Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

Over-expression of AQP7 contributes to improve insulin resistance in adipocytes.

OBJECTIVE: Aquaglyceroporin 7 (AQP7) is required for efflux of glycerol from adipocytes. In this study, we aimed to analyze expression profiles of AQP7 in the different differentiation phases of adipocytes and to investigate the role of AQP7 in the insulin resistance of adipocytes. METHODS: 3T3-L1 pre-adipocyte cells were induced to be fully differentiated adipocytes and then insulin resistance was induced by Dexamethasone (DXM) or TNF-α. Adenovirus vector with over-expression AQP7 (Ad-AQP7) was constructed and transfected into adipocytes. The expression level of AQP7 and phosphorylated PKB (p-PKB) were measured. The glycerol released from adipocytes and glucose consuming rate were tested too. RESULTS: AQP7 expression was gradually up-regulated along with the differentiation processing of 3T3-L1 preadipocytes, which was consistent with the expression level of p-PKB. Dexamethasone down-regulated the expression of AQP7, p-PKB and the glycerol content in adipocytes. Over-expression of AQP7 by transfecting Ad-AQP7 to insulin resistant adipocytes restored the phosphorylation of PKB and attenuated the glycerol secretion and glucose consuming rate of adipocytes. CONCLUSIONS: AQP7 is down-regulated in adipocytes with insulin resistance. The over-expression of AQP7 contributes to improve insulin resistance in adipocytes, which is potentially correlated with the increased phosphorylation of PKB.

Free Triiodothyronine and Free Triiodothyronine to Free Thyroxine Ratio Predict All-Cause Mortality in Patients with Diabetic Foot Ulcers.

PURPOSE: Free triiodothyronine (FT3) and FT3/free thyroxine (FT4) ratio have been associated with mortality in various diseases. However, no study to date has identified a link between FT3, FT3/FT4 ratio and all-cause mortality in patients with diabetic foot ulcers (DFUs). This study aimed to investigate this relationship. METHODS: This retrospective cohort study included 726 patients diagnosed with DFUs in a public hospital from January 2015 to October 2019. Patients were classified by the optimal cut-off values of the FT3 and FT3/FT4 ratio, respectively. The association of FT3 and FT3/FT4 ratio with all-cause mortality was evaluated in a multivariable cox regression model. Directed acyclic graphs were used to assess the minimally sufficient sets of confounding variables. RESULTS: Log rank tests indicated that patients with low FT3 and FT3/FT4 ratio had lower overall survival rates (all p < 0.001). The adjusted HRs for all-cause mortality were 0.48 (95% CI: 0.32-0.73, P = 0.001) when comparing high versus low FT3 and 0.47 (95% CI: 0.32-0.70, P < 0.001) when comparing high versus low FT3/FT4 ratio. Subgroup analyses showed that these associations existed only in elderly patients (≥65 years) and women, after adjustment. In men, only high FT3/FT4 ratio was associated with low all-cause mortality, after adjustment. CONCLUSION: Routine assessment of FT3 and FT3/FT4 ratio may be a simple and effective way to identify high-risk patients with DFUs, especially in elderly patients and women.

Three Nutritional Indices Are Effective Predictors of Mortality in Patients With Type 2 Diabetes and Foot Ulcers.

Introduction: Malnutrition has been associated with mortality in various diseases. This retrospective cohort study aimed to investigate the relationship between three nutritional indices and all-cause mortality in patients with diabetic foot ulcers (DFUs). Materials and Methods: A total of 771 patients diagnosed with DFUs in the First Affiliated Hospital of Wenzhou Medical University from 2015 to 2019 were included in this retrospective cohort study. Patients were classified as high nutritional risk groups or low nutritional risk groups according to the optimal cut-off values of the geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status (CONUT), respectively. The associations of three nutritional indices with all-cause mortality were evaluated by multivariable Cox regression analyses. Results: Log-rank tests indicated that patients with high nutritional risk had lower overall survival rates (all p < 0.001). The multivariable Cox regression revealed that low GNRI (adjusted HR 2.01, 95% CI: 1.37-2.96, P < 0.001), low PNI (adjusted HR 2.04, 95% CI: 1.29-3.23, P = 0.002) and high CONUT (adjusted HRs 1.54, 95% CI: 1.07-2.23, P = 0.021) were independently associated with high all-cause mortality. In subgroup analyses, only GNRI predicted higher all-cause mortality in patients with severe DFUs, while all of the three indices persisted as independent prognostic factors in patients with no severe DFUs. Discussion: The present study demonstrated that three nutritional indices were effective predictors of all-cause mortality in patients with DFUs. Routine screening for malnutrition using any of the three nutritional indices might be a simple and effective way to identify high-risk patients with DFUs. GNRI can be used as an independent prognostic indicator in patients with severe DFUs.

Association between heart rate-corrected QT interval and severe peripheral arterial disease in patients with type 2 diabetes and foot ulcers.

BACKGROUND: A prolonged heart rate-corrected QT interval (QTc) has been associated with peripheral artery disease (PAD) in the general population. However, no study to date has identified a link between prolonged QTc and the severity of PAD in patients with diabetes mellitus and foot ulcers (DFUs). This study aimed to investigate this relationship. METHODS: This multicenter study enrolled 281 patients with DFUs. The severity of PAD was classified into no severe PAD group (without stenosis or occlusion) and severe PAD group (with stenosis or occlusion) based on duplex ultrasonography. The association of prolonged QTc with severe PAD was evaluated in a multivariable mixed-effect logistic regression model, with the hospital as a random effect. Directed acyclic graphs were used to drive the selection of variables to fit the regression model. RESULTS: Patients with severe PAD had longer QTc than those without. Based on the multivariable mixed-effect logistic regression model, a prolonged QTc was positively associated with severe PAD (odds ratio (OR) = 2.61; 95% CI: 1.07-6.35) and severe DFUs (Wagner grade score ≥ 3) (OR = 2.87; 95% CI: 1.42-5.81). CONCLUSIONS: A prolonged QTc was associated with severe PAD in patients with DFUs. Further research is required to ascertain whether the association is causal.

Inverted U-Shaped Associations between Glycemic Indices and Serum Uric Acid Levels in the General Chinese Population: Findings from the China Cardiometabolic Disease and Cancer Cohort (4C) Study.

OBJECTIVE: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. METHODS: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. RESULTS: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). CONCLUSION: An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.

Molecular interplay between microRNA-130a and PTEN in palmitic acid-mediated impaired function of endothelial progenitor cells: Effects of metformin.

Metformin serves an important role in improving the functions of endothelial progenitor cells (EPCs). MicroRNAs (miRNAs), small non­coding RNAs, have been investigated as significant regulators of EPC vascular functions. The present study investigated the molecular crosstalk between metformin and miRNA­130a (miR­130a) in the functions of EPCs exposed to palmitic acid (PA). Isolated EPCs were treated with metformin, PA, and metformin + PA, respectively. Cell Counting Kit­8, Transwell and Matrigel assays were performed to detect the proliferation, migration and tube formation ability of EPCs following different treatments. The expression of miR­130a, phosphatase and tensin homolog (PTEN) and phosphorylated­AKT was analyzed by reverse transcription­quantitative polymerase chain reaction and western blotting. The specific mechanism underlying the function of metformin in EPCs was further elucidated by transfecting miR­130a mimics and inhibitor to overexpress and inhibit the expression of miR­130a in EPCs, respectively. EPCs exhibited impaired functions of proliferation (P<0.01 compared with the control), migration (P<0.01 compared with the control) and tube formation (P<0.01 compared with the control) following treatment with PA, and the expression levels of miR­130a and PTEN were decreased and increased, respectively. However, the presence of metformin, or the overexpression of miR­130a using miR­130a mimic alleviated the impairment of angiogenesis and proliferation, decreased the expression of PTEN and activated the phosphoinositide­3 kinase/AKT pathway in EPCs exposed to PA. By contrast, downregulating the expression of miR­130a with a miR­130a inhibitor reversed the metformin­mediated protection. These results demonstrate the beneficial effect of miR­130a/PTEN on EPC functions, which can be regulated by metformin. The effects of metformin on improving PA­induced EPC dysfunction are mediated by miR­130a and PTEN, which may assist in the prevention and/or treatment of diabetic vascular disease.

SDC4 Gene Silencing Favors Human Papillary Thyroid Carcinoma Cell Apoptosis and Inhibits Epithelial Mesenchymal Transition via Wnt/ß-Catenin Pathway.

As the most common type of endocrine malignancy, papillary thyroid cancer (PTC) accounts for 85-90% of all thyroid cancers. In this study, we presented the hypothesis that SDC4 gene silencing could effectively attenuate epithelial mesenchymal transition (EMT), and promote cell apoptosis via the Wnt/ß-catenin signaling pathway in human PTC cells. Bioinformatics methods were employed to screen the determined differential expression levels of SDC4 in PTC and adjacent normal samples. PTC tissues and adjacent normal tissues were prepared and their respective levels of SDC4 protein positive expression, in addition to the mRNA and protein levels of SDC4, Wnt/ß-catenin signaling pathway, EMT and apoptosis related genes were all detected accordingly. Flow cytometry was applied in order to detect cell cycle entry and apoptosis. Finally, analyses of PTC migration and invasion abilities were assessed by using a Transwell assay and scratch test. In PTC tissues, activated Wnt/ß-catenin signaling pathway, increased EMT and repressed cell apoptosis were determined. Moreover, the PTC K1 and TPC-1 cell lines exhibiting the highest SDC4 expression were selected for further experiments. In vitro experiments revealed that SDC4 gene silencing could suppress cell migration, invasion and EMT, while acting to promote the apoptosis of PTC cells by inhibiting the activation of the Wnt/ß-catenin signaling pathway. Besides, si-ß-catenin was observed to inhibit the promotion of PTC cell migration and invasion caused by SDC4 overexpression. Our study revealed that SDC4 gene silencing represses EMT, and enhances cell apoptosis by suppressing the activation of the Wnt/ß-catenin signaling pathway in human PTC.

Xenogeneic Decellularized Scaffold: A Novel Platform for Ovary Regeneration.

Women younger than 40 years may face early menopause because of premature ovarian failure (POF). The cause of POF can be idiopathic or iatrogenic, especially the cancer-induced oophorectomy and chemo- or radiation therapy. The current treatments, including hormone replacement therapy (HRT) and cryopreservation techniques, have increased risk of ovarian cancer and may reintroduce malignant cells after autografting. Decellularization technique has been regarded as a novel regenerative medicine strategy for organ replacement, wherein the living cells of an organ are removed, leaving the extracellular matrix (ECM) for cellular seeding. This study aimed to produce a xenogeneic decellularized ovary (D-ovary) scaffold as a platform for ovary regeneration and transplantation. We have developed a novel decellularization protocol for porcine ovary by treatment with physical, chemical, and enzymatic methods. Using hematoxylin and eosin (H&E) staining, DAPI staining, scanning electron microscopy (SEM), and quantitative analysis, this approach proved effective in removing cellular components and preserving ECM. Furthermore, the results of biological safety evaluation demonstrated that the D-ovary tissues were noncytotoxic for rat ovarian cells in vitro and caused only a minimal immunogenic response in vivo. In addition, the D-ovary tissues successfully supported rat granulosa cell penetration ex vivo and showed an improvement in estradiol (E2) hormone secretion.

Establishment and Validation of GV-SAPS II Scoring System for Non-Diabetic Critically Ill Patients.

BACKGROUND AND AIMS: Recently, glucose variability (GV) has been reported as an independent risk factor for mortality in non-diabetic critically ill patients. However, GV is not incorporated in any severity scoring system for critically ill patients currently. The aim of this study was to establish and validate a modified Simplified Acute Physiology Score II scoring system (SAPS II), integrated with GV parameters and named GV-SAPS II, specifically for non-diabetic critically ill patients to predict short-term and long-term mortality. METHODS: Training and validation cohorts were exacted from the Multiparameter Intelligent Monitoring in Intensive Care database III version 1.3 (MIMIC-III v1.3). The GV-SAPS II score was constructed by Cox proportional hazard regression analysis and compared with the original SAPS II, Sepsis-related Organ Failure Assessment Score (SOFA) and Elixhauser scoring systems using area under the curve of the receiver operator characteristic (auROC) curve. RESULTS: 4,895 and 5,048 eligible individuals were included in the training and validation cohorts, respectively. The GV-SAPS II score was established with four independent risk factors, including hyperglycemia, hypoglycemia, standard deviation of blood glucose levels (GluSD), and SAPS II score. In the validation cohort, the auROC values of the new scoring system were 0.824 (95% CI: 0.813-0.834, P< 0.001) and 0.738 (95% CI: 0.725-0.750, P< 0.001), respectively for 30 days and 9 months, which were significantly higher than other models used in our study (all P < 0.001). Moreover, Kaplan-Meier plots demonstrated significantly worse outcomes in higher GV-SAPS II score groups both for 30-day and 9-month mortality endpoints (all P< 0.001). CONCLUSIONS: We established and validated a modified prognostic scoring system that integrated glucose variability for non-diabetic critically ill patients, named GV-SAPS II. It demonstrated a superior prognostic capability and may be an optimal scoring system for prognostic evaluation in this patient group.

Platelet-to-Lymphocyte Ratio: A Novel Prognostic Factor for Prediction of 90-day Outcomes in Critically Ill Patients With Diabetic Ketoacidosis.

Diabetic ketoacidosis (DKA) is a life-threatening acute complication of diabetes mellitus and the novel systemic inflammation marker platelet-to-lymphocyte ratio (PLR) may be associated with clinical outcome in patients with DKA. This study aimed to investigate the utility of PLR in predicting 90-day clinical outcomes in patients with DKA. Patient data exacted from the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II) database was analyzed. A cutoff value for PLR of 267.67 was determined using Youden index (P < 0.05) and used to categorize subjects into a high PLR group and a low PLR group. The hazard ratios (HRs) and 95% confidence intervals (CIs) for DKA were calculated across PLR. Clinical outcomes in our study were defined as intensive care unit (ICU) 90-day readmission and all-cause mortality. A total of 278 ICU admissions were enrolled and stratified by cutoff value of PLR. The incidence of readmission and mortality was 17.8% in the high PLR group, significantly higher than 7.4% in the low PLR group. In the multivariable model, after adjusting for known confounding variables including clinical parameters, comorbidities, laboratory parameters, the HRs for DKA were 2.573 (95% CI 1.239-5.345; P = 0.011), 2.648 (95% CI 1.269-5.527; P = 0.009), and 2.650 (95% CI 1.114-6.306; P = 0.028), respectively. The Kaplan-Meier survival curve showed that a high PLR level was associated with a higher risk for 90-day outcomes in patients with DKA. The authors report that higher PLR presents a higher risk for 90-day incidence of readmission and mortality in patients with DKA. It appears to be a novel independent predictor of 90-day outcomes in critically ill DKA patients in ICU units.

G6PD deficiency-induced hemolysis in a Chinese diabetic patient: a case report with clinical and molecular analysis.

A 59-year-old Chinese male patient was admitted at diagnosis of type 1 diabetes with ketoacidosis. During the normalization of blood glucose with insulin, the patient developed acute hemolysis. The factors predisposing to hemolysis were not found, except the significantly diminished activity of glucose-6-phosphate dehydrogenase (G6PD). DNA analysis did not show any coding or intronic mutation in the G6PD gene. This is the first reported case of a Chinese patient in diabetic ketoacidosis with hemolysis induced by G6PD deficiency in the absence of mutations in the G6PD gene.

[Clinical application of alendronate for osteoporosis/osteopenia secondary to hyperthyroidism].

OBJECTIVE: To evaluate the efficacy and safety of alendronate for the treatment of osteoporosis/osteopenia secondary to hyperthyroidism. METHODS: From April 2008 to November 2009, 27 patients with hyperthyroidism with osteoporosis/ osteopenia measured by dual energy X-ray absorptiometry (DXA) were included in this study, and then they were randomly divided into two groups (group A and group B) by simple random sampling. Group A consisted of 14 patients treated with antithyroid drug and caltrate D, the antithyroid drug change with thyroid function, and caltrate D 600 mg per day. Group B consisted of 13 patients treated with antithyroid drug, caltrate D and alendronate, antithyroid drug and caltrate D the same as group A, and alendronate 70 mg weekly. Meanwhile, 21 healthy voluntary adults were chosen as control group. And compared with the control group which was treated with nothing. Followed-up for one year, the bone mineral density (including T-score, Z-score, BMD) in lumbar spine (LS), femoral neck (FN) and distal radius (DR) and general information, were compared before and after treatment. RESULTS: BMD at FN and DR were significantly higher at 12 months after treatment than at the baseline in group A (P = 0.000); T-score, Z-score, and BMD at the LS, FN and DR were all significantly higher at 12 months after treatment than at the baseline in group B (P < 0.05), but these data could not arrive to normal level. In group A, the percentage increased in BMD at the LS, FN, and DR were (4.34 +/- 10.5)%, (3.21 +/- 1.38)%, (1.95 +/- 0.44)%, respectively, at 12 months after treatment. In group B, the percentage increased in BMD at the LS, FN, and DR were (6.10 +/- 8.12)%, (4.10 +/- 5.64)%, (3.10 +/- 3.23)%, respectively, at 12 months after treatment. There was significant difference in the rate of increase between two groups (P < 0.05). AKP decreased, weight, BMI increased, and thyroid function decreased, after treatment than those before in both of the two groups. (P < 0.05). CONCLUSION: Alendronate can significantly increase BMD in treating patients with hyperthyroidism and osteoporosis/osteopenia. Compared with anti-thyroid drugs alone, treatment with alendronate can obtain more clinical effect and also very safety.