Care, control and complications of hospitalised patients with type 1 diabetes in China: A nationwide-based registry study.

AIMS: To evaluate the status quo of type 1 diabetes (T1D) management and characteristics of hospitalised patients with T1D in China through a nationwide multicentre registry study, the China Diabetes Type 1 Study (CD1S). MATERIALS AND METHODS: Clinical data from the electronic hospital records of all people with T1D were retrospectively collected in 13 tertiary hospitals across 7 regions of China from January 2016 to December 2021. Patients were defined as newly diagnosed who received a diagnosis of diabetes for less than 3 months. RESULTS: Among the 4993 people with T1D, the median age (range) at diagnosis was 23.0 (1.0-87.0) years and the median disease duration was 2.0 years. The median haemoglobin A1c (HbA1c) level was 10.7%. The prevalence of obesity, overweight, dyslipidemia, and hypertension were 2.5%, 10.8%, 62.5% and 25.9%, respectively. The incidence rate of diabetic ketoacidosis at disease onset was 41.1%, with the highest in children <10 years of age (50.6%). In patients not newly diagnosed, 60.7% were diagnosed with at least one chronic diabetic complication, with the highest proportion (45.3%) of diabetic peripheral neuropathy. Chronic complications were detected in 79.2% of people with T1D duration ≥10 years. CONCLUSIONS: In the most recent years, there were still unsatisfactory metabolic control and high incidence of diabetic ketoacidosis as well as chronic diabetic complications among inpatients with T1D in China. The ongoing CD1S prospective study aims to improve the quality of T1D management nationally.

Efficacy and safety of basal-bolus insulin at 1:1.5 ratio compared to 1:1 ratio using a weight-based initiation and titration (WIT2) algorithm in hospitalized patients with type 2 Diabetes: a multicenter, randomized, clinical study.

BACKGROUND: Most studies initiated basal-bolus insulin in a ratio of 1:1 and titrated based on glucose. This study aimed to investigate the effectiveness and safety of a weight-based and ratio of 1:1.5 basal-bolus insulin using an algorithm for both initiation and titration in hospitalized patients with type 2 diabetes (T2D). METHODS: Hospitalized patients with T2D were randomly assigned to two groups in equal numbers to receive 1:1.5 and 1:1 ratios of basal-bolus insulin using a weight-based algorithm for both initiation and titration. The primary outcome was the time taken to reach the fasting blood glucose (FBG) target and 2-h postprandial blood glucose (2hBG) targets after three meals. The secondary outcome included insulin dosage to achieve glycemic control and the incidence of hypoglycemia during hospitalization. RESULTS: 250 patients were screened between October 2021 and June 2022, 220 were randomly grouped, and 182 completed the trial (89 in the 1:1.5 and 93 in the 1:1 groups). The time taken to reach FBG targets was comparable between the two groups (3.4 ± 1.7 vs. 3.0 ± 1.3 days, p = 0.137) within about 3 days. The 2hBG after three meals was shorter in the 1:1.5 group than in the 1:1group (2.9 ± 1.5 vs. 3.4 ± 1.4 days, p = 0.015 for breakfast, 3.0 ± 1.6 vs. 3.6 ± 1.4 days, p = 0.005 for lunch, and 3.1 ± 2.1 vs. 4.0 ± 1.5 days, p = 0.002 for dinner). No significant difference in insulin dosages was found between the two groups at the end of the study. The incidence of hypoglycemia was similar in both groups. CONCLUSIONS: We demonstrated that fixed dose-ratio basal-bolus insulin at 1:1.5 calculated using a weight-based initiation and titration algorithm was simple, as effective, and safe as ratio at 1:1 in managing T2D in hospitalized patients. Trial Registration ChiCTR 2,100,050,963. Date of registration: September 8, 2021.

Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.

Potential clinical biomarkers and perspectives in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication and the leading cause of death in diabetic patients. Patients typically do not experience any symptoms and have normal systolic and diastolic cardiac functions in the early stages of DCM. Because the majority of cardiac tissue has already been destroyed by the time DCM is detected, research must be conducted on biomarkers for early DCM, early diagnosis of DCM patients, and early symptomatic management to minimize mortality rates among DCM patients. Most of the existing implemented clinical markers are not very specific for DCM, especially in the early stages of DCM. Recent studies have shown that a number of new novel markers, such as galactin-3 (Gal-3), adiponectin (APN), and irisin, have significant changes in the clinical course of the various stages of DCM, suggesting that we may have a positive effect on the identification of DCM. As a summary of the current state of knowledge regarding DCM biomarkers, this review aims to inspire new ideas for identifying clinical markers and related pathophysiologic mechanisms that could be used in the early diagnosis and treatment of DCM.

Novel model predicts diastolic cardiac dysfunction in type 2 diabetes.

OBJECTIVE: Diabetes mellitus complicated with heart failure has high mortality and morbidity, but no reliable diagnoses and treatments are available. This study aimed to develop and verify a new model nomogram based on clinical parameters to predict diastolic cardiac dysfunction in patients with Type 2 diabetes mellitus (T2DM). METHODS: 3030 patients with T2DM underwent Doppler echocardiography at the First Affiliated Hospital of Shenzhen University between January 2014 and December 2021. The patients were divided into the training dataset (n = 1701) and the verification dataset (n = 1329). In this study, a predictive diastolic cardiac dysfunction nomogram is developed using multivariable logical regression analysis, which contains the candidates selected in a minor absolute shrinkage and selection operator regression model. Discrimination in the prediction model was assessed using the area under the receiver operating characteristic curve (AUC-ROC). The calibration curve was applied to evaluate the calibration of the alignment nomogram, and the clinical decision curve was used to determine the clinical practicability of the alignment map. The verification dataset was used to evaluate the prediction model's performance. RESULTS: A multivariable model that included age, body mass index (BMI), triglyceride (TG), creatine phosphokinase isoenzyme (CK-MB), serum sodium (Na), and urinary albumin/creatinine ratio (UACR) was presented as the nomogram. We obtained the model for estimating diastolic cardiac dysfunction in patients with T2DM. The AUC-ROC of the training dataset in our model was 0.8307, with 95% CI of 0.8109-0.8505. Similar to the results obtained with the training dataset, the AUC-ROC of the verification dataset in our model was 0.8083, with 95% CI of 0.7843-0.8324, thus demonstrating robust. The function of the predictive model was as follows: Diastolic Dysfunction = -4.41303 + 0.14100*Age(year)+0.10491*BMI (kg/m2) +0.12902*TG (mmol/L) +0.03970*CK-MB (ng/mL) -0.03988*Na(mmol/L) +0.65395 * (UACR > 30 mg/g) + 1.10837 * (UACR > 300 mg/g). The calibration plot diagram of predicted probabilities against observed DCM rates indicated excellent concordance. Decision curve analysis demonstrated that the novel nomogram was clinically useful. CONCLUSION: Diastolic cardiac dysfunction in patients with T2DM can be predicted by clinical parameters. Our prediction model may represent an effective tool for large-scale epidemiological study of diastolic cardiac dysfunction in T2DM patients and provide a reliable method for early screening of T2DM patients with cardiac complications.KEY MESSAGESThis study used clinical parameters to predict diastolic cardiac dysfunction in patients with T2DM. This study established a nomogram for predicting diastolic cardiac dysfunction by multivariate logical regression analysis. Our predictive model can be used as an effective tool for large-scale epidemiological study of diastolic cardiac dysfunction in patients with T2DM and provides a reliable method for early screening of cardiac complications in patients with T2DM.

Case report: Two rare uterine cesarean scar mass cases.

RATIONALE: Gestational trophoblastic neoplasia (GTN) located in the cesarean scar is a rare disease that has imaging appearances similar to those of an exogenous scar incision pregnancy and is often misdiagnosed due to insufficient clinical experience. PATIENT CONCERNS: We report 2 cases of uterine cesarean scar mass. Two patients with different diagnoses had similar clinical complaints as abnormal vaginal bleeding, enlargement of uterus isthmus by physical examination, and mixed echo mass in uterine low segment by ultrasound examination; however, their magnetic resonance imaging images showed very different features. DIAGNOSES: One patient was diagnosed with cesarean scar pregnancy (CSP) and one patient was diagnosed with cesarean scar GTN. INTERVENTIONS: The CSP patient underwent surgery by laparoscopy combined with hysteroscopy after uterine artery embolism and obtained pathological confirmation. The GTN patient received chemotherapy. OUTCOMES: For the CSP patient, her serum ß-human chorionic gonadotropin (hCG) concentration returned to normal 2 weeks later, and B-ultrasound showed that the niche was completely repaired 3 months after the operation. The intrauterine lesions of the GTN patient disappeared completely 3 months after serum ß-hCG normalization. And her ß-hCG was normal at all follow-up visits until now. LESSONS: Clinicians should consider GTN when identifying masses at scar incision sites. Magnetic resonance imaging images improve the understanding of the imaging features in patients suspected of having CSP/GTN.

N-glycomic profiling reveals dysregulated N-glycans of peripheral neuropathy in type 2 diabetes.

Given the increasing morbidity of diabetes mellitus type 2 (T2DM) with peripheral neuropathy (PN), efficient screening for T2DM-PN is of great significance. Altered N-glycosylation is closely associated with T2DM progression, whereas its association with T2DM-PN remains uncharacterized. In this study, N-glycomic profiling was performed to identify the N-glycan features between T2DM patients with (n = 39, T2DM-PN) and without PN (n = 36, T2DM-C). Another independent set of T2DM patients (n = 29 for both T2DM-C and T2DM-PN) were utilized to validate these N-glycomic features. There were 10 N-glycans varied significantly between T2DM-C and T2DM-PN (p < 0.05 and 0.7 < AUC < 0.9), of which T2DM-PN was associated with increased oligomannose and core-fucosylation of sialylated glycans, and decreased bisected mono-sialylated glycan. Notably, these results were validated by an independent set of T2DM-C and T2DM-PN. This is the first profiling for N-glycan features in T2DM-PN patients, which reliably differentiates them from T2DM controls, thus providing a prospective profile of glyco-biomarkers for the screening and diagnosis of T2DM-PN.

Blood glucose may be another index to initiate insulin treatment besides glycated hemoglobin A1c after oral antidiabetic medications failure for glycemic control: A real-world survey.

Objective: The inertia of insulin initiation is a barrier to achieving glycemic control when oral antidiabetic drugs fail to control glucose during the treatment of type 2 diabetes (T2D). Insulin initiation is usually based on glycated hemoglobin A1c (A1C). To investigate whether there is another index for insulin initiation besides A1C, we conducted a cross-sectional survey in the real world. Methods: We conducted a multicenter cross-section survey with a total of 1034 T2D patients. All patients, at the time of the survey, decided to initiate insulin therapy due to failure of controlling glucose using only oral antidiabetic drugs. We analyzed the differences of blood glucose between patients who were tested for A1C and those who were not. Results: 666 (64.4%) patients were tested A1C and 368 (35.6%) were not. Neither fasting blood glucose (FBG) (12.0 ± 2.9 vs 12.3 ± 2.9 mmol/L, t = 1.494, P = 0.135) nor postprandial blood glucose (PBG) (18.4 ± 4.8 vs 17.9 ± 4.8 mmol/L, t = 1.315, P = 0.189) were significantly different between patients with and without A1C. Conclusion: Our results demonstrated that initiating insulin based on FBG or PBG is a common clinical practice, at least in China; moreover, since it is easier to obtain than A1C, it can be a simple and effective way to overcome clinical inertia for initiating insulin.

Association of mean arterial pressure with 5-year risk of incident diabetes in Chinese adults：a secondary population-based cohort study.

OBJECTIVE: Hypertension predicts the development of diabetes. However, there are still lacking high-quality studies on the correlation between mean arterial pressure (MAP) and incident diabetes. We aimed to explore the relationship between MAP and diabetes in Chinese adults. DESIGN: This is a secondary retrospective cohort study and the data were downloaded from the 'DATADRYAD' database (www.Datadryad.org). PARTICIPANTS: The study included 210 418 adults without diabetes at baseline between 2010 and 2016 across 32 sites and 11 cities in China. SETTING: The target-independent and dependent variables were MAP measured at baseline and diabetes occurred during follow-up. Cox proportional hazards regression was used to explore the relationship between MAP and diabetes. PRIMARY OUTCOME MEASURES: The outcome was incident diabetes, which was defined as fasting blood glucose ≥7.00 mmol/L and/or self-reported diabetes during follow-up. Patients were censored either at the time of the diagnosis or at the last visit, whichever comes first. RESULTS: 3927 participants developed diabetes during a 5-year follow-up. After adjusting covariates, MAP positively correlated with diabetes (HR=1.008, 95% CI 1.005 to 1.011, p<0.001), and the absolute risk difference was 0.02%. E-value analysis and multiple imputations were used to explore the robustness of the results. The relationship between MAP and diabetes was also non-linear, and the inflection point of MAP was 100.333 mm Hg. Subgroup analysis revealed a stronger association between MAP and diabetes in people with age (≥30,<50 years old), fasting plasma glucose <6.1 mmol/L and drinking. Additionally, receiver operating characteristic (ROC) curves showed the predictive performance of MAP for diabetes was similar to systolic blood pressure (SBP) (area under the curve (AUC)=0.694 with MAP vs AUC=0.698 with SBP). CONCLUSIONS: MAP is an independent predictor for a 5-year risk of incident diabetes among Chinese adults. The relationship between MAP and diabetes is also non-linear. When MAP is below 100.333 mm Hg, MAP is closely positively related to diabetes.

Comparative efficacy and safety of two insulin aspart formulations (Rapilin and NovoRapid) when combined with metformin, for patients with diabetes mellitus: a multicenter, randomized, open-label, controlled clinical trial.

OBJECTIVE: This phase 3 confirmatory diabetes mellitus treatment study compared the safety and efficacy of Rapilin and NovoRapid insulin asparts in combination with metformin. METHODS: This 24-week, open-label, randomized, active-controlled, noninferiority phase 3 confirmatory study conducted across centers in China aimed to enroll patients with type 2 diabetes mellitus and blood sugar glucose inadequately controlled by oral antidiabetic drugs. Randomized patients received subcutaneous mealtime Rapilin or NovoRapid (3:1) injections, with metformin. The primary objectives were to demonstrate noninferiority (margin of 0.4%) in HbA1c change from baseline and compare safety profiles of Rapilin versus NovoRapid after 24 weeks. Secondary outcomes included 2-h postprandial plasma glucose (PPG), fasting plasma glucose (FPG), and patients achieving HbA1c <7.0% and ≤6.5%. RESULTS: 590 patients with type 2 diabetes mellitus were randomized to Rapilin (n = 441) and NovoRapid (n = 149) groups. After 24 weeks, the mean HbA1c change from baseline was -2.20% (Rapilin) and -2.32% (NovoRapid); the estimated treatment difference based on least-square means was 0.04% (95% CI: -0.17, 0.26), meeting the noninferiority criteria for Rapilin versus NovoRapid. Comparable improvements were reported for mean 2-hour PPG (6.14 and 6.29 mmol/L), FPG (2.02 and 1.70 mmol/L), and patients with HbA1c <7.0% (52.6% and 51.0%) and ≤6.5% (34.2% and 30.9%), in the Rapilin and NovoRapid groups, respectively, with no significant safety or immunogenicity outcome differences. CONCLUSIONS: Rapilin demonstrated non-inferior glycemic control, and matching safety and immunogenicity to NovoRapid in patients with type 2 diabetes mellitus also receiving metformin over 24 weeks. TRIAL REGISTRATION: ChiCTR20003129041.

Metabonomic Characteristics of Myocardial Diastolic Dysfunction in Type 2 Diabetic Cardiomyopathy Patients.

Diabetic cardiomyopathy (DCM) is one of the most essential cardiovascular complications in diabetic patients associated with glucose and lipid metabolism disorder, fibrosis, oxidative stress, and inflammation in cardiomyocytes. Despite increasing research on the molecular pathogenesis of DCM, it is still unclear whether metabolic pathways and alterations are probably involved in the development of DCM. This study aims to characterize the metabolites of DCM and to identify the relationship between metabolites and their biological processes or biological states through untargeted metabolic profiling. UPLC-MS/MS was applied to profile plasma metabolites from 78 patients with diabetes (39 diabetes with DCM and 39 diabetes without DCM as controls). A total of 2,806 biochemical were detected. Compared to those of DM patients, 78 differential metabolites in the positive-ion mode were identified in DCM patients, including 33 up-regulated and 45 down-regulated metabolites; however, there were only six differential metabolites identified in the negative mode including four up-regulated and two down-regulated metabolites. Alterations of several serum metabolites, including lipids and lipid-like molecules, organic acids and derivatives, organic oxygen compounds, benzenoids, phenylpropanoids and polyketides, and organoheterocyclic compounds, were associated with the development of DCM. KEGG enrichment analysis showed that there were three signaling pathways (metabolic pathways, porphyrin, chlorophyll metabolism, and lysine degradation) that were changed in both negative- and positive-ion modes. Our results demonstrated that differential metabolites and lipids have specific effects on DCM. These results expanded our understanding of the metabolic characteristics of DCM and may provide a clue in the future investigation of reducing the incidence of DCM. Furthermore, the metabolites identified here may provide clues for clinical management and the development of effective drugs.

Quantification of Glucose, fructose and 1,5-Anhydroglucitol in plasma of diabetic patients by ultra performance liquid chromatography tandem mass spectrometry.

Type 2 diabetes mellitus (T2DM), a worldwide disease that affects the quality of human life and social development. Glucose, fructose and 1,5-anhydroglucitol are closely related to diabetes mellitus. However, few methods have been reported to achieve these three carbohydrates in the blood simultaneously. In this study, a UPLC-MS/MS method allowing to quantify glucose, fructose, and 1,5-anhydroglucitol simultaneously in human plasma was developed. The analysis was performed by UPLC-MS/MS system with HILIC column. This new method provided satisfactory results in terms of calibration curves with good linearity (R2 > 0.99) over 3 order of magnitude range, precision (coefficient of variation of intra-day and inter-day: 0.72-10.23% and 2.21-13.8%), accuracy (results of intra-day and inter-day: 97-113%, 100-107%), matrix effects (87-109%), recovery (93-119%), carry-over (0.004-0.014%), as well as stability (0.04-6.9%) within the acceptance criteria. The reproducible, precise and accurate method with suitable dynamic ranges was successfully applied to the analysis of glucose, fructose and 1,5-anhydroglucitol in T2DM under different pathophysiological conditions.

Association of Sex Hormones and Fat Distribution in Men with Different Obese and Metabolic Statuses.

PURPOSE: Although several studies have explored the association of sex hormones with glucose metabolism, the association between sex hormones and body fat distribution, which is closely related to insulin resistance, has not been fully elucidated. We have tried to explore the relationship of testosterone (T) and estradiol (E2) with visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) mass in Chinese men with different obese and metabolic statuses. PATIENTS AND METHODS: A total of 128 men from the Health Management Center of the Second Xiangya Hospital, Central South University were collected and grouped in accordance with their obese and metabolic syndrome (MS) statuses: metabolically healthy non-overweight/obese men (MHNO), metabolically healthy overweight/obese men (MHO) and metabolically unhealthy overweight/obese men (MUO). Multiple regression analyses were performed to estimate contributions of sex hormones levels to the variations of body fat distribution and the contributions of body fat distribution to the variations of sex hormone levels. RESULTS: With fat mass parameters as independent variables, SAT had a strong negative association with T in MHNO (ß = -2.772, P = 0.034), VAT was positively correlated with E2 in MHO (ß = 22.269, P = 0.009), and SAT was negatively associated with T in MUO (ß = -3.315, P = 0.010). With sex hormones as independent variables, E2 positively correlated with VAT (ß = -176.259, P = 0.048), while T negatively correlated with VAT in MHO (ß = 183.150, P = 0.029). In MUO, an inverse association of T with SAT was observed (ß = -213.689, P = 0.021). CONCLUSION: E2 and VAT had a mutual influence, thus resulting in a vicious circle, and the negative correlation between T and VAT may be related to the decrease of the MS occurrence in the MHO group. There were bi-directional relationships between sex hormones and fat distribution in men with different obese and metabolic statuses. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-EOC-16010194. Retrospectively registered.

Iron overload inhibits cell proliferation and promotes autophagy via PARP1/SIRT1 signaling in endometriosis and adenomyosis.

Emerging evidence suggests that excess iron accumulates in endometriotic and adenomyotic lesions. However, the role iron overload plays in the pathogenesis of endometriosis or adenomyosis remains unknown. Primary human eutopic endometrial stromal cells (EuESCs) from endometriosis or adenomyosis patients were used as the in vitro model of endometriosis or adenomyosis in this study. We found that iron, manifesting as ferric ammonium citrate (FAC; 0.05-4.8 mM), significantly inhibited cell growth, induced oxidative stress through the Fenton reaction, and functionally activated autophagy in EuESCs, as measured by 5-ethynyl-2'-deoxyuridine incorporation assay, MitoSOX™ Red staining, LC3 turnover assay, and tandem mCherry-eGFP-LC3B fluorescence microscopy. Immunohistochemistry analysis of Ki67 expression in proliferative-phase endometrial tissues revealed that cell proliferation in ectopic tissues was dramatically compromised, suggesting that iron overload may play a role in cell growth inhibition in vivo. We observed that autophagy may alleviate the FAC-induced inhibition of endometrial stromal cell proliferation. Furthermore, sequential FAC (0.8 mM, 24 h) and hydrogen peroxide (H2O2; 300 µM, 2 h) treatment successfully induced the Fenton reaction in EuESCs and caused extensive apoptosis, whereas the disruption of autophagy by the knockdown of BECN1 further aggravated cell death. MitoSOX™ Red staining showed that autophagy may promote the survival of EuESCs by decreasing of the Fenton reaction-induced reactive oxygen species generation. In addition, we observed that the Fenton reaction-induced oxidative stress significantly suppressed iron overload-induced autophagy. Moreover, we found that FAC treatment impaired poly(ADP-ribose)-polymerase 1 (PARP1) expression while simultaneously upregulating SIRT1 expression in EuESCs. Our data further showed that PARP1 expression decreased in endometriotic lesions, which may partially result from iron overload. We also found that PARP1 inhibition aggravated iron overload-induced cell growth suppression, and was implicated in iron overload-induced autophagy. In addition, SIRT1 silencing alleviated iron overload-induced PARP1 downregulation and autophagy activation. Overall, our data suggest that iron overload in endometrial stromal cells of endometriotic or adenomyotic lesions may be involved in the inhibition of cell proliferation, simultaneously with the activation of protective autophagy via PARP1/SIRT1 signaling.

MicroRNA-126 inhibits the migration and invasion of endometrial cancer cells by targeting insulin receptor substrate 1.

[This retracts the article DOI: 10.3892/ol.2015.4001.].

Gleevec and Rapamycin Synergistically Reduce Cell Viability and Inhibit Proliferation and Angiogenic Function of Mouse Bone Marrow-Derived Endothelial Progenitor Cells.

OBJECTIVE: This study investigates the synergistic effects of Gleevec (imatinib) and rapamycin on the proliferative and angiogenic properties of mouse bone marrow-derived endothelial progenitor cells (EPCs). MATERIALS AND METHODS: EPCs were isolated from mouse bone marrow and treated with different concentrations of Gleevec or rapamycin individually or in combination. The cell viability and proliferation were examined using the MTT assay. An analysis of cell cycle and apoptosis was performed using flow cytometry. Formation of capillary-like tubes was examined in vitro, and the protein expression of cell differentiation markers was determined using Western blot analysis. RESULTS: Gleevec significantly reduced cell viability, cell proliferation, and induced cell apoptosis in EPCs. Rapamycin had similar effects on EPCs, but it did not induce cell apoptosis. The combination of Gleevec and rapamycin reduced the cell proliferation but increased cell apoptosis. Although rapamycin had no demonstratable effect on tube formation, the combined therapy of Gleevec and rapamycin significantly reduced tube formation when compared with Gleevec alone. Mechanistically, Gleevec, but not rapamycin, induced a significant elevation in caspase-3 activity in EPCs, and it attenuated the expression of the endothelial protein marker platelet-derived growth factor receptor α. Functionally, rapamycin, but not Gleevec, significantly enhanced the expression of endothelial differentiation marker proteins, while attenuating the expression of mammalian target of rapamycin signaling-related proteins. CONCLUSIONS: Gleevec and rapamycin synergistically suppress cell proliferation and tube formation of EPCs by inducing cell apoptosis and endothelial differentiation. Mechanistically, it is likely that rapamycin enhances the proapoptotic and antiangiogenic effects of Gleevec by promoting the endothelial differentiation of EPCs. Given that EPCs are involved in the pathogenesis of some cardiovascular diseases and critical to angiogenesis, pharmacological inhibition of EPC proliferation by combined Gleevec and rapamycin therapy may be a promising approach for suppressing cardiovascular disease pathologies associated with angiogenesis.

Machine Learning for Predicting the 3-Year Risk of Incident Diabetes in Chinese Adults.

Purpose: We aimed to establish and validate a risk assessment system that combines demographic and clinical variables to predict the 3-year risk of incident diabetes in Chinese adults. Methods: A 3-year cohort study was performed on 15,928 Chinese adults without diabetes at baseline. All participants were randomly divided into a training set (n = 7,940) and a validation set (n = 7,988). XGBoost method is an effective machine learning technique used to select the most important variables from candidate variables. And we further established a stepwise model based on the predictors chosen by the XGBoost model. The area under the receiver operating characteristic curve (AUC), decision curve and calibration analysis were used to assess discrimination, clinical use and calibration of the model, respectively. The external validation was performed on a cohort of 11,113 Japanese participants. Result: In the training and validation sets, 148 and 145 incident diabetes cases occurred. XGBoost methods selected the 10 most important variables from 15 candidate variables. Fasting plasma glucose (FPG), body mass index (BMI) and age were the top 3 important variables. And we further established a stepwise model and a prediction nomogram. The AUCs of the stepwise model were 0.933 and 0.910 in the training and validation sets, respectively. The Hosmer-Lemeshow test showed a perfect fit between the predicted diabetes risk and the observed diabetes risk (p = 0.068 for the training set, p = 0.165 for the validation set). Decision curve analysis presented the clinical use of the stepwise model and there was a wide range of alternative threshold probability spectrum. And there were almost no the interactions between these predictors (most P-values for interaction >0.05). Furthermore, the AUC for the external validation set was 0.830, and the Hosmer-Lemeshow test for the external validation set showed no statistically significant difference between the predicted diabetes risk and observed diabetes risk (P = 0.824). Conclusion: We established and validated a risk assessment system for characterizing the 3-year risk of incident diabetes.

Association of hypertension and incident diabetes in Chinese adults: a retrospective cohort study using propensity-score matching.

BACKGROUND: Reliable quantification of the relationship between hypertension and diabetes risk is limited, especially among Chinese people. We aimed to investigate the association between hypertension and the risk of diabetes in a large cohort of the Chinese population. METHODS: This was a retrospective propensity score-matched cohort study among 211,809 Chinese adults without diabetes at baseline between 2010 and 2016. The target independent and dependent variable were hypertension at baseline and incident diabetes during follow-up respectively. The propensity score matching using a non-parsimonious multivariable logistic regression was conducted to balance the confounders between 28,711 hypertensive patients and 28,711 non-hypertensive participants. The doubly robust estimation method was used to investigate the association between hypertension and diabetes. RESULTS: In the propensity-score matching cohort, diabetes risk increased by 11.0% among hypertensive patients (HR = 1.110, 95% confidence interval (CI): 1.031-1.195, P = 0.00539). And diabetes risk dropped to 8.3% among hypertensive subjects after adjusting for the propensity score (HR = 1.083, 95%CI: 1.006-1.166, P = 0.03367). Compared to non-hypertensive participants with low propensity score, the risk of incident diabetes increased by 2.646 times among hypertensive patients with high propensity score (HR = 3.646, 95%CI: 2.635-5.045, P < 0.0001). CONCLUSION: Hypertension was associated with an 11.0% increase in the risk of developing diabetes in Chinese adults. And the figure dropped to 8.3% after adjusting the propensity score. Additionally, compared to non-hypertensive participants with low propensity scores, the risk of incident diabetes increased by 2.646 times among hypertensive patients with high propensity scores.

Applying latent class analysis to risk stratification of incident diabetes among Chinese adults.

OBJECTIVE: To use latent class analysis to identify unobservable subpopulations amongst the heterogeneous population and explore the relationship between subpopulations and incident diabetes among Chinese adults. METHODS: The retrospective study included 32,312 Chinese adults without diabetes at baseline. Latent class indicators included demographic and clinical variables. The outcome was incident diabetes. The relationship between latent class and outcome was evaluated with Cox proportional hazard regression analysis. RESULTS: After screening, the two-class latent class model best fits the population. Participants in class 2 are characterized by higher age, body mass index, systolic and diastolic blood pressure, fasting plasma glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, serum creatinine, serum urea nitrogen, alanine aminotransferase, and a higher proportion of males, ever/current smokers and drinkers, but lower high-density lipoprotein cholesterol and a lower proportion of family history of diabetes. The risk of diabetes in class 2 was 5.451 times (HR: 6.451, 95%CI: 4.179-9.960, P < 0.00001) and 5.264 times (HR: 6.264, 95%CI: 4.680-8.385, P < 0.00001) higher than that in class 1 during 3-year and 5-year follow-up, respectively. CONCLUSIONS: We used latent class analysis to identify two distinct subpopulations with differential risk of diabetes during 3-year and 5-year follow-up.

Calcium Dobesilate (CaD) Attenuates High Glucose and High Lipid-Induced Impairment of Sarcoplasmic Reticulum Calcium Handling in Cardiomyocytes.

Calcium dobesilate (CaD) is used effectively in patients with diabetic microvascular disorder, retinopathy, and nephropathy. Here we sought to determine whether it has an effect on cardiomyocytes calcium mishandling that is characteristic of diabetic cardiomyopathy. Cardiomyocytes were sterile isolated and cultured from 1 to 3 days neonatal rats and treated with vehicle (Control), 25 mM glucose+300 µM Palmitic acid (HG+PA), 100 µM CaD (CaD), or HG+PA+CaD to test the effects on calcium signaling (Ca2+ sparks, transients, and SR loads) and reactive oxygen species (ROS) production by confocal imaging. Compared to Control, HG+PA treatment significantly reduced field stimulation-induced calcium transient amplitudes (2.22 ± 0.19 vs. 3.56 ± 0.21, p < 0.01) and the levels of caffeine-induced calcium transients (3.19 ± 0.14 vs. 3.72 ± 0.15, p < 0.01), however significantly increased spontaneous Ca2+ sparks firing levels in single cardiomyocytes (spontaneous frequency 2.65 ± 0.23 vs. 1.72 ± 0.12, p < 0.01) and ROS production (67.12 ± 4.4 vs. 47.65 ± 2.12, p < 0.05), which suggest that HG+PA treatment increases the Spontaneity Ca2+ spark frequency, and then induced partial reduction of SR Ca2+ content and subsequently weaken systolic Ca2+ transient in cardiomyocyte. Remarkably, these impairments in calcium signaling and ROS production were largely prevented by pre-treatment of the cells with CaD. Therefore, CaD may contribute to a good protective effect on patients with calcium mishandling and contractile dysfunction in cardiomyocytes associated with diabetic cardiomyopathy.