The efficacy and safety of beinaglutide alone or in combination with insulin glargine in Chinese patients with type 2 diabetes mellitus who are inadequately controlled with oral antihyperglycemic therapy: A multicenter, open-label, randomized trial.

BACKGROUND: To compare glycemic control in Chinese patients with type 2 diabetes mellitus (T2DM) whose blood glucose levels were inadequately controlled with oral antidiabetic drugs after beinaglutide alone or combined with insulin glargine (IGlar). METHODS: In this 16-week multicenter, randomized clinical trial, 68 participants randomly received beinaglutide or IGlar for 8 weeks, then the two drugs in combination for 8 weeks. The primary outcomes were the proportion of individuals achieving their glycemic target and the change in glucose variability as measured with a continuous glucose monitoring system from baseline to 8 and 16 weeks. RESULTS: Both the beinaglutide and IGlar groups showed increased proportions achieving their glycemic target at 8 weeks, and the combination augmented the proportion reaching the glycated hemoglobin target from 25.42% at 8 weeks to 40.68% at 16 weeks. The beinaglutide group showed a significant reduction in body weight, body mass index, waist circumference, and systolic blood pressure. Beinaglutide elevated high-density lipoprotein cholesterol by 0.08 mmol/L (95% confidence interval [CI], 0.00-0.16), and diminished low-density lipoprotein cholesterol by 0.21 mmol/L (95% CI, 0.05-0.48), whereas IGlar showed no effect. Though IGlar was more efficient in lowering fasting plasma glucose than beinaglutide at comparable efficacies (to -1.57 mmol/L [95% CI, -2.60 to -0.54]), this difference was abolished in patients whose fasting C-peptide was ≥0.9 ng/mL. CONCLUSION: Beinaglutide exhibited a favorable hypoglycemic effect on patients with T2DM, and in combination with IGlar, glucose level was further decreased. Low fasting C-peptide in patients may reduce the glycemic response to beinaglutide therapy. We recommend that C-peptide levels be evaluated when using or switching to the novel glucagon-like peptide-1 receptor agonists beinaglutide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03829891.

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.

Shared and specific biological signalling pathways for diabetic retinopathy, peripheral neuropathy and nephropathy by high-throughput sequencing analysis.

OBJECTIVES: We aimed to explore the shared and specific signalling pathways involved in diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN). METHODS: Differentially expressed mRNAs and lncRNAs were identified by high-throughput sequencing. Subsequently, functional enrichment analysis, protein-protein interaction (PPI) analysis and lncRNAs-mRNAs networks were conducted to determine the pathogenic mechanisms underlying DR, DPN and DN. RESULTS: Twenty-six biological pathways were shared among DR, DPN and DN groups compared to the type 2 diabetes mellitus (T2DM) group without complications, and most of the shared pathways and core proteins were involved in immune and inflammatory responses of microvascular damage. Cytokine‒cytokine receptor interactions and chemokine signalling pathway were the most significant and specific pathways for DR, and the lncRNA‒mRNA regulatory networks affected DR by targeting these pathways. Sphingolipid metabolism and neuroactive ligand-receptor pathways were found to be specific for the pathogenesis of DPN. Moreover, multiple amino acid metabolic pathways were involved in the occurrence and progression of DN. CONCLUSIONS: Diabetic retinopathy, DPN and DN exhibited commonality and heterogeneity simultaneously. The shared pathologic mechanisms underlying these diabetic complications are involved in diabetic microvascular damage via immune and inflammatory pathways. Our findings predict several biomarkers and therapeutic targets for these diabetic complications.

Establishment and characterization of IPS-OGC-C1: a novel induced pluripotent stem cell line from healthy human ovarian granulosa cells.

Ovarian granulosa cell (OGC) is a critical somatic component of the ovary, which provides physical support and the microenvironment required for the developing oocyte. Human OGCs are easy to obtain and culture as a by-product of follicular aspiration performed during in vitro fertilization (IVF) procedures. Therefore, OGCs offer a potent cell source to generate induced pluripotent stem cells (iPSCs). This study established a novel OGCs-derived iPSC cell line from the follicular fluid of a healthy female donor with a Chinese Han genetic background and named it IPS-OGC-C1. IPS-OGC-C1 was verified for embryonic stem cell morphology, cell marker expression, alkaline phosphatase (AP) activity, transcriptomic profile, and pluripotency capability in developing all three embryonic germ layers in vivo and in vitro.

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.

Efficacy and safety of a needle-free injector in Chinese patients with type 2 diabetes mellitus treated with basal insulin: a multicentre, prospective, randomised, crossover study.

Objective: To evaluate the efficacy and safety of a needle-free injector in Chinese patients with type 2 diabetes mellitus treated with basal insulin. Methods: 62 patients with type 2 diabetes were enrolled in a multicenter, randomised, prospective, open-label, crossover study. All patients received subcutaneous insulin glargine administered by a needle-free injector or a glargine pen for 7 ~ 14 days, and were then crossed over after wash out. Results: Patients in the insulin needle-free injector (NFI) and glargine pen (GP) groups achieved similar fasting blood glucose control . However, the dosage of insulin required to achieve the target FBG level in the NFI group was lower than in the GP group (16.14 ± 5.13 U/day vs 19.25 ± 6.20 U/day, respectively; p = 0.0046). This difference was more significant in patients who received higher insulin dosages compared with those receiving lower dosages. Use of the needle-free injector was also associated with significantly less pain (p < 0.001) and less fear of injection (p < 0.001) than glargine pens. Conclusion: The use of a needle-free injector can significantly lower the dosage of insulin required to achieve good glycemic control and reduce topical adverse reactions and the fear of injections as well, which help to improve patient compliance. Clinical Trial Registration Number KY20172077-1; NCT03420040.

MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1α signaling.

Type 2 diabetes (T2DM) has been considered to be associated with a higher likelihood of hearing impairment (HI). However, the molecular mechanisms underlying the association between diabetes and HI are poorly understood. MicroRNAs have recently been demonstrated to be closely associated with hearing loss and considered as promising therapeutic targets. Herein, we investigated whether miR-34a contributes to diabetes-related cochlear hair cell apoptosis and sought to identify the underlying mechanism. The results showed that miR-34a was up-regulated in the cochleas of db/db mice, accompanied by significant hearing threshold elevation and hair cell loss. However, the expression of SIRT1 was significantly down-regulated, while hypoxia-inducible factor-1alpha (HIF-1α) levels were dramatically increased in the cochleas of db/db mice. In addition, in the high-glucose cultured House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line, miR-34a overexpression inhibited sirtuin1 (SIRT1) expression, increased HIF-1α levels and promoted apoptosis. MiR-34a knockdown exerted effects that were diametrically opposed to those observed with overexpression. Interestingly, HIF-1α knockdown almost eliminated the cell apoptosis induced by high glucose levels. We also examined the modulation of HIF-1α expression by SIRT1. The results showed that SIRT1 knockdown further promoted high-glucose-induced HIF-1α expression, while SIRT1 overexpression significantly inhibited HIF-1α level induced by high glucose. These findings point to a new mechanism by which miR-34a exerts its detrimental effects by negatively regulating SIRT1/HIF-1α signaling and provide new therapeutic targets for treating hearing impairment during diabetes.

Netrin-1 restores cell injury and impaired angiogenesis in vascular endothelial cells upon high glucose by PI3K/AKT-eNOS.

Diabetic foot ulceration (DFU) represents a common vascular complication of diabetes mellitus (DM) with high morbidity and disability resulting from amputation. Netrin-1 level was decreased in type 2 DM patients and has been identified as a protective regulator against diabetes-triggered myocardial infarction and nephropathy. Unfortunately, its role and molecular mechanism in DFU remain poorly elucidated. Here, netrin-1 levels were reduced in DM and DFU patients relative to healthy controls, with netrin-1 levels being the lowest in DFU patients. Moreover, exposure to high glucose (HG) also suppressed netrin-1 expression in human umbilical vein endothelial cells (HUVECs). Elevated netrin-1 expression by infection with Ad-netrin-1 adenovirus vector protected against HUVEC injury in response to HG by ameliorating the inhibitory effects on cell viability, lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, cell apoptotic rate and caspase-3 activity. Importantly, HG-impaired angiogenesis was improved after netrin-1 overexpression by elevating cell migration, capillary-like tube formation and VEGF production. Mechanism assay substantiated that netrin-1 elevation increased the phosphorylation levels of AKT and eNOS, and NO production, which was notably suppressed by HG, indicating that netrin-1 overexpression restored HG-triggered impairment of the PI3K/AKT-eNOS pathway. More intriguingly, preconditioning with LY294002 (PI3K/AKT antagonist) or NG-monomethyl-l-arginine (eNOS inhibitor) antagonized netrin-1-induced activation of the PI3K/AKT-eNOS pathway. Concomitantly, treatment with these antagonists also attenuated the protective role of netrin-1 in endothelial dysfunction upon HG stimulation. These results suggest that elevation of netrin-1 may restore HG-triggered impairment of HUVEC and angiogenesis by activating the PI3K/AKT-eNOS pathway, indicating a potential agent for wound healing in DFU patients.

A comparison of ultrasound and magnetic resonance imaging to assess visceral fat in the metabolic syndrome.

Visceral adipose tissue (VAT) plays a key role in the metabolic syndrome. Easy detection of VAT could be an important tool to increase understanding of the metabolic syndrome. To study the relationship between the area of the inferior part of the perirenal fat (AIPPF) and anthropometric, imaging and cardiovascular risk factors of metabolic syndrome, seventy two subjects with metabolic syndrome were recruited including 44 men and 28 women (age: 26-68 yr). Each subject underwent ultrasound detection of AIPPF, intraabdominal fat thickness and magnetic resonance imaging (MRI) to calculate abdominal VAT (MRI VAT). Anthropometric and cardiovascular risk factors were also evaluated. AIPPF measured by ultrasonography demonstrated excellent reproducibility. Receiver operating characteristic analysis revealed that AIPPF has the best sensitivity for women, specificity for men and accuracy of the various measures to predict visceral obesity (MRI VAT value > or = 110 cm2) for both genders. AIPPF was related to MRI VAT, ultrasound measured intraabdominal fat, waist circumference, the ratio of waist and hip circumferences (of men), body mass index and the main cardiovascular risk factors of metabolic syndrome. Multiple stepwise linear regression analysis suggested that MRI VAT affected AIPPF independent of other investigated obesity indices. This study showed that AIPPF could be applied as an easy and reliable imaging indicator of visceral obesity and cardiovascular risk factors in the metabolic syndrome.