visceral fat areas (all adjusted p values for pre–post comparisons <0.05). Both arms showed drug-specific and shared changes in relative abundances of multiple gut microbial species and pathways, especially the common reductions in Bacteroidetes species. Three months and 6 months of acarbose-induced changes in microbial composition were highly similar in type 2 diabetes patients from the two independent studies. Vildagliptin treatment significantly enhanced fasting active glucagon-like peptide-1 (GLP-1) levels. Baseline gut microbiota, rather than baseline GLP-1 levels, were strongly associated with GLP-1 response to vildagliptin, and to a lesser extent with GLP-1 response to acarbose.Conclusions/interpretationThis study reveals common microbial responses in type 2 diabetes patients treated with two glucose-lowering drugs targeting the gut differently and acceptable performance of baseline gut microbiota in classifying individuals with different GLP-1 responses to vildagliptin. Our findings highlight bidirectional interactions between gut microbiota and glucose-lowering drugs.Trial registrationClinicalTrials.gov NCT02999841FundingNational Key Research and Development Project: 2016YFC1304901.Graphical abstract

Longitudinal assessment of type 3 macular neovascularization using 3D volume-rendering OCTA

ObjectiveTo investigate the evolution of treatment-naive type 3 macular neovascularization (MNV) undergoing anti-vascular endothelial growth factor (VEGF) treatment through volume rendered three-dimensional (3D) optical coherence tomography angiography (OCTA). DesignRetrospective observational study. ParticipantsPatients with type 3 MNV and age-related macular degeneration (AMD). MethodsIncluded subjects had three loading injections of an anti-VEGF agent. The OCTA volume data at baseline and follow-up were processed with a previously published algorithm in order to obtain a volume-rendered representation of type 3 MNV. Progressive changes in type 3 lesions were analyzed via 3D OCTA volume rendering. ResultsA total of 14 treatment-naive eyes with type 3 MNV from 11 AMD patients (7 females) were included. At both baseline and follow-up visits, a type 3 MNV complex was identifiable. Each complex was composed of a mean number of 2.5 ± 0.7 vascular branches at baseline and 1.4 ± 0.6 at the follow-up visit (p < 0.0001). The mean changes in central macular thickness and visual acuity were significantly correlated with modifications in the number of type 3 MNV branches (ρ = –0.533, p = 0.049, and ρ = –0.581, and p = 0.040, respectively). ConclusionsThis study demonstrated that type 3 lesions do not disappear completely after loading treatment, as indicated previously by histopathologic studies. Importantly, quantitative volume changes in type 3 lesions are directly associated with treatment response.

Imaging Biomarkers of 1-Year Activity in Type 1 Macular Neovascularization.

PurposeThe purpose of this study was to evaluate the predictive value of optical coherence tomography (OCT) and OCT angiography (OCTA) parameters at baseline on lesion's activity at the 1-year follow-up in type 1 macular neovascularizations (MNVs) treated with 1-year fixed regimen of intravitreal aflibercept injections (q8 IAIs).MethodsAll patients were imaged by structural OCT to evaluate central macular thickness (CMT), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), intraretinal fluid (IRF) and intraretinal hyper-reflective dots (HRDs), and by Swept-Source OCTA to measure baseline MNV area, perfusion density (PD), vessel length density (VLD), and vessel diameter index. At the end of q8 IAI, patients were classified in two groups: active-MNV (A-MNV) and inactive-MNV (I-MNV), considering the OCT signs of activity. Three binary logistic regression models were developed: (1) OCT-based, (2) OCTA-based, and (3) OCT/OCTA-based model.ResultsThirty-one treatment-naïve type 1 MNVs were enrolled (13 A-MNV and 18 I-MNV). No differences were observed in baseline OCT and OCTA characteristics between A-MNV and I-MNV. Among the models developed, model 3 that combined OCT/OCTA parameters showed a performance of 87.5% and excellent sensitivity for A-MNV lesions (100%). By analyzing the model, the A-MNV group appears more likely to show at baseline SRF, greater CMT, wider MNV area, and lower PD and VLD compared to I-MNV.ConclusionsOur study demonstrated that the combination of baseline OCT and OCTA parameters allowed to achieve a good models’ performance in the prediction of MNV activity permitting to correctly classifying the active lesions at the end of follow-up period, with excellent sensitivity.Translational RelevanceOCT/OCTA could integrate statistical models potentially useful for artificial intelligence.

Alpha and Beta Cell Dysfunction Improves With Effective Insulin Therapy in Treatment Naive Type 2 Diabetes - a Prospective Observational Study

: Type 2 diabetes mellitus is characterized by insulin resistance and progressive beta cell decline. Elevated glucagon levels and impaired incretin axis also contribute to the poor glycemic status. Early intensive glycemic control, reduces long-term vascular complications and may preserve β-cell function. Clinical studies of effect of early insulin therapy on combined alpha and beta cell function are lacking. Objective: To determine the effect of early insulin therapy on combined alpha and beta cell dysfunction (islet cell dysfunction) in newly diagnosed type 2 diabetes. Methods: 56 newly diagnosed type 2 diabetes patients, attending the endocrinology OPD at a tertiary teaching hospital were enrolled in this treatment related follow up study after institutional ethical committee clearance, conducted between May 2017 to December 2018. Patients with HbA1C > 8.5% to <12.5% (n=56) were included in the study. Metabolic (FPG, PPG, HbA1c), and Hormonal parameters (plasma glucagon levels,fasting and 2 hour mixed meal stimulated C peptide and levels) were assessed both at baseline and after 6 months of insulin treatment. Initiating dose of insulin was 0.5 U/kg/day and the dose was titrated according to FPG and 2 hr PPG in order to maintain glycemic goals as per ADA standards. Results: The study included 56 subjects with mean age of 41.24 ± 5.64 years and a mean BMI of 25.5 kg/m2. At the end of 6 months of the study, a significant reduction in the mean FPG, PPG, HbA1C were observed,[FPG (139±14.47 mg/dl), PPG (179.89 ± 19.42mg/dl),HbA1c (7.54± 0.63%)] as compared to baseline mean FPG, (216.30 ± 42.35 mg/dl),2 hour PPG (338.44 ±62.89 mg/dl), HbA1C (10.39 ± 1.56 %) (p <0.001). Baseline glucagon levels were high (197.68± 49.09 pg/ml), and were significantly reduced at 6 months of insulin therapy (107.06±49.09 pg/ml).(p <0.001). In comparison to the baseline a significant increase in both fasting (0.73±0.27 ng/ml) and stimulated c-peptide (1.54±1.02 ng/ml) (p<0.001) levels was observed at end of the study. Conclusion: Combined alpha and beta cell (Islet) dysfunction prevails in newly diagnosed T2DM. And early insulin therapy significantly improves both these defects. The documentation of this novel beneficial effect on islet cell dysfunction in our study strengthens the concept of early insulin therapy in newly diagnosed Type 2 diabetes patients.

A salivary microbiome-based auxiliary diagnostic model for type 2 diabetes mellitus

ObjectiveStudies have shown that oral microbiota composition is altered in type 2 diabetes mellitus, implying that it is a potential biomarker for diabetes. This study aimed at constructing a noninvasive auxiliary diagnostic model for diabetes based on differences in the salivary microbial community. DesignSalivary microbiota from 24 treatment-naive type 2 diabetes mellitus patients and 21 healthy populations were detected through 16S rRNA gene sequencing, targeting the V3/V4 region using the MiSeq platform. Salivary microbiome diversity and composition were analyzed so as to establish a diagnostic model for type 2 diabetes. ResultsSalivary microbiome for treatment-naive type 2 diabetes mellitus patients was imbalanced with certain taxa, including Slackia, Mitsuokella, Abiotrophia, and Parascardovia that being significantly dominant, while the abundance of Moraxella was high in healthy controls. Diabetic patients exhibited varying levels of Prevotella nanceiensis and Prevotella melaninogenica which were negatively correlated with glycosylated hemoglobin and fasting blood glucose levels, as well as fasting blood glucose levels, respectively. Based on differences in salivary microbiome composition between diabetic and healthy groups, we developed a diagnostic model that can be used for the auxiliary diagnosis of type 2 diabetes mellitus with an accuracy of 80 %. ConclusionsThese findings elucidate on the differences in salivary microbiome compositions between type 2 diabetic and non-diabetic populations, and the diagnostic model provides a promising approach for the noninvasive auxiliary diagnosis of diabetes mellitus.

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study

Aims/hypothesisGlucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes.MethodsIn this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 μg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug.ResultsWe randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 μg, 150 μg and 200 μg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were −7.76 mmol/mol (95% CI −9.23, −4.63, p < 0.001) (−0.72%, 95% CI −1.01, −0.43), −12.89 mmol/mol (95% CI −16.05, −9.72, p < 0.001) (−1.18%, 95% CI −1.47, −0.89) and −11.14 mmol/mol (95% CI −14.19, −7.97, p <0 .001) (−1.02%, 95% CI −1.30, −0.73) in the 75 μg, 150 μg and 200 μg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death.Conclusions/interpretationAll tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes.Trial registrationClinicalTrials.gov NCT03520972FundingThe study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.Graphical abstract

Obstructive Sleep Apnea, Glucose Tolerance, and β-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study

Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models. Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or β-cell responses. In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.

Intra- and Intergrader Agreement for Detection of OCT Angiographic Characteristics Associated With Type 3 Neovascularization.

PurposeTo examine the intra- and intergrader agreement on morphologic characteristics of type 3 neovascularization on optical coherence tomography angiography (OCT-A).MethodsOCT-A images of 22 eyes from 21 patients with a new-onset, treatment-naive type 3 neovascularization were included in this cross-sectional retrospective agreement study. Each image was graded three times by two independent medical retina specialists to assess intra- and intergrader agreement. The graders scored the presence or absence of the following vascular and structural features: intraretinal neovascularization (IRN), subretinal neovascularization, sub-retinal pigment epithelium (RPE) neovascularization (SRPEN), retinal choroidal anastomosis (RCA), intraretinal cysts, subretinal fluid, and pigment epithelial detachment. Agreement was analyzed for each feature using Gwet's AC1, к statistics, and percentage of agreement.ResultsThe best agreement (AC1) was found for intraretinal neovascularization (withingrader1: 0.94; withingrader2: 0.93 and between: 1.00) and intraretinal cysts (withingrader1, 1.00; withingrader2, 0.97 and between, 1.00). The poorest intragrader agreements were observed for SRPEN (withingrader1, 0.54 and withingrader2, 0.36) and RCA (withingrader1, 0.45 and withingrader2, 0.52), and the poorest intergrader agreement was found for SRPEN, RCA, and pigment epithelial detachment (0.18, 0.37, and 0.15, respectively).ConclusionsAlthough the agreement values were high for intraretinal features, considerable grader variability was found for the vascular and structural features in the deeper retina or under the RPE. Clinicians should be careful to base therapeutic decisions on qualitative OCT-A assessment, because even well-trained specialists show a considerable grader variation in their subjective evaluation.Translational RelevanceThe clinical value of OCT-A imaging largely depends on the agreement of subjective evaluations by ophthalmologists.

Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes.

The Restoring Insulin Secretion (RISE) Adult Medication Study compared pharmacological approaches targeted to improve β-cell function in individuals with impaired glucose tolerance (IGT) or treatment-naive type 2 diabetes of <12 months duration. A total of 267 adults with IGT (n = 197, 74%) or recently diagnosed type 2 diabetes (n = 70, 26%) were studied. Participants were randomized to receive 12 months of metformin alone, 3 months of insulin glargine with a target fasting glucose <5 mmol/L followed by 9 months of metformin, 12 months of liraglutide combined with metformin, or 12 months of placebo. β-Cell function was assessed using hyperglycemic clamps at baseline, 12 months (on treatment), and 15 months (3 months off treatment). The primary outcome was β-cell function at 15 months compared with baseline. All three active treatments produced on-treatment reductions in weight and improvements in HbA1c compared with placebo; the greatest reductions were seen in the liraglutide plus metformin group. At 12 months, glucose-stimulated C-peptide responses improved in the three active treatment groups and were greatest in the liraglutide plus metformin group, but the arginine-stimulated incremental C-peptide response was reduced in the liraglutide plus metformin group. Despite on-treatment benefits, 3 months after treatment withdrawal there were no sustained improvements in β-cell function in any treatment group. In adults with IGT or recently diagnosed type 2 diabetes, interventions that improved β-cell function during active treatment failed to produce persistent benefits after treatment withdrawal. These observations suggest that continued intervention may be required to alter the progressive β-cell dysfunction in IGT or early type 2 diabetes.

One-Year Results of Fixed Aflibercept Treatment Regime in Type 3 Neovascularization

Purpose: To evaluate the effect of intravitreal aflibercept injections in treatment-naive type 3 neovascularization using a fixed treatment regime during the first year of therapy. Methods: Fourteen eyes of 14 patients diagnosed with type 3 neovascularization were studied. All patients were treated with intravitreal aflibercept injections using a fixed treatment regime of 3 consecutive monthly dosages followed by 2-month interval injections. Results were assessed after a 12-month follow-up period. Changes of best corrected visual acuity (BCVA), central retinal thickness (CRT), central macular volume (CMV), and retinal pigment epithelium (RPE) atrophy at fundus autofluorescence and infrared reflectance images were recorded and analyzed. Results: BCVA improved from 60.3 ± 11.7 ETDRS letters at the baseline to 70.9 ± 10.3 ETDRS letters at 12-months follow-up (p = 0.036). Also, CRT and CMV statistically improved after the treatment (from 425 ± 117 to 308 ± 117 µm [p = 0.031] and from 9.52 ± 1.90 to 8.29 ± 0.95 mm³ [p = 0.073], respectively). In 4 patients, development and progression of RPE atrophy were observed, and it was associated with the presence of serous pigment epithelium detachment at the baseline. Furthermore, the development of a fibrotic lesion eccentric to the fovea was observed in 5 patients, without significant impairment of BCVA (p = 0.290). Conclusion: Intravitreal aflibercept administered in a fixed treatment regime during the first year of therapy may be effective for the improvement and stabilization of BCVA in eyes with type 3 neovascularization. However, RPE atrophy and subretinal/intraretinal fibrosis can develop during the treatment.

Comparison of endothelial function and sympathetic nervous system activity along the glucose continuum in individuals with differing metabolic risk profiles and low dietary sodium intake

Objective: Low sodium intake may trigger sympathetic nervous system (SNS) activation and endothelial dysfunction. Studies have not explored these associations along the glucose continuum. Accordingly, we compared endothelial function and...

Implication of critical pharmacokinetic gene variants on therapeutic response to metformin in Type 2 diabetes.

Metformin, an oral hypoglycemic drug is the first line of treatment for Type 2 diabetes individuals. We studied the effect of critical gene single nucleotide polymorphisms on the glucose lowering effect of metformin. We performed a prospective study on 221 newly diagnosed, treatment-naive Type 2 diabetes subjects. Individuals were started with metformin monotherapy and followed up for 12 weeks. Our association analysis revealed that SLC22A2 rs316019 and SLC47A2 rs12943590 were significantly associated with metformin drug response across co-dominant and dominant models, respectively. SLC22A2 rs316019 GG and SLC47A2 rs12943590 GA combined genotypes showed maximum average change in HbA1c level. The present study proposes a role of SLC22A2 rs316019 and SLC47A2 rs12943590 in the pharmacokinetic action of metformin.

Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY CHANGES IN EARLY TYPE 3 NEOVASCULARIZATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT.

To investigate the morphologic changes on optical coherence tomography angiography (OCTA) of treatment-naive Type 3 neovascularization secondary to exudative age-related macular degeneration after 1 year of anti-vascular endothelial growth factor therapy. Consecutive patients diagnosed with treatment-naive early-stage Type 3 neovascularization were enrolled in this retrospective study. All patients underwent color fundus photographs/MultiColor (Heidelberg Engineering) imaging, fluorescein angiography, indocyanine green angiography, structural spectral domain OCT, and OCTA Optovue RTVue XR Avanti (Optovue) at baseline, and repeated OCTA and structural spectral domain OCT at Month 12. Qualitative analysis of the 3 × 3 OCTA examinations at baseline and Month 12 was then compared, to assess changes after anti-vascular endothelial growth factor therapy. A total of 15 treatment-naive eyes of 15 consecutive patients were included in the analysis. At 12-month follow-up after pro-re-data anti-vascular endothelial growth factor therapy (5.75 ± 1.48 injections of ranibizumab, and injections of 6.33 ± 1.21 of aflibercept), OCTA demonstrated persistence of the deep capillary plexus abnormalities in 13/15 eyes. In the outer retina and choriocapillaris, the initial lesion became undetectable in 7/15 cases, accompanied by choriocapillaris atrophy. The abnormal vascular complex persisted in the form of a tuft-shaped lesion in the outer retinal segmentation in 9/15 eyes, which in the choriocapillaris segmentation was associated with sub-retinal pigment epithelium neovascularization in 8 cases. Optical coherence tomography angiography showed that the tuft-shaped abnormal outer retinal lesion, frequently associated with a small clew-like flow signal in the choriocapillaris, after 1 year of anti-vascular endothelial growth factor therapy, either becomes undetectable or develops sub-retinal pigment epithelium neovascularization.

Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug.

Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.

Effect of Saxagliptin on Circulating Endothelial Progenitor Cells and Endothelial Function in Newly Diagnosed Type 2 Diabetic Patients.

Endothelial dysfunction is associated with the risk of cardiovascular complications in diabetic patients. Endothelial progenitor cells (EPCs) and flow-mediated dilation (FMD) are common markers of endothelial function. In this study, we aim to investigate whether the DPP-4 inhibitor saxagliptin modulate EPCs number and FMD in newly diagnosed, treatment-naive type 2 diabetic patients. This was a controlled, randomized, open-label clinical trial. Saxagliptin group and metformin group consumed either saxagliptin 5 mg per day or metformin 1 500 mg per day respectively for 12 weeks. Changes of FMD and EPCs number after 12-week intervention were the primary endpoints. 31 patients were initially enrolled and randomized to saxagliptin group (n=16) and metformin group (n=15). 27 patients completed the trial (saxagliptin group n=14 and metformin group n=13), and 4 patients dropped out during the study. FMD and EPCs number increased significantly in both saxagliptin group and metformin group, and there was no significant difference between groups. 2-h postprandial plasma glucose, HbA1c and diastolic blood pressure improved significantly in both groups, and there was no significant difference between groups. Saxagliptin and metformin had comparable beneficial effects on endothelial function.