Reciprocal regulation of TWIST1 and OGT determines the decitabine efficacy in MDS/AML.

Chemoresistance poses a significant impediment to effective treatment strategies for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our previous study unveiled that oncogene TWIST1 interacted with DNA methyltransferase 3a (DNMT3a) to regulate the decitabine (DAC) resistance in MDS/AML. However, the underlying mechanism of TWIST1 dysregulation in DAC resistance remained enigmatic. Here, we found that O-GlcNAc modification was upregulated in CD34+ cells from MDS/AML patients who do not respond to DAC treatment. Functional study revealed that O-GlcNAcylation could stabilize TWIST1 by impeding its interaction with ubiquitin E3 ligase CBLC. In addition, as one typical transcription factor, TWIST1 could bind to the promoter of O-GlcNAc transferase (OGT) gene and activate its transcription. Collectively, we highlighted the crucial role of the O-GlcNAcylated TWIST1 in the chemoresistance capacity of MDS/AML clonal cells, which may pave the way for the development of a new therapeutic strategy targeting O-GlcNAcylated proteins and reducing the ratio of MDS/AML relapse. Video Abstract.

DACH1 inhibits the proliferation and migration of papillary thyroid carcinoma.

DACH1 is an important component of the retinal determinate gene network (RDGN), which regulates the expression of target genes by directly binding or interacting with other factors. DACH1 shows inhibitory effects in most tumors, but its role in papillary thyroid carcinoma is unclear and warrants further investigation. We assessed the expression of DACH1 in different tissues and correlation with immune infiltration by The Cancer Genome Atlas (TCGA) and Tumor Immune Estimation Resource (TIMMER2.0 databases). The effects of DACH1 on the proliferation and migration of TPC-1 and Bcpap cells were assessed by cell viability assay, colony formation assay, wound healing assay, transwell migration assay, and flow cytometry. Finally, the effects of DACH1 on CXCL8, CXCL10, and CXCL12 expression in Nthy-ori-3-1, TPC-1 and Bcpap cells were assessed by enzyme-linked immunosorbent assay kit and real-time polymerase chain reaction, respectively. The results showed that DACH1 was differentially expressed in different tumors and tissues. Basal expression of DACH1 was lower in thyroid and papillary thyroid carcinoma than in other normal tissues and corresponding tumors, and positively correlated with CD8+ T cell infiltration. In Nthy-ori-3-1, TPC-1 and Bcpap cells, overexpression of DACH1 inhibited cell migration and proliferation, and the opposite results was obtained by knocking down DACH1 using small interfering RNA. We also demonstrated that DACH1 regulated chemokines CXCL8, CXCL10, and CXCL12, thereby modulating tumor immunity.

Serum glycated albumin as good biomarker for predicting type 2 diabetes: A retrospective cohort study of China National Diabetes and Metabolic Disorders Survey.

AIMS: Glycated albumin (GA) is a biomarker for short-term (2-3 weeks) glycaemic control. However, the predictive utility of GA for diabetes and prediabetes is largely uncharacterised. We aimed to investigate the relationships of baseline serum GA levels with incident diabetes and prediabetes. METHODS: This was a longitudinal cohort study involving 516 subjects without diabetes or prediabetes at baseline. Blood glucose levels were observed during follow-up. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using COX proportional hazard models. Receiver operating characteristic curves and areas under the curves (AUCs) were used to evaluate the discriminating abilities of glycaemic biomarkers and prediction models. RESULTS: During a 9-year follow-up, 51 individuals (9.88%) developed diabetes and 92 (17.83%) prediabetes. Unadjusted HRs (95% CI) for both diabetes and prediabetes increased proportionally with increasing GA levels in a dose-response manner. Multivariable-adjusted HRs (95% CI) for diabetes were significantly elevated from 1.0 (reference) to 5.58 (1.86-16.74). However, the trend was no longer significant for prediabetes after multivariable adjustment. AUCs for GA, fasting blood glucose (FBG) and 2-h postprandial blood glucose (2h-PBG) for predicting diabetes were 0.698, 0.655 and 0.725, respectively. The AUCs for GA had no significant differences compared with those for FBG (p = 0.376) and 2h-PBG (p = 0.552). Replacing FBG or 2h-PBG or both with GA in diabetes prediction models made no significant changes to the AUCs of the models. CONCLUSIONS: GA is of good prognostic utility in predicting diabetes. However, GA may not be a useful biomarker for predicting prediabetes.

Using noninvasive anthropometric indices to develop and validate a predictive model for metabolic syndrome in Chinese adults: a nationwide study.

PURPOSE: Metabolic syndrome (Mets) is a pathological condition that includes many abnormal metabolic components and requires a simple detection method for rapid use in a large population. The aim of the study was to develop a diagnostic model for Mets in a Chinese population with noninvasive anthropometric and demographic predictors. PATIENTS AND METHODS: Least absolute shrinkage and selection operator (LASSO) regression was used to screen predictors. A large sample from the China National Diabetes and Metabolic Disorders Survey (CNDMDS) was used to develop the model with logistic regression, and internal, internal-external and external validation were conducted to evaluate the model performance. A score calculator was developed to display the final model. RESULTS: We evaluated the discrimination and calibration of the model by receiver operator characteristic (ROC) curves and calibration curve analysis. The area under the ROC curves (AUCs) and the Brier score of the original model were 0.88 and 0.122, respectively. The mean AUCs and the mean Brier score of 10-fold cross validation were 0.879 and 0.122, respectively. The mean AUCs and the mean Brier score of internal-external validation were 0.878 and 0.121, respectively. The AUCs and Brier score of external validation were 0.862 and 0.133, respectively. CONCLUSIONS: The model developed in this study has good discrimination and calibration performance. Its stability was proved by internal validation, external validation and internal-external validation. Then, this model has been displayed by a calculator which can exhibit the specific predictive probability for easy use in Chinese population.

Acoustic Sensor-Based Soundscape Analysis and Acoustic Assessment of Bird Species Richness in Shennongjia National Park, China.

Passive acoustic sensor-based soundscape analysis has become an increasingly important ecological method for evaluation of ecosystem conditions using acoustic indices. Understanding the soundscape composition and correlations between acoustic indices and species richness of birds, the most important sound source in the ecosystem, are of great importance for measuring biodiversity and the level of anthropogenic disturbance. In this study, based on yearlong sound data obtained from five acoustic sensors deployed in Dalongtan, Shennongjia National Park, we analyzed the soundscape composition by comparing the distributions of the soundscape power in different frequency ranges, and examined the correlations between acoustic indices and bird species richness by means of the Spearman rank correlation coefficient method. The diurnal dynamic characteristics of acoustic indices in different seasons were also described. Results showed that the majority of sounds were in the frequency of 2-8 kHz, in which over 50% sounds were in 2-6 kHz, commonly considered the bioacoustic frequency range. The Acoustics Complexity Index, Bioacoustic Index, and Normalized Difference Soundscape Index were significantly correlated with bird species richness, suggesting that these indices can be used for evaluation of bird species richness; Apparent diurnal dynamic patterns of bird acoustic activities were observed in spring, summer, and autumn; however, the intensity and duration of bird acoustic activities in summer is larger/longer than in spring and autumn.

The synergistic function of long and short forms of ß4GalT1 in p53-mediated drug resistance in bladder cancer cells.

ß1,4-galactosyltransferase-1 (ß4GalT1) is a type II membrane protein that catalyzes the transfer of galactose (Gal) from UDP-Gal to N-acetylglucosamine (GlcNAc) and forms a LacNAc structure. ß4GalT1 has a long form (termed ß4GalT1-L) and a short form (termed ß4GalT1-S) in mammalian cells. Although ß4GalT1 has been proven to play an important role in many biological and pathological processes, such as differentiation, immune responses and cancer development, the different functions of the two ß4GalT1 forms remain ambiguous. In this study, we demonstrated that total ß4GalT1 was upregulated in bladder cancer. Overexpression of ß4GalT1-S, but not ß4GalT1-L, increased drug resistance in bladder epithelial cells by upregulating p53 expression. Glycoproteomic analysis revealed that the substrate specificities of the two ß4GalT1 forms were different. Among the LacNAcylated proteins, the E3 ligase MDM2 could be preferentially modified by ß4GalT1-L compared to ß4GalT1-S, and this modification could increase the binding of MDM2 and p53 and further facilitate the degradation of p53. Our data proved that the two forms of ß4GalT1 could synergistically regulate p53-mediated cell survival under chemotherapy treatment. These results provide insights into the role of ß4GalT1-L and ß4GalT1-S and suggest their differentially important implications in the development of bladder cancer.

Clonal MDS/AML cells with enhanced TWIST1 expression reprogram the differentiation of bone marrow MSCs.

Bone marrow-derived mesenchymal stem cells (BMMSCs) derived from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients often show a shift in the balance between osteoblastogenesis and adipogenesis. It was suggested that BMMSCs can potentially undergo reprogramming or educational processes. However, the results of reprogrammed differentiation have been inconclusive. In this study, clinical samples, co-culture models and mouse models were employed to explore the association of MDS/AML clonal cells and BMMSCs differentiation. We found that clonal MDS/AML cells promoted adipogenic differentiation and inhibited osteogenic differentiation of BMMSCs, which in turn promoted MDS expansion. Mass spectrometry and cytokine array were used to identify the molecules to drive the BMMSCs differentiation in MDS/AML. Mechanistically, highly expressed transcription factor TWIST1 in clonal MDS/AML cells induces MDS/AML cells to secrete more IFN-γ, which can induce oxidative stress through STAT1-dependent manner, ultimately causing enhanced adipogenic differentiation and inhibited osteogenic differentiation in BMMSCs. Overall, our findings suggest that targeting the driving oncogenes in malignant clonal cells, such as TWIST1, may offer new therapeutic strategies by remodeling the surrounding bone marrow microenvironment in the treatment of MDS/AML and other hematopoietic malignancies.

G9a inactivation in progenitor cells with Isl1-Cre with reduced recombinase activity models aspects of Dandy-Walker complex.

G9a, also known as EHMT2, is essential for embryogenesis and has specific functions in multiple developmental processes. G9a inactivation affects development of the nervous system, which is formed with contribution of descendants of progenitor cells expressing the transcription factor Isl1. However, the function of G9a in Isl1-expressing progenitors is unknown. Here, we show that G9a is required for proper development of multiple structures formed with contribution of Isl1-expressing progenitors. A Cre-dependent GFP reporter revealed that the recombinase activity of the Isl1-Cre used in this study to inactivate G9a was reduced to a subset of Isl1-expressing progenitor cells. G9a mutants reached endpoint by 7 weeks of age with cardiac hypertrophy, hydrocephalus, underdeveloped cerebellum and hind limb paralysis, modeling aspects of Dandy-Walker complex. Moreover, neuroepithelium of the lateral ventricle derived from Isl1-expressing progenitors was thinner and disorganized, potentially compromising cerebrospinal fluid dynamics in G9a mutants. Micro-computed tomography after iodine staining revealed increased volume of the heart, eye lens and brain structures in G9a mutant fetuses. Thus, altered development of descendants of the second heart field and the neural crest could contribute to multicomponent malformation like Dandy-Walker.

Serum uric acid to high-density lipoprotein cholesterol ratio is a promising marker for identifying metabolic syndrome in nondiabetic Chinese men.

OBJECTIVES: To explore the relationship between serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) ratio (UHR) and metabolic syndrome (MetS) in nondiabetic individuals. METHODS: A total of 15,760 nondiabetic participants were screened from the China National Diabetes and Metabolic Disorders Study. Pearson correlation was used to determine the correlation between the components of MetS and UHR, HDL-C, and UA. Receiver operating characteristic curves were used to evaluate the ability of UHR, HDL-C, and UA to identify MetS in the nondiabetic population. RESULTS: A total of 6,386 men and 9,374 women were enrolled in this study. There were 1,480 (23.2%) men and 1,828 (19.5%) women with MetS. UHR significantly correlated with the components of MetS in men and women, especially with waist circumference  and triglyceride. In men, although HDL-C showed a higher specificity index, UHR presented higher sensitivity index and area under the curve (AUC) than HDL-C (P = 0.0001) and UA (P < 0.0001), with AUC (95% CI) of 0.762 (0.752-0.773). Higher AUCs of UHR relative to HDL-C and UA were also observed in the age groups <40 and 40-59 years. There was no significant difference in AUC between UHR and HDL-C in the age group ≥60 years (P = 0.370). However, similar results were not observed in women. CONCLUSION: UHR significantly correlated with the components of MetS and could serve as a novel and reliable marker for identifying the population at a high risk of MetS in nondiabetic men, especially in younger adults.

Serum 25-hydroxyvitamin D level is associated with short-term glycemic variability metrics derived from continuous glucose monitoring in T2DM.

This study aims to investigate the association between 25-hydroxyvitamin D (25OHD) and continuous glucose monitoring-assessed short-term glycemic variability (GV) and HbA1c among patients with type 2 diabetes mellitus (T2DM). We conducted a cross-sectional study recruiting 325 patients. The association between 25OHD and GV metrics (mean amplitude of glycemic excursions [MAGE], coefficient of variation [CV], standard deviation of sensor glucose [SD], and TIR) and HbA1c were analyzed using multivariable linear and logistic regression analyses. The 25OHD level and GV metrics showed significant differences among HbA1c groups (P < 0.01). CV, MAGE, SD and HbA1c decreased, and TIR increased with ascending 25OHD tertiles (P < 0.05). Serum 25OHD was inversely associated with CV (ß = - 0.211 [- 0.350 to - 0.071], P < 0.01) and HbA1c (ß = - 0.061 [- 0.114 to - 0.031], P < 0.01), and further multivariable analyses confirmed these results (P < 0.05). However, no association of HbA1c and 25OHD was found with the highest tertile of CV. These findings revealed that increased GV and HbA1c were both associated with lower 25OHD, and the relationship between HbA1c and 25OHD was attenuated with higher glucose CV in T2DM. Taken together, the analyses suggest that increasing vitamin D status has effects on improvements in long-term glycemic control and low glycemic variability.

Comprehensive retinal vascular measurements: time in range is associated with peripheral retinal venular calibers in type 2 diabetes in China.

AIM: Retinal vascular parameters are biomarkers of diabetic microangiopathy. We aimed to investigate the relationship between time in range (TIR) assessed by continuous glucose monitoring (CGM) and retinal vascular parameters in patients with type 2 diabetes in China. METHODS: The TIR assessed by CGM and retinal photographs were obtained at the same time from adults with type 2 diabetes who were recruited. Retinal vascular parameters were extracted from retinal photographs by a validated fully automated computer program, and TIR was defined as between 3.9-7.8 mmol/L over a 24-h period. The association between TIR and caliber of retinal vessels distributed in different zones were analyzed using multivariable linear regression analyses. RESULTS: For retinal vascular parameters measurements, the peripheral arteriovenous and middle venular calibers widen with decreasing TIR quartiles (P < 0.05). Lower TIR was associated with wider peripheral venule after adjusting for potential confounders. Even after further correction for GV, there was still a significant correlation between TIR and peripheral vascular calibers (CV: ß = - 0.015 [- 0.027, - 0.003], P = 0.013; MAGE: ß = - 0.013 [- 0.025, - 0.001], P = 0.038) and SD: ß = - 0.013 [- 0.026, - 0.001], P = 0.004). Similar findings were not found for the middle and central venular calibers or arterial calibers located in different zones. CONCLUSIONS: The TIR was associated with adverse changes to peripheral retinal venules but not central and middle vessels in patients with type 2 diabetes, suggesting that peripheral retinal vascular calibers may be affected by glycemic fluctuations earlier.

Loss of bisecting GlcNAcylation on MCAM of bone marrow stoma determined pro-tumoral niche in MDS/AML.

Bone marrow (BM) stroma plays key roles in supporting hematopoietic stem cell (HSC) growth. Glycosylation contributes to the interactions between HSC and surrounding microenvironment. We observed that bisecting N-acetylglucosamine (GlcNAc) structures, in BM stromal cells were significantly lower for MDS/AML patients than for healthy subjects. Malignant clonal cells delivered exosomal miR-188-5p to recipient stromal cells, where it suppressed bisecting GlcNAc by targeting MGAT3 gene. Proteomic analysis revealed reduced GlcNAc structures and enhanced expression of MCAM, a marker of BM niche. We characterized MCAM as a bisecting GlcNAc-bearing target protein, and identified Asn 56 as bisecting GlcNAc modification site on MCAM. MCAM on stromal cell surface with reduced bisecting GlcNAc bound strongly to CD13 on myeloid cells, activated responding ERK signaling, and thereby promoted myeloid cell growth. Our findings, taken together, suggest a novel mechanism whereby MDS/AML clonal cells generate a self-permissive niche by modifying glycosylation level of stromal cells.

Insulin-like growth factor binding protein-1 and insulin in polycystic ovary syndrome: a systematic review and meta-analysis.

Background: Insulin-like growth factor binding protein-1 (IGFBP-1) is considered a decline in polycystic ovary syndrome (PCOS), but it remains controversial that whether such reduction is attributed to obesity. Aims: This systematic review aims to explore whether IGFBP-1 is reduced in PCOS, and whether such reduction is associated with obesity. Results: Our pooled study included 12 studies with a total of 450 participants. IGFBP-1 levels in PCOS were significantly lower than that in non-PCOS (SMD (95%CI)=-0.49(-0.89, -0.09), P=0.02). No significant difference in IGFBP-1 levels between patients with or without PCOS classified by BMI. Whilst, stratification by PCOS status revealed a significant decrease in IGFBP-1 in overweight (SMD (95%CI)=-0.92(-1.46, -0.37), P=0.001). When comparing fasting insulin in the same way, PCOS patients had significantly elevated fasting insulin level but not statistically declined IGFBP-1 after classified by BMI. Conclusion: This meta-analysis provides evidence that the decrease of IGFBP-1 in PCOS was more strongly influenced by comorbid obesity than by PCOS itself. Additionally, contrast to previous findings that insulin significantly suppresses IGFBP-1, our results suggested that the suppression of PCOS-related hyperinsulinemia on IGFBP-1 seemed diminished. Overall, our work may provide a novel perspective on the mechanism between insulin and IGFBP-1 underlying PCOS development.

Dynamic regulation of O-GlcNAcylation and phosphorylation on STAT3 under hypoxia-induced EMT.

Activation of signal transducer and activator of transcription 3 (STAT3) is associated with hypoxia-induced epithelial-mesenchymal transition (EMT). Activation of STAT3 requires its phosphorylated form, and STAT3 can also be post-translationally modified by O-GlcNAcylation. Dynamic regulation of STAT3 O-GlcNAcylation in relation to STAT3 phosphorylation remains poorly understood. We observed, based on chemical enzyme labeling and click chemistry methods in combination with mass spectrometric analysis, that O-GlcNAcylation of STAT3 is significantly reduced under hypoxia. Results of functional experiments indicated that O-GlcNAcylation maintains stability of STAT3 and prevents its degradation via ubiquitination during hypoxia-induced EMT. O-GlcNAcylation of STAT3 facilitated its phosphorylation. Following STAT3 phosphorylation, existing STAT3 O-GlcNAcylation was antagonistically released. Our experimental findings, in combination with structure modeling, indicate that O-GlcNAcylation of STAT3 at residue T717 is essential for its phosphorylation at Y705. In contrast, mutation of STAT3 at phosphorylation site Y705 had no effect on its O-GlcNAcylation. O-GlcNAcylation and phosphorylation of STAT3 evidently occur in a strict sequential order under hypoxia-induced EMT. Dynamic regulation of STAT3 function clearly involves crosstalk between O-GlcNAcylation and phosphorylation. O-GlcNAcylation of STAT3 at T717 facilitates EMT process by promoting STAT3 phosphorylation, and provides a potential therapeutic target that may be useful in anticancer drug design.

Normal weight obesity and the risk of diabetes in Chinese people: a 9-year population-based cohort study.

We evaluated the risk of developing diabetes in Chinese individuals with normal weight obesity (NWO). This 9-year population-based cohort study was based on the China National Diabetes and Metabolic Disorders Survey. A total of 1128 subjects without diabetes were included. Body fat percentage (BF%) was assessed by electrical bioimpedance. NWO was defined as subjects with a normal BMI (< 24 kg/m2) and an excess BF% (≥ 24% in men; ≥ 33% in women). Of 1128 individuals, 528 individuals were normal weight non-obese (NWNO), 118 (10.5%) were normal weight obese (NWO), 63 were overweight non-obese (OWNO), and 419 were overweight obese (OWO). During a follow-up of 9.0 years (interquartile range: 8.9-9.3), 113 (10.0%) individuals developed diabetes. The incidence rates of diabetes in NWNO, NWO, OWNO and OWO people were 5.69 (27 cases), 11.30 (12 cases), 3.53 (2 cases) and 19.09 (72 cases) per 1000 person-years, respectively. Cox regression analyses indicated multivariate-adjusted hazard ratios of diabetes in NWO, OWNO and OWO people were 2.110 (95% CI 1.026-4.337, p = 0.025), 0.441 (95% CI 0.101-1.928, p = 0.232) and 3.465 (95% CI 2.163-5.551, p < 0.001), respectively, relative to NWNO people. Chinese people with NWO are at increased risk of developing diabetes. We strongly suggest the incorporation of BF% measurement into the regular physical examination in Chinese medical practice.

The Fecal Microbiota Is Already Altered in Normoglycemic Individuals Who Go on to Have Type 2 Diabetes.

Objective: Mounting evidence has suggested a link between gut microbiome characteristics and type 2 diabetes (T2D). To determine whether these alterations occur before the impairment of glucose regulation, we characterize gut microbiota in normoglycemic individuals who go on to develop T2D. Methods: We designed a nested case-control study, and enrolled individuals with a similar living environment. A total of 341 normoglycemic individuals were followed for 4 years, including 30 who developed T2D, 33 who developed prediabetes, and their matched controls. Fecal samples (developed T2D, developed prediabetes and controls: n=30, 33, and 63, respectively) collected at baseline underwent metagenomics sequencing. Results: Compared with matched controls, individuals who went on to develop T2D had lower abundances of Bifidobacterium longum, Coprobacillus unclassified, and Veillonella dispar and higher abundances of Roseburia hominis, Porphyromonas bennonis, and Paraprevotella unclassified. The abundance of Bifidobacterium longum was negatively correlated with follow-up blood glucose levels. Moreover, the microbial Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of carbohydrate metabolism, methane metabolism, amino acid metabolism, fatty acid metabolism, and membrane transport were changed between the two groups. Conclusions: We found that fecal microbiota of healthy individuals who go on to develop T2D had already changed when they still were normoglycemic. These alterations of fecal microbiota might provide insights into the development of T2D and a new perspective for identifying individuals at risk of developing T2D.

Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study.

BACKGROUND: Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination. METHODS: This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment. RESULTS: Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of - 0.50, 95% CI [- 0.85, - 0.15] mmol/L, and - 0.55, 95% CI [- 0.91, - 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline. CONCLUSIONS: Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017.

Comparison of Blood Glucose Variability Between Exenatide and Biphasic Insulin Aspart 30 in Chinese Participants with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy: A Multicenter, Open-Label, Randomized Trial.

INTRODUCTION: To compare blood glucose variability (GV) in Chinese participants with type 2 diabetes mellitus (T2DM) whose blood glucose levels are inadequately controlled with metformin monotherapy after twice-daily exenatide or biphasic insulin aspart 30 (BIAsp30). METHODS: In this 16-week multicenter, randomized clinical trial, 104 participants were randomized 1:1 to receive exenatide (exenatide group) or BIAsp30 (BIAsp30 group) twice daily. All participants continued metformin treatment. The primary outcome was the change in GV as measured by a continuous glucose monitoring system (CGMS) from baseline to 16 weeks. RESULTS: At 16 weeks, both the Exenatide and BIAsp30 groups effectively decreased mean glucose (MG), but neither group changed the mean amplitude of glycemic excursion (MAGE), largest amplitude of glycemic excursion (LAGE), mean of daily difference (MODD), or standard deviation of blood glucose (SDBG). The decrease in 2-h post-breakfast glucose excursions was greater in the Exenatide group compared to the BIAsp30 group, with a least square (LS) mean difference [95% CI] of (1.58 [0.53, 2.63]). Exenatide also significantly reduced 2-h post-lunch glucose excursion compared to BIAsp30 (LS mean difference [95% CI], 1.19 [0.18, 2.20]). The Exenatide group had significantly reduced body weight and body mass index (BMI), while the BIAsp30 group had increased weight and had no change in BMI. Both treatments were well tolerated with no serious hypoglycemic events and with fewer identified hypoglycemic events in the Exenatide group than in the BIAsp30 group (5.77% vs. 17.31%, P < 0.01). CONCLUSION: Although there was no difference in change of GV between Exenatide and BIAsp30, exenatide provided more improvement in postprandial glucose excursion and weight control, without increasing the risk of hypoglycemia in Chinese patients with T2DM whose blood glucose was inadequately controlled with metformin. These findings may provide new options for patients who choose further hypoglycemic treatment, especially in patients with obesity who have large postprandial plasma glucose excursions. TRIAL REGISTRATION: ClinicalTrials.gov indentifier: NCT02449603.

Greater macrovascular and microvascular morbidity from type 2 diabetes in northern compared with southern China: A cross-sectional study.

AIMS/INTRODUCTION: There are substantial differences in genes, diet, culture and environment between the northern and southern Chinese populations, which might influence treatment strategy and screening policy. We studied the differences in type 2 diabetes and diabetic complications between northern and southern China. MATERIALS AND METHODS: We carried out a cross-sectional survey using data from the China Cardiometabolic Registries on blood pressure, blood lipids and blood glucose in 25,398 Chinese type 2 diabetes patients. Macrovascular, microvascular and other complications were collected by self-report or medical records, and then divided into the northern and southern groups by the boundary of the Yangtze River. RESULTS: Northern patients were younger, and had heavier weight, greater body mass index and waist circumference, higher blood pressure, higher total cholesterol, higher low-density lipoprotein cholesterol, and higher hemoglobin A1C. The prevalence of cardiovascular, cerebrovascular and macrovascular complications were 1.76-fold, 1.24-fold and 1.47-fold more in northern than that in southern Chinese patients. In addition, the prevalence of diabetic nephropathy, retinopathy, neuropathy and microvascular complications in northern Chinese patients also increased. When stratified by age, the difference in both cardiovascular disease and ischemic stroke morbidity became significant, even in the 35-44 years age group. CONCLUSIONS: More macrovascular and microvascular complications were found in northern compared with southern patients, and the largest difference also appeared in the younger age groups <55 years, which might be meaningful to a screening and treatment strategy according to geographic differences.

Fasting triglycerides and glucose index is more suitable for the identification of metabolically unhealthy individuals in the Chinese adult population: A nationwide study.

AIMS/INTRODUCTION: Metabolic unhealth can be defined by the components of metabolic syndrome, which is closely connected to insulin resistance. We aimed to determine a simple index to identify metabolic unhealth in the Chinese adult population. MATERIALS AND METHODS: A total of 30,291 individuals were screened from the China National Diabetes and Metabolic Disorders Study carried out from June 2007 to May 2008. Metabolic unhealth was defined using components of metabolic syndrome, except waist circumference. We compared the three surrogate indices of insulin resistance: the product of fasting triglycerides and glucose (TyG), triglycerides divided by high-density lipoprotein cholesterol and the metabolic score for insulin resistance for the evaluation of metabolic status. RESULTS: All indices had high sensitivity and specificity for the identification of metabolic unhealth, especially the TyG index with an area under the curve of 0.863 for men and 0.867 for women. Participants were divided into subgroups for further analysis. The TyG index also showed high diagnostic values, especially for younger individuals and men with normal waist circumference. Sex-specific cut-offs for three indices were also used to define metabolic unhealth. The TyG index showed the highest agreement with κ values of 0.603 and 0.605 for men and women between the components of metabolic syndrome and three indices. CONCLUSIONS: We propose that the TyG index, just read in one blood laboratory test report, is simpler and more suitable for the identification of metabolically unhealthy individuals as well as who have high risk of cardiometabolic diseases of the Chinese adult population.