Improvement of early-phase insulin secretion is an independent factor for achieving glycaemic control: A pooled analysis of SEED and DAWN study.

AIM: To investigate the effect of improving early phase insulin secretion function for glycaemic control in patients with type 2 diabetes mellitus treated with a new class of antidiabetic drug dorzagliatin. MATERIALS AND METHODS: Early insulin secretion function was studied in 726 participants of which 414 were treated with dorzagliatin in the SEED and DAWN study. The early insulinogenic index (IGI30min ) and disposition index (DI) were used to assess early-phase insulin secretion function in this study. Logistic regression analysis was performed to verify the importance of IGI30min and DI indices for achieving effective glycaemic control. RESULTS: The reduction in HbA1c has a significant correlation with the improvement of IGI30min for patients that received 24 weeks of dorzagliatin treatment (p < .001), and this correlation was not observed in the placebo group (p = .364). In the dorzagliatin treatment group, the responders showed significant improvements in homeostasis model assessment 2-ß, IGI30min and DI compared with the non-responders. Logistic regression analysis revealed that the odds ratio (OR) for achieving glycaemic control was 1.28 (95% CI 1.14-1.43) for baseline IGI30min , and 1.24 (95% CI 1.14-1.35) for the 24-week incremental IGI30min from baseline. The OR for baseline DI and 24-week changes in DI from baseline were 1.39 (95% CI 1.2-1.6) and 1.30 (95% CI 1.19-1.43) respectively. The timing of insulin secretion analysis showed the significant contribution of early-phase insulin secretion, rather than late-phase insulin secretion, to postprandial glucose control with the OR for the incremental IGI30min and IGI2h to postprandial glucose control were 1.3 (95% CI 1.19-1.42) and 1 (95% CI 1-1.01) respectively. CONCLUSIONS: Restoring the impaired early-phase insulin secretion function in patients with type 2 diabetes mellitus is a critical factor for improving the glycaemic control by dorzagliatin treatment.

Effects of age and disease duration on the efficacy and safety of iGlarLixi in Asian people with type 2 diabetes: A post hoc analysis of the LixiLan-O-AP and LixiLan-L-CN trials.

AIM: To evaluate the effect of age and disease duration on the efficacy and safety of iGlarLixi versus insulin glargine 100 units/ml (iGlar) or lixisenatide (Lixi) alone in Asian people with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (LixiLan-O-AP) or basal insulin ± oral antidiabetic drugs (LixiLan-L-CN). MATERIALS AND METHODS: In this post hoc analysis, the glycated haemoglobin (HbA1c) changes were assessed from baseline to week 24 (LixiLan-O-AP) or 30 (LixiLan-L-CN) in subgroups defined by baseline age (<65, ≥65 years) and duration of T2D. The proportion who achieved the composite of HbA1c <7% (<53.0 mmol/mol) without weight gain and without symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L) and the incidences of hypoglycaemia and gastrointestinal disorders were also analysed. RESULTS: HbA1c reductions were consistently greater with iGlarLixi versus iGlar or Lixi across all subgroups, including participants aged ≥65 years and those with T2D for ≥15 or ≥20 years. Greater proportions of participants achieved HbA1c <7% (<53.0 mmol/mol) without weight gain or hypoglycaemia with iGlarLixi versus iGlar or Lixi, regardless of age or T2D duration. Hypoglycaemia incidence was similar with iGlarLixi versus iGlar across most subgroups; the incidence of gastrointestinal disorders was lower with iGlarLixi versus Lixi in all subgroups. CONCLUSIONS: iGlarLixi showed consistent efficacy and safety across all age and disease duration subgroups in Asian people with uncontrolled T2D, including older individuals and those with longstanding disease.

Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

Expression patterns of mechanosensitive ion channel PIEZOs in irreversible pulpitis.

BACKGROUND: Mechanosensitive ion channel PIEZOs have been widely reported to involve inflammation and pain. This study aimed to clarify expression patterns of PIEZOs and their potential relations to irreversible pulpitis. MATERIALS AND METHODS: Normal pulp tissues (n = 29) from patients with impacted third molars and inflamed pulp tissues (n = 23) from patients with irreversible pulpitis were collected. Pain levels were assessed using a numerical rating scale. PIEZO expressions were measured using real-time PCR and then confirmed using GEO datasets GSE77459, immunoblot, and immunohistochemistry staining. Correlations of PIEZO mRNA expression with inflammatory markers, pain markers, or clinical pain levels were evaluated using Spearman's correlation analysis. Univariate analysis was conducted to analyze PIEZO expressions based on pain description and clinical examinations of cold test, percussion, palpation, and bite test. RESULTS: Compared with normal pulp tissues, mRNA expression levels of PIEZO1 were significantly increased in inflamed pulp tissues, while PIEZO2 was significantly decreased, which was further confirmed in GSE77459 and on a protein and histological level. The positive correlation of the mRNA expression levels between PIEZO1 and inflammatory markers, as well as between PIEZO2 and pain markers, was verified. PIEZO2 expression was also positively correlated with pain levels. Besides, irreversible pulpitis patients who reported continuous pain and who detected a positive response to cold stimulus exhibited a higher expression level of PIEZO2 in the inflamed pulp tissues. By contrast, patients reporting pain duration of more than one week showed a higher expression level of PIEZO1. CONCLUSIONS: This study demonstrated the upregulation of PIEZO1 and the downregulation of PIEZO2 in irreversible pulpitis and revealed the potential relation of PIEZO1 and PIEZO2 to inflammation and pain. These findings suggested that PIEZOs might play critical roles in the progression of irreversible pulpitis and paved the way for further investigations aimed at novel therapies of irreversible pulpitis by targeting PIEZOs.

Exploring high-resolution chromatin interaction changes and functional enhancers of myogenic marker genes during myogenic differentiation.

Skeletal muscle differentiation (myogenesis) is a complex and highly coordinated biological process regulated by a series of myogenic marker genes. Chromatin interactions between gene's promoters and their enhancers have an important role in transcriptional control. However, the high-resolution chromatin interactions of myogenic genes and their functional enhancers during myogenesis remain largely unclear. Here, we used circularized chromosome conformation capture coupled with next generation sequencing (4C-seq) to investigate eight myogenic marker genes in C2C12 myoblasts (C2C12-MBs) and C2C12 myotubes (C2C12-MTs). We revealed dynamic chromatin interactions of these marker genes during differentiation and identified 163 and 314 significant interaction sites (SISs) in C2C12-MBs and C2C12-MTs, respectively. The interacting genes of SISs in C2C12-MTs were mainly involved in muscle development, and histone modifications of the SISs changed during differentiation. Through functional genomic screening, we also identified 25 and 41 putative active enhancers in C2C12-MBs and C2C12-MTs, respectively. Using luciferase reporter assays for putative enhancers of Myog and Myh3, we identified eight activating enhancers. Furthermore, dCas9-KRAB epigenome editing and RNA-Seq revealed a role for Myog enhancers in the regulation of Myog expression and myogenic differentiation in the native genomic context. Taken together, this study lays the groundwork for understanding 3D chromatin interaction changes of myogenic genes during myogenesis and provides insights that contribute to our understanding of the role of enhancers in regulating myogenesis.

Saxagliptin combined with additional oral antihyperglycaemic agents in drug-naive diabetic patients with high glycosylated haemoglobin: A 24-week, multicentre, randomized, open-label, active parallel-controlled group clinical trial in China (SUCCESS).

AIM: To assess the efficacy and safety of a dipeptidyl peptidase-4 (DPP-4) inhibitor combined respectively with three oral antihyperglycaemic agents in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM) with high levels of glycated haemoglobin (HbA1c). MATERIALS AND METHODS: Between 30 December 2014 and 1 November 2017, a 24-week, multicentre, parallel-controlled study was performed on drug-naive T2DM patients. In total, 648 patients with 8.0% ≤ HbA1c ≤ 11.0%, aged 18-80 years and body mass index (BMI) 19-40 kg/m2 were randomly assigned 1:1:1 to receive saxagliptin (Saxa) combined with metformin (Met), acarbose (Aca) or gliclazide (Gli) modified release (MR) tablets (Saxa + Met, Saxa + Aca and Saxa + Gli). The primary outcome was the absolute change in HbA1c from baseline; secondary outcome was the percentage of patients achieving HbA1c <7.0% and ≤6.5%. RESULTS: Each treatment arm contained 216 patients; overall, 583 completed the 24-week trial. At 24 weeks, the mean (95% confidence interval) change in HbA1c from baseline in Saxa + Met, Saxa + Aca and Saxa + Gli were, respectively: -2.9% [-3.1, -2.8]; -2.6% [-2.8, -2.5]; and -2.8% [-2.9, -2.6] (overall p = .04, Saxa + Aca vs. Saxa + Met, p = .010, Saxa + Gli vs. Saxa + Met, p = 0.18). At 24 weeks, 84.9%, 74.7% and 80.3% of participants were at HbA1c <7.0% (overall p = .05); and 72.6%, 59.8% and 63.3% were HbA1c ≤6.5% (overall p = 0.10). The rates of minor or symptomatic hypoglycaemia were very low. CONCLUSIONS: Initial treatment with a DPP-4 inhibitor combined with Metform, alpha-glycosidase inhibitor or sulphonylurea was safe and effective for patients with newly diagnosed T2DM and high HbA1c. DPP-4 inhibitor combined with Met showed the best efficacy for this population.

iGlarLixi provides a higher derived time-in-range versus insulin glargine 100 U/mL or lixisenatide in Asian Pacific people with type 2 diabetes: A post hoc analysis.

AIM: To evaluate the efficacy of iGlarLixi in the Asian Pacific (AP) population with type 2 diabetes (T2D) using derived time-in-ranges calculated from seven-point self-measured blood glucose. METHODS: Two phase III trials were analysed. LixiLan-O-AP was performed in insulin-naive T2D patients (n = 878) randomized to iGlarLixi, glargine 100 units/mL (iGlar) or lixisenatide (Lixi). LixiLan-L-CN was performed in insulin-treated T2D patients (n = 426) randomized to iGlarLixi or iGlar. Changes in derived time-in-ranges from baseline to end-of-treatment (EOT) and estimated treatment differences (ETDs) were analysed. The proportions of patients achieving 70% or higher derived time-in-range (dTIR), 5% or higher dTIR improvement, and the composite triple target (≥ 70% dTIR, < 4% derived time-below-the-range [dTBR] and < 25% derived time-above-the-range [dTAR]) were calculated. RESULTS: The changes from baseline to EOT in dTIR with iGlarLixi were greater versus iGlar (ETD1 : 11.45% [95% CI, 7.66% to 15.24%]) or Lixi (ETD2 : 20.54% [95% CI, 15.74% to 25.33%]) in LixiLan-O-AP, and versus iGlar (ETD: 16.59% [95% CI, 12.09% to 21.08%]) in LixiLan-L-CN. In LixiLan-O-AP, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT with iGlarLixi were 77.5% and 77.8%, respectively, higher than with iGlar (61.1% and 75.3%) or Lixi (47.0% and 53.0%). In LixiLan-L-CN, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT were 71.4% and 59.8% with iGlarLixi, greater than with iGlar (45.4% and 39.5%). More patients achieved the triple target with iGlarLixi compared with iGlar or Lixi. CONCLUSION: iGlarLixi achieved greater improvements in dTIR parameters versus iGlar or Lixi in insulin-naïve and insulin-experienced AP people with T2D.

Efficacy and safety benefits of iGlarLixi versus insulin glargine 100 U/mL or lixisenatide in Asian Pacific people with suboptimally controlled type 2 diabetes on oral agents: The LixiLan-O-AP randomized controlled trial.

AIMS: To compare the efficacy and safety of iGlarLixi with insulin glargine 100 units/mL (iGlar) and lixisenatide (Lixi), in Asian Pacific people with suboptimally controlled type 2 diabetes (T2D) on metformin with or without a second oral antihyperglycaemic drug (OAD). MATERIALS AND METHODS: LixiLan-O-AP (NCT03798054) was a 24-week multicentre study in adults (n = 878, mean age 56.0 years, mean body mass index 26.0 kg/m2 ) with glycated haemoglobin (HbA1c) levels ≥53 mmol/mol (7%) and ≤97 mmol/mol (11%) on OAD(s), randomized (2:2:1) to open-label once-daily iGlarLixi, iGlar or Lixi while on continued metformin ± sodium-glucose cotransporter-2 inhibitors. The primary efficacy endpoint was change in HbA1c. RESULTS: After 24 weeks, greater reductions in HbA1c from baseline (67 mmol/mol; 8.3%) were seen with iGlarLixi (-21 mmol/mol; -1.9%) compared with iGlar (-16 mmol/mol; -1.4%; P < 0.0001) and Lixi (-10 mmol/mol; -0.9%; P < 0.0001). Greater proportions of participants achieved HbA1c <53 mmol/mol (<7%) with iGlarLixi versus iGlar or Lixi (79%, 60% and 30%, respectively), overall and as composite endpoints including weight and hypoglycaemia. iGlarLixi improved 2-hour postprandial glucose versus iGlar and Lixi and mitigated the weight gain seen with iGlar (least squares mean difference -1.1 kg; P < 0.0001). Documented ≤3.9 mmol/L (≤70 mg/dL) hypoglycaemia was similar between iGlarLixi and iGlar (both 3.38 events per participant-year). The incidence rates of nausea and vomiting were lower with iGlarLixi (14% and 6%) than Lixi (21% and 11%). CONCLUSIONS: iGlarLixi achieved significant HbA1c reductions, to near-normoglycaemic levels, compared with iGlar or Lixi, with no meaningful additional risk of hypoglycaemia and mitigated body weight gain versus iGlar, with fewer gastrointestinal adverse events versus Lixi. iGlarLixi with specifically adapted ratios may provide an efficacious and well-tolerated treatment option for Asian Pacific people with T2D.

PRDX6 alleviates lipopolysaccharide-induced inflammation and ferroptosis in periodontitis.

OBJECTIVE: Periodontitis is a progressive and inflammatory oral disease and results in the damage of the supporting tissues of teeth. Peroxiredoxin 6 (PRDX6) is an antioxidant enzyme identified as a regulator in ferroptosis. This study aimed to investigate whether PRDX6 could protect human gingival fibroblasts (HGFs) from lipopolysaccharide (LPS)-induced inflammation and its mechanisms. MATERIAL AND METHODS: Both inflamed and non-inflamed human gingival tissues were collected to assess the expression of PRDX6 and nuclear factor erythropoietin 2-related factor 2 (NRF2) by Immunohistochemistry and Western blotting. Furthermore, the molecular mechanisms of PRDX6 have been clarified in PRDX6 silenced cells. The inflammatory cytokines in HGFs were measured by RT-qPCR and ELISA. The lipid hydroperoxide (LOOH) was detected by C11-BODIPY. RESULTS: The expression of PRDX6 and NRF2 were decreased in gingival tissues of severe periodontitis patients. The increased LPS-induced LOOH and inflammatory cytokines were found in PRDX6 knockdown HGFs. Besides, the inhibition of ferroptosis or PRDX6 phospholipase A2 activity (PLA2) alleviated LPS-induced inflammatory cytokines and LOOH. However, inhibiting NRF2 signalling upregulated those in HGFs. CONCLUSIONS: Therefore, this study provided a new mechanistic insight that PRDX6, regulated by the NRF2 signalling, alleviates LPS-induced inflammation and ferroptosis in human gingival fibroblasts.

Genetic mapping high protein content QTL from soybean 'Nanxiadou 25' and candidate gene analysis.

BACKGROUND: Soybean is a globally important legume crop that provides a primary source of high-quality vegetable protein and oil. Seed protein content (SPC) is a valuable quality trait controlled by multiple genes in soybean. RESULTS: In this study, we performed quantitative trait loci (QTL) mapping, QTL-seq, and RNA sequencing (RNA-seq) to reveal the genes controlling protein content in the soybean by using the high protein content variety Nanxiadou 25. A total of 50 QTL for SPC distributed on 14 chromosomes except chromosomes 4, 12, 14, 17, 18, and 19 were identified by QTL mapping using 178 recombinant inbred lines (RILs). Among these QTL, the major QTL qSPC_20-1 and qSPC_20-2 on chromosome 20 were repeatedly detected across six tested environments, corresponding to the location of the major QTL detected using whole-genome sequencing-based QTL-seq. 329 candidate DEGs were obtained within the QTL region of qSPC_20-1 and qSPC_20-2 via gene expression profile analysis. Nine of which were associated with SPC, potentially representing candidate genes. Clone sequencing results showed that different single nucleotide polymorphisms (SNPs) and indels between high and low protein genotypes in Glyma.20G088000 and Glyma.16G066600 may be the cause of changes in this trait. CONCLUSIONS: These results provide the basis for research on candidate genes and marker-assisted selection (MAS) in soybean breeding for seed protein content.

Efficacy and safety of linagliptin as add-on therapy to insulin in Chinese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial.

This 24-week, double-blind, placebo-controlled, phase III trial evaluated the efficacy and safety of linagliptin in 206 Chinese patients with inadequately controlled (glycated haemoglobin [HbA1c] 7.5%-10.0%) type 2 diabetes mellitus (T2DM) receiving insulin (basal or premixed) ± metformin. Patients were randomized (1:1) to receive linagliptin 5 mg/d or placebo. The decrease from baseline in HbA1c (primary endpoint) was greater with linagliptin than with placebo (-0.61% vs. -0.20%, adjusted mean difference -0.40%; P = 0.0016). Linagliptin demonstrated significantly greater improvement in 2-hour postprandial glucose (-1.77 mmol/L [-31.95 mg/dL]; P < 0.001), and a numerical reduction in fasting plasma glucose (-0.34 mmol/L [-6.2 mg/dL]; P = 0.2241) versus placebo. Proportionally more patients on linagliptin achieved a HbA1c reduction of ≥0.5% versus those on placebo (odds ratio 2.293, P < 0.01). Adverse events in both groups were similar, with no new safety findings or clinically relevant changes in body weight. Among investigator-defined hypoglycaemic events (linagliptin: 17.3%; placebo: 12.7%; odds ratio 1.48, P = 0.337), none were severe. In Chinese patients with T2DM, linagliptin add-on to insulin improved glycaemic control and was well tolerated, without increased risk of hypoglycaemia or weight gain.

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double-blind, placebo-controlled phase 3a clinical trial.

AIM: To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. MATERIALS AND METHODS: In a multicentred, randomized, double-blinded, placebo-controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%-10.5%, fasting plasma glucose <13.9 mmol/L) were randomized (1:1:1) for weekly subcutaneous injections: placebo, PEX168/100 µg or PEX168/200 µg. The 24-week treatment was followed by a 28-week extension, during which placebo-treated patients were randomly assigned to PEX168/100 µg or PEX168/200 µg. The primary efficacy endpoint was the HbA1c change from baseline to week 24. RESULTS: The three groups had similar demographics and baseline characteristics. The HbA1c least-square mean (95% CI) change from baseline to week 24 was greater for PEX168/100 µg (-1.02% [-1.21%, -0.83%]) and PEX168/200 µg (-1.34% [-1.54%, -1.15%]) than for placebo (-0.17% [-0.36%, 0.02%]); (superiority: P < .0001). The proportions of patients with less than 7% HbA1c in the placebo, PEX168/100 µg and PEX168/200 µg groups were 15.7%, 34.7% and 46.6%, respectively. Common gastrointestinal adverse events (AEs) were nausea (5.6%, 10.0% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively) and vomiting (2.4%, 8.3% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively). Six (1.6%) patients (PEX168/100 µg: N = 2 [1.6%], PEX168/200 µg: N = 3 [2.5%] and placebo: N = 1 [0.8%]) discontinued treatment because of AEs. Four (1.2%) patients (PEX168/100 µg: N = 3 [2.5%] and PEX168/200 µg: N = 1 [0.9%]) developed PEX168 antidrug antibodies. CONCLUSION: PEX168 monotherapy significantly improved glycaemic control in T2D patients with a safety profile resembling that of other glucagon-like peptide-1 receptor agonists.

Gender-differential effects on blood glucose levels between acarbose and metformin in Chinese patients with newly diagnosed type 2 diabetes: a sub-analysis of the MARCH trial.

Using the data from the trial of Metformin and AcaRbose in Chinese as the initial Hypoglycemic treatment (MARCH), this study was performed to compare the differential effects of acarbose and metformin on glucose metabolism after stratification by gender. Six hundred and forty patients who had finished the whole 48-week follow-up were included. The reduction of haemoglobin A1c (HbA1c) was comparable between acarbose- and metformin-treated patients among either females or males, and it was also similar between males and females treated with either acarbose or metformin for 24 and 48 weeks. The dropping of fasting plasma glucose (FPG) in acarbose-treated females was significantly less than that in metformin-treated females at both 24 and 48 weeks. Furthermore, the decrease of 2-hour postprandial glucose (2hPPG) in acarbose-treated males was significantly greater than that in metformin-treated males at both 24 and 48 weeks. Multiple linear regression analysis showed that drug selection was an independent factor affecting the decrease of FPG in female patients while it independently influenced 2hPPG in males at week 24 and 48. The reductions of FPG and 2hPPG at week 24 and 48 were also significantly different between metformin-treated females and metformin-treated males although gender was not an independent regulating factor. Our study indicates that there might be gender-differential effects on FPG and 2hPPG reduction when the comparisons are made between acarbose and metformin treatments.

Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease.

To investigate the effect of antidiabetic agents on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), 75 patients with T2DM and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on liraglutide, sitagliptin, or insulin glargine in this 26-week trial. The primary endpoint was the change in intrahepatic lipid (IHL) from baseline to week 26 as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF). Secondary endpoints included changes in abdominal adiposity (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]), glycated hemoglobin, and body weight from baseline to week 26. We analysed data from intent-to-treat population. MRI-PDFF, VAT, and weight decreased significantly with liraglutide (15.4% ± 5.6% to 12.5% ± 6.4%, P < 0.001; 171.4 ± 27.8 to 150.5 ± 30.8, P = 0.003; 86.6 ± 12.9 kg to 82.9 ± 11.1 kg, P = 0.005, respectively) and sitagliptin (15.5% ± 5.6% to 11.7% ± 5.0%, P = 0.001; 153.4 ± 31.5 to 139.8 ± 27.3, P = 0.027; 88.2 ± 13.6 kg to 86.5 ± 13.2 kg, P = 0.005, respectively). No significant change in MRI-PDFF, VAT, or body weight was observed with insulin glargine. SAT decreased significantly in the liraglutide group (239.9 ± 69.0 to 211.3 ± 76.1; P = 0.020) but not in the sitagliptin and insulin glargine groups. Changes from baseline in MRI-PDFF, VAT, and body weight were significantly greater with liraglutide than insulin glargine but did not differ significantly between liraglutide and sitagliptin. Conclusion: Combined with metformin, both liraglutide and sitagliptin, but not insulin glargine, reduced body weight, IHL, and VAT in addition to improving glycemic control in patients with T2DM and NAFLD.

Early-onset type 2 diabetes is associated with genetic variants of ß-cell function in the Chinese Han population.

AIMS: To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations. MATERIALS AND METHODS: For 2734 newly diagnosed type 2 diabetes patients and 4041 normal glycemic controls, 25 single nucleotide polymorphisms from 24 genomic loci linked to diabetes were successfully genotyped. Three genetic risk scores (GRSs) were constructed, including the weighted type 2 diabetes-related GRS (wT-GRS), the weighted ß-cell function-related GRS (wB-GRS), and the weighted GRS constructed by risk alleles not related to ß-cell function (wNB-GRS). For patients with diabetes, EOD, middle-age-onset type 2 diabetes (MOD), and late-onset type 2 diabetes (LOD) were defined by onset ages ≤40, 40 to 60, and ≥60 years, respectively. RESULTS: From single marker analysis, different gene profiles were identified between EOD and LOD patients. EOD patients had greater wT-GRS and wB-GRS values than LOD patients. After adjustment for sex, elevated wT-GRS and wB-GRS values were significantly associated with an increased risk for EOD by 1.11- and 1.21-fold per allele (P = 1.69 × 10-7 ; 6.07 × 10-8 ). The wT-GRS and wNB-GRS were nominally related to an increased risk of LOD by 1.03-fold per allele (P = 1.03 × 10-2 , 1.78 × 10-2 ). In patients with diabetes, higher wT-GRS and wB-GRS were associated with younger onset age [wT-GRS: ß (SE) = -0.0033(0.0016), P = 3.74 × 10-2 ; wB-GRS: -0.0076(0.0028), 7.45 × 10-3 ] and decreased insulinogenic index [wT-GRS: -0.0384(0.0098), 9.39 × 10-5 ; wB-GRS: -0.0722(0.0176), 4.21 × 10-5 ]. CONCLUSION: Our findings indicate a strong genetic predisposition for EOD, which can be mainly attributed to genetic variants linked to ß-cell function, suggesting the ß-cell dysfunction plays a key role in the pathogenesis of EOD in Chinese Han individuals.

Prevalences and associated factors of electrocardiographic abnormalities in Chinese adults: a cross-sectional study.

BACKGROUND: Electrocardiogram (ECG) is widely used to screen cardiac diseases. To date, no large population study has provided estimates of the prevalences of ECG findings in China. We aim to investigate the prevalences and associated factors of ECG abnormalities in a general population of Chinese adults. METHODS: ECG data were obtained from 34,965 participants in the 2007-2008 China National Diabetes and Metabolic Disorders Study. ECG abnormalities were classified according to the Minnesota coding (MC) criteria. Prevalences of variant ECG abnormalities were calculated. The associations between ECG abnormalities and gender, age and other risk factors for cardiovascular diseases (CVD) were analyzed by multivariate logistic regression test. RESULTS: The prevalences of major arrhythmias were 1.70, 2.37 and 1.04% in the whole population, men and women, respectively. Atrial fibrillation/flutter was found in 0.35% of men and 0.20% of women. ST depression and T abnormalities accounted for 10.96, 7.54 and 14.32% in the whole population, men and women, respectively. Independent of gender and other CVD risk factors, older age significantly increased the odds of having atrial fibrillation/flutter, complete left bundle branch block, complete right bundle branch block, sinus tachycardia, atrial/junctional/ventricular premature beats, ST depression and T abnormalities, tall R wave left, left/right atrial hypertrophy, left axis deviation and low voltage. Hypertension, overweight, obesity and hypercholesterolemia all independently increased the odds of having ST depression and T abnormalities. History of cardiovascular/cerebrovascular diseases was positively associated with major arrhythmias, ST depression and T abnormalities and tall R wave left. CONCLUSIONS: This study provides estimates of the prevalences of ECG findings in a large population of Chinese adults. Gender, age, CVD risk factors and history of cardiovascular/cerebrovascular diseases were significantly associated with ECG abnormalities.

Determining the optimal fasting glucose target for patients with type 2 diabetes: Results of the multicentre, open-label, randomized-controlled FPG GOAL trial.

The optimal fasting blood glucose (FBG) target of achieving HbA1c less than 7.0% in type 2 diabetes (T2D) patients remains controversial. This open-label trial randomized (1:3:3) 947 adults with uncontrolled T2D (HbA1c >7% to ≤10.5%) who were using one to three oral antidiabetic drugs to achieve an FBG target of 3.9 < FBG ≤5.6 mmol/L (Group 1), 3.9 < FBG ≤6.1 mmol/L (Group 2) or of 3.9 < FBG ≤7.0 mmol/L (Group 3). Targets were achieved using a pre-defined insulin glargine 100 U/mL titration scheme. The primary endpoint was proportion of patients achieving HbA1c <7.0% at 24 weeks. At 24 weeks, 44.4%, 46.1% and 37.7% of patients achieved HbA1c <7.0% in Groups 1, 2 and 3, respectively (P = 0.017; Group 2 vs Group 3). Alert hypoglycaemia (glucose ≤3.9 mmol/L) was significantly more frequent in Group 1 than in Group 3 (38.9 vs 23.3%; P < 0.001) but was not in Group 2 vs Group 3 (27.5% vs 23.3%; P = 0.177). Clinically important hypoglycaemia (glucose ≤3.0 mmol/L) was reported in 4.8%, 2.0% and 3.8% of patients in Groups 1, 2 and 3, respectively. In conclusion, the optimal FBG target for most Chinese patients with T2D appears to be 3.9-6.1 mmol/L.

Efficacy and safety of insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Chinese adults with type 2 diabetes: A phase III, open-label, 2:1 randomized, treat-to-target trial.

AIMS: To assess the efficacy and safety of twice-daily insulin degludec/insulin aspart (IDegAsp) versus biphasic insulin aspart 30 (BIAsp 30) twice daily, both ± metformin, in Chinese adults (N = 543) with type 2 diabetes (T2D) inadequately controlled on premixed/self-mixed or basal insulin ± metformin. MATERIALS AND METHODS: We conducted a 26-week, phase III, open-label, treat-to-target, 2:1 randomized trial. Hierarchical testing was used with non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 26 as the primary endpoint and superiority for the confirmatory secondary endpoints which were as follows: change from baseline in fasting plasma glucose (FPG); nocturnal confirmed hypoglycaemic episodes (12:01-5:59 am, inclusive); total confirmed hypoglycaemic episodes (severe or plasma glucose <3.1 mmol/L with/without symptoms); body weight; and percentage of responders (HbA1c <53 mmol/mol [<7.0%]) without confirmed hypoglycaemic episodes. RESULTS: Non-inferiority for change from baseline to week 26 in HbA1c and superiority of IDegAsp twice daily versus BIAsp 30 twice daily for change in FPG, nocturnal confirmed and total confirmed hypoglycaemic episodes, was demonstrated. Estimated rates of nocturnal confirmed and total confirmed hypoglycaemic episodes were 47% and 43% lower, respectively, with IDegAsp twice daily versus BIAsp 30 twice daily. Superiority for change in body weight was not confirmed. Participants were more likely to reach the HbA1c goal of <53 mmol/mol (<7.0%) without confirmed hypoglycaemia with IDegAsp twice daily versus BIAsp 30 twice daily by trial end. No new safety signals were identified. CONCLUSIONS: The efficacy and safety of IDegAsp in Chinese patients with T2D was demonstrated, confirming results from international trials.

Identification of autoimmune type 1 diabetes and multiple organ-specific autoantibodies in adult-onset non-insulin-requiring diabetes in China: A population-based multicentre nationwide survey.

AIMS: To investigate the prevalence of adult-onset autoimmune diabetes (ADM) and predisposition to autoimmune diseases by quantifying serum organ-specific autoantibodies in people with phenotype of type 2 diabetes (T2D). MATERIALS AND METHODS: We included a nationally representative sample of 46 239 adults aged ≥20 years from 14 provinces, of whom 4671 had diabetes, plus 1000 control subjects with normal glucose tolerance (NGT). Participants were screened centrally for autoantibodies to glutamic acid decarboxylase (GAD), islet antigen 2 (IA2) and zinc transporter isoform-8 (Znt8) and were defined as having ADM where positive for these antibodies. We then assayed thyroid peroxidase (TPO), tissue transglutaminase (tTG) and 21-hydroxylase (21-OH) autoantibodies in randomly selected participants with ADM and in age-matched, sex-matched and non-ADM controls with T2D plus controls with NGT. RESULTS: Post-normalization, the standardized prevalence rate of ADM was 6.0% (95% confidence interval [CI] 5.3-6.8) in initially non-insulin-requiring participants with ADM, corresponding to six million adults in China, in whom adjusted antibody positivity was: TPO autoantibodies 16.3% (95% CI 10.8-21.8), tTG autoantibodies 2.1% (95% CI 0.0-4.2), and 21-OH autoantibodies 1.8% (95% CI -0.2 to 3.8). Those participants with ADM who were GAD autoantibody-positive had high risk of TPO autoantibody positivity (odds ratio [OR] 2.39, P = 0.0031) and tTG autoantibody positivity (OR 6.98, P = 0.027), while those positive for IA2 autoantibodies had a high risk of tTG autoantibody positivity (OR 19.05, P = 0.001). CONCLUSIONS: A proportion of people with phenotype of T2D in China have ADM, with diabetes-associated autoantibodies, and may be at risk of developing other organ-specific autoimmune diseases; therefore, it may be clinically relevant to consider screening such Chinese populations.

Comparison of therapeutic effects of acarbose and metformin under different ß-cell function status in Chinese patients with type 2 diabetes.

MARCH study suggested that acarbose had similar therapeutic effect on glycated hemoglobin reduction compared to metformin in newly diagnosed type 2 diabetes patients as initial therapy in China. We aimed to investigate whether the efficacy of acarbose was still similar to metformin under different ß-cell function status. According to the homeostasis model assessment (HOMA)-ß level, 670 patients were divided into better ß-cell function group, medium ß-cell function group and poor ß-cell function group. Patients received acarbose 300 mg/d or metformin 1,500 mg/d for 48 weeks. We found both acarbose and metformin could decrease glycated hemoglobin to similar levels after 48 weeks treatment in all groups. In medium ß-cell function group, the decrease of fasting blood glucose after metformin treatment was more significant compared to acarbose (p = 0.040); however, the decrease of post-challenge blood glucose after acarbose treatment was more significant compared to metformin (p = 0.020). Moreover, in poor ß-cell function group, the decrease of body weight and body mass index after acarbose treatment were significant compared to metformin (p = 0.004 and p = 0.031, respectively). Therefore, acarbose contributed a similar therapeutic effect to plasma glucose control compared to metformin treatment, even under different ß-cell function status.