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.

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.

Secondary analysis of newly diagnosed type 2 diabetes subgroups and treatment responses in the MARCH cohort.

OBJECTIVE: To incorporate new clusters in the MARCH (Metformin and AcaRbose in Chinese patients as the initial Hypoglycemic treatment) cohort of newly diagnosed type 2 diabetes (T2D) patients and compare the anti-glycemic effects of metformin and acarbose across different clusters. METHODS: K-means cluster analysis was performed based on six clinical indicators. The diabetic clusters in the MARCH cohort were retrospectively associated with the response to metformin and acarbose. RESULTS: A total of 590 newly diagnosed T2D patients were classified by data-driven clusters into the MARD (mild obesity-related diabetes) (34.1 %), MOD (mild obesity-related diabetes) (34.1 %), SIDD (severe insulin-deficient diabetes) (20.3 %) and SIRD (severe insulin-resistant diabetes) (11.5 %) subgroups at baseline. At 24 and 48 weeks, 346 participants had finished the follow-up. After the adjustment of age, gender, weight, baseline HbA1c, baseline fasting glucose and 2-h postprandial blood glucose (2hPG), metformin mainly decreased the fasting glucose (0.07 ± 0.89 vs -0.26 ± 0.83, P = 0.043) in the MARD subgroup presented with OGTT (oral glucose tolerance test) results compared with acarbose group at 24 weeks. Acarbose led to a greater decrease in 2hPG in the MOD subgroup compared with metformin group (0.08 ± 0.86 vs -0.24 ± 0.92, P = 0.037) at 24 weeks. There was a also significant interaction between cluster and treatment efficacy in HbA1c (glycated hemoglobin) reduction in metformin and acarbose groups at 24 and 48 weeks (pinteraction<0.001). CONCLUSIONS: Metformin and acarbose affected different metabolic variables depending on the diabetes subtype.

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.

Changes in the prevalence of diabetes and control of risk factors for diabetes among Chinese adults from 2007 to 2017: An analysis of repeated national cross-sectional surveys.

INTRODUCTION: To examine changes in the prevalence of diabetes and the control of risk factors for diabetes over 10 years among adults in China. METHODS: Two population-based cross-sectional surveys were used to obtain a nationally representative sample of adults aged 20 years and older in mainland China in 2007 (n = 46 239) and 2017 (n = 73 340). Changes in the prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and prediabetes, as diagnosed by the World Health Organization criteria, were assessed over time. RESULTS: The weighted prevalence of diagnosed diabetes (3.8% vs 6.3%, p = .0001) and total diabetes (9.7% vs 11.7%, p = .005) increased among the overall population between 2007 and 2017. The weighted prevalence of undiagnosed diabetes (5.9% vs 5.4%, p = .7), impaired fasting glucose (2.7% vs 2.6%, p = .68), impaired glucose tolerance (12.7% vs 12.5%, p = .95), prediabetes (15.4% vs 15.1%, p = .79), the treatment of diabetes (34.1% vs 32.5%, p = .44), and the control of diabetes (31.1% vs 32.8%, p = .73) did not significantly change over this period. The awareness of diabetes (39.4% vs 53.6%, p = .0004) increased over 10 years among the overall population. The proportion of achieved high-density lipoprotein cholesterol targets increased (p = .005), but the proportion of achieved body mass index (p = .01) and waist circumference (p = .0002) targets decreased significantly. CONCLUSIONS: Between 2007 and 2017, the prevalence of total diabetes (diagnosed by the World Health Organization criteria), especially diagnosed diabetes, increased among adults in China. Although awareness of diabetes improved, effective interventions and clinical strategies are urgently required.

Cardiovascular disease risk in early-onset vs late-onset type 2 diabetes in China: A population-based cross-sectional study.

BACKGROUND: This study investigated the effects of early-onset type 2 diabetes (EOD) vs late-onset type 2 diabetes (LOD) on nonfatal cardiovascular diseases (CVD) in China. METHODS: We conducted a cross-sectional survey of 46 239 participants from 14 provinces in China from 2007 to 2008, selecting 4949 participants with type 2 diabetes for analysis. Participants were categorized as EOD (<40 years) or LOD (≥40 years) based on age at diabetes diagnosis. Sociodemographic and nonfatal CVD information was collected through an interviewer-assisted questionnaire and clinical examination. Logistic regression analysis was used to investigate the nonfatal CVD risk. RESULTS: Out of 4949 participants with type 2 diabetes, 390 (7.88%) had nonfatal CVD. Participants with EOD had a higher age-standardized prevalence of nonfatal CVD than those with LOD (11.4% vs 4.4%). Compared to LOD patients, EOD patients tended to be males and had a higher family history of diabetes, unhealthy lifestyle behaviors, and lower blood pressure levels. After adjustment for age and sex, EOD patients had a higher risk of nonfatal CVD than LOD patients (odds ratio [OR] 2.3, 95% CI 1.5-3.5). After further adjustment for diabetes duration, use of drugs, and other risk factors, the OR of nonfatal CVD was reduced but significant (OR 1.8, 95% CI 1.1-2.9). Sensitivity analysis revealed that EOD patients with metabolic syndrome had an increased nonfatal CVD risk compared to LOD patients (OR 2.0, 95% CI 1.2-3.5). CONCLUSIONS: EOD patients are at increased risk of nonfatal CVD. Individualized intervention and management measures for EOD patients are necessary.

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.

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.

Data-driven subgroups of newly diagnosed type 2 diabetes and the relationship with cardiovascular diseases at genetic and clinical levels in Chinese adults.

BACKGROUND: To subgroup Chinese patients with newly diagnosed type 2 diabetes (T2D) by K-means cluster analysis on clinical indicators, and to explore whether these subgroups represent different genetic features and calculated cardiovascular risks. METHODS: The K-means clustering analysis was performed on two cohorts (n = 590 and 392), both consisting of Chinese participants with newly diagnosed T2D. To assess genetic risks, multiple polygenic risk scores (PRSs) and mitochondrial DNA copy numbers (mtDNA-CN) were calculated for all participants. Furthermore, Framingham risk scores (FRS) of cardiovascular diseases in two cohorts were also calculated to verify the genetic risks. RESULTS: Four clusters were identified including the mild age-related diabetes (MARD)(35.08%), mild obesity-related diabetes (MOD) (34.41%), severe autoimmune diabetes (SAID) 19.15%, and severe insulin-resistant diabetes (SIRD) 11.36% subgroups in the MARCH (metformin, and acarbose in Chinese patients as the initial hypoglycemic treatment) cohort. There was a significant difference in PRS for cardiovascular diseases (CVD) across four subgroups in the MARCH cohort (p < 0.05). Compared with the SIDD and SIRD subgroups, patients in the MOD subgroup had a relatively lower PRS for CVD (p < 0.05) in the MARCH cohort. Females had a higher PRS compared to males, with no significant difference in FRS across the four clusters. The MOD subgroup had a significantly lower FRS which was consistent with the results of PRS. Similar results of PRS and FRS were also replicated in the CONFIDENCE (comparison of glycemic control and b-cell function among newly diagnosed patients with type 2 diabetes treated with exenatide, insulin or pioglitazone) cohort. CONCLUSION: There are different CVD risks in diabetic subgroups based on clinical and genetic evidence which may promote precision medicine.

Postprandial glucagon-like peptide 1 secretion is associated with urinary albumin excretion in newly diagnosed type 2 diabetes patients.

BACKGROUND: Microalbuminuria is an early and informative marker of diabetic nephropathy. Our study found that microalbuminuria developed in patients with newly diagnosed type 2 diabetes mellitus (T2DM). AIM: To investigate the association between glucagon-like peptide 1 (GLP-1) and microalbuminuria in newly diagnosed T2DM patients. METHODS: In total, 760 patients were recruited for this cross-sectional study. The GLP-1 levels during a standard meal test and urinary albumin-creatinine ratio (UACR) were determined. RESULTS: Patients with microalbuminuria exhibited lower GLP-1 levels at 30 min and 120 min during a standard meal test than patients with normal albuminuria (30 min GLP-1, 16.7 ± 13.3 pmol vs 19.9 ± 15.6 pmol, P = 0.007; 120 min GLP-1, 16.0 ± 14.1 pmol vs 18.4 ± 13.8 pmol, P = 0.037). The corresponding area under the curve for active GLP-1 (AUCGLP-1) was also lower in microalbuminuria patients (2257, 1585 to 3506 vs 2896, 1763 to 4726, pmol × min, P = 0.003). Postprandial GLP-1 levels at 30 min and 120 min and AUCGLP-1 were negatively correlated with the UACR (r = 0.159, r = 0.132, r = 0.206, respectively, P < 0.001). The prevalence of microalbuminuria in patients with newly diagnosed T2DM was 21.7%, which decreased with increasing quartiles of AUCGLP-1 levels (27.4%, 25.3%, 18.9% and 15.8%). After logistic regression analysis adjusted for sex, age, hemoglobin A1c, body mass index, systolic blood pressure, estimated glomerular filtration rate, homeostasis model assessment of insulin resistance, AUCglucose and AUCglucagon, patients in quartile 4 of the AUCGLP-1 presented a lower risk of microalbuminuria compared with the patients in quartile 1 (odds ratio = 0.547, 95% confidence interval: 0.325-0.920, P = 0.01). A consistent association was also found between 30 min GLP-1 or 120 min GLP-1 and microalbuminuria. CONCLUSION: Postprandial GLP-1 levels were independently associated with microalbuminuria in newly diagnosed Chinese T2DM patients.

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.

Mitochondrial DNA Copy Number Is a Potential Biomarker for Treatment Choice Between Metformin and Acarbose.

Metformin is the first-line drug for type 2 diabetes (T2D) while acarbose is suggested as a viable alternative in Chinese patients with newly diagnosed T2D. However, few biomarkers have been established to guide the choice between these two agents. Mitochondrial DNA (mtDNA) copy number (mtDNA-CN) is a biomarker of mitochondrial function, which is associated with various metabolic outcomes. Using data from the trial of Metformin and Acarbose in Chinese as the Initial Hypoglycaemic Treatment (MARCH) (metformin n = 214; acarbose n = 198), we examined whether mtDNA-CN was associated with response to the drugs in terms of glycemic response and ß-cell function protection response. The glycemic response is defined as the maximum glucose reduction of glycated hemoglobin A1c , fasting plasma glucose, or postprandial blood glucose during 48 weeks. ß-cell function protection response is defined as the maximum increment of insulinogenic index (IGI) or disposition index (DI). For all three glycemic responses, mtDNA-CN was not significantly associated with either metformin or acarbose. Importantly, for ß-cell function protection response, we found the increased mtDNA-CN was significantly associated with more IGI increment (beta: 0.84; 95% confidence interval (CI), 0.02 to 1.66) in the metformin group, but less IGI increment (beta: -1.38; 95% CI, -2.52 to -0.23) in the acarbose group. A significant interaction (P = 0.008) between mtDNA-CN and the treatment group was observed. Consistent results were also obtained when DI increment was used as a measure of ß-cell function response. This study demonstrated the potential application of mtDNA-CN in guiding the treatment choice between metformin and acarbose based on ß-cell protection.

Higher mitochondrial DNA copy number is associated with metformin-induced weight loss.

BACKGROUND: Considerable variability exists in response to metformin with few effective biomarkers to guide the treatment. Here we evaluated whether whole blood derived mitochondrial DNA copy number (mtDNA-CN) is a biomarker of metformin response as measured by glucose reduction or weight loss. METHODS: Using data from the trial of Metformin (n = 304) and AcaRbose (n = 300) in Chinese as the initial Hypoglycaemic treatment (MARCH), we examined the association between mtDNA-CN and two metformin response outcomes of HbA1c reduction and weight loss. The acarbose arm was used as a comparator group. Whole blood mtDNA-CN was estimated by deep whole genome sequencing with adjustments for confounders. Multiple linear regression and repeated measurement analyses were used to evaluate the association between mtDNA-CN and drug response outcomes. RESULTS: Here we show that glucose reduction is not significantly associated with mtDNA-CN and in either treatment arm. In the metformin arm, each increase of 1 SD in mtDNA-CN is significantly (P = 0.006) associated with a 0.43 kg more weight loss. Repeated measurement analysis shows that after 16 weeks of metformin monotherapy, patients in the top tertile of mtDNA-CN consistently lost 1.21 kg more weight than those in the bottom tertile (P < 0.001). In comparison, mtDNA-CN is not significantly associated with acarbose-induced weight loss. CONCLUSIONS: Patients with higher mtDNA-CN are likely to lose more weight upon metformin treatment, suggesting mtDNA-CN as a potential novel biomarker for more effective weight management in type 2 diabetes.

Treatment of diabetes with the drug metformin can lead to beneficial weight loss. However, there is considerable variability in how patients respond to metformin and few markers or tests are available to guide prescribing. Here, we look at data from patients who took part in a trial comparing metformin with another diabetes drug and determine whether a particular marker­mitochondrial DNA copy number (mtDNA-CN)­is associated with weight loss with these treatments. mtDNA-CN is a proxy for the function of the mitochondria, an important organelle for the generation of metabolic energy in eukaryotic cells. Our results show that patients with diabetes with a higher mtDNA-CN lost more weight upon metformin treatment. This marker could potentially be used to guide treatment with metformin. Our findings warrant further exploration of mtDNA-CN as a marker of response to other drugs.

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.

Yogliptin monotherapy in type 2 diabetes: A 12-week randomized, double-blind, placebo-controlled phase II study.

BACKGROUND: The new xanthine dipeptidyl peptidase-4 inhibitor yogliptin has exhibited excellent hypoglycemic activity in experimental disease models. The present work aimed to assess the efficacy of yogliptin as a monotherapy in individuals with type 2 diabetes mellitus (T2DM). METHODS: A 12-week, double-blind, placebo-controlled phase II study was performed. T2DM patients (new diagnosis or inadequately controlled) were randomly divided into groups (1:1:1:1) and administered either a placebo or weekly doses of 200, 300, or 400 mg yogliptin, respectively. The primary efficacy end point in this analysis was hemoglobin A1c (HbA1c) change at 12 weeks relative to baseline. Relevant secondary outcomes were also examined, including fasting plasma glucose (FPG), 2 h-postprandial plasma glucose (PPG), body weight, and the rate of individuals who achieved the treatment goal of HbA1c ≤ 7% at 12 weeks from baseline. RESULTS: A total of 81 cases who received either the placebo (20 cases) or 200 (20 cases), 300 (20 cases), or 400 (21 cases) mg yogliptin were examined in the full analysis set. At 12 weeks, changes in HbA1c levels from baseline were 0.17 (-0.22, 0.57) in the placebo group, and -0.75 (-1.15, -0.35), -0.52 (-0.93, -0.11) and -1.02 (-1.41, -0.64) (mean % [95% confidence interval], p < .001 vs. placebo) in the 200, 300, and 400 mg yogliptin groups, respectively. From week four, significant improvements in secondary efficacy outcomes among patients administered the yogliptin monotherapy were observed. FPG showed markedly more pronounced reduction after treatment with yogliptin at 200, 300, and 400 mg in comparison with placebo patients at 4, 8, and 12 weeks. At 12 weeks, goal attainment (HbA1c ≤ 7%) was reached in 0%, 20.00%, 15.80%, and 33.33% of the placebo and three Yogliptin dosage groups, respectively. Adverse events were comparable in all groups. CONCLUSIONS: This study demonstrated that yogliptin controlled glycemia in Chinese T2DM cases, with a great safety profile. The current findings supported that any of the three doses of yogliptin, administered once a week, could be used for phase III clinical studies.

Development and validation of a risk assessment model for prediabetes in China national diabetes survey.

BACKGROUND: Prediabetes risk assessment models derived from large sample sizes are scarce. AIM: To establish a robust assessment model for prediabetes and to validate the model in different populations. METHODS: The China National Diabetes and Metabolic Disorders Study (CNDMDS) collected information from 47325 participants aged at least 20 years across China from 2007 to 2008. The Thyroid Disorders, Iodine Status and Diabetes Epidemiological Survey (TIDE) study collected data from 66108 participants aged at least 18 years across China from 2015 to 2017. A logistic model with stepwise selection was performed to identify significant risk factors for prediabetes and was internally validated by bootstrapping in the CNDMDS. External validations were performed in diverse populations, including populations of Hispanic (Mexican American, other Hispanic) and non-Hispanic (White, Black and Asian) participants in the National Health and Nutrition Examination Survey (NHANES) in the United States and 66108 participants in the TIDE study in China. C statistics and calibration plots were adopted to evaluate the model's discrimination and calibration performance. RESULTS: A set of easily measured indicators (age, education, family history of diabetes, waist circumference, body mass index, and systolic blood pressure) were selected as significant risk factors. A risk assessment model was established for prediabetes with a C statistic of 0.6998 (95%CI: 0.6933 to 0.7063) and a calibration slope of 1.0002. When externally validated in the NHANES and TIDE studies, the model showed increased C statistics in Mexican American, other Hispanic, Non-Hispanic Black, Asian and Chinese populations but a slightly decreased C statistic in non-Hispanic White individuals. Applying the risk assessment model to the TIDE population, we obtained a C statistic of 0.7308 (95%CI: 0.7260 to 0.7357) and a calibration slope of 1.1137. A risk score was derived to assess prediabetes. Individuals with scores ≥ 7 points were at high risk of prediabetes, with a sensitivity of 60.19% and specificity of 67.59%. CONCLUSION: An easy-to-use assessment model for prediabetes was established and was internally and externally validated in different populations. The model had a satisfactory performance and could screen individuals with a high risk of prediabetes.

Development and assessment of diabetic nephropathy prediction model using hub genes identified by weighted correlation network analysis.

Diabetic nephropathy (DN) is one microvascular complication of diabetes. About 30% of diabetic patients can develop DN, which is closely related to the high incidence and mortality of heart diseases, and then develop end-stage renal diseases. Therefore, early detection and screening of high-risk patients with DN is important. Herein, we explored the differences of serum transcriptomics between DN and non-DN in type II diabetes mellitus (T2DM) patients. We obtained 110 target genes using weighted correlation network analysis. Gene Ontology enrichment analysis indicates these target genes are mainly related to membrane adhesion, alpha-amino acid biosynthesis, metabolism, and binding, terminus, inhibitory synapse, clathrinid-sculpted vesicle, kinase activity, hormone binding, receptor activity, and transporter activity. Kyoto Encyclopedia of Genes and Genomes analysis indicates the process of DN in diabetic patients can involve synaptic vesicle cycle, cysteine and methionine metabolism, N-Glycan biosynthesis, osteoclast differentiation, and cAMP signaling pathway. Next, we detected the expression levels of hub genes in a retrospective cohort. Then, we developed a risk score tool included in the prediction model for early DN in T2DM patients. The prediction model was well applied into clinical practice, as confirmed by internal validation and several other methods. A novel DN risk model with relatively high prediction accuracy was established based on clinical characteristics and hub genes of serum detection. The estimated risk score can help clinicians develop individualized intervention programs for DN in T2DM. External validation data are required before individualized intervention measures.

Predictors of HbA1c reduction and hypoglycemia in type 2 diabetes mellitus individuals switching from premixed to basal insulin: an exploratory analysis of optimization study.

OBJECTIVE: To identify population with type 2 diabetes mellitus (T2DM) who are more likely to benefit from switching to basal insulin (BI) treatment from premixed insulin. METHODS: This secondary analysis included data from a previously published study (Optimization: NCT00693771) which was a single-arm, multicenter, 16 weeks, phase IV study. The analysis included participants with T2DM inadequately controlled with premixed insulin plus oral hypoglycemic drugs (OADs) who switched to BI plus OADs. RESULTS: Among the 297 participants included for analysis, subjects with fasting C-peptide (FCP)>1.2 nmol/L group showed a trend for greater reduction in HbA1c [Least square mean difference (LSMD), -0.59; 95% confidence interval (CI), -0.98 to -0.21; p = 0.003] and FPG (LSMD, -1.36; 95% CI, -2.20 to -0.53; p = 0.002) than those with FCP ≤ 0.4 nmol/L. The baseline insulin glargine 100 U/mL (Gla-100) dose increased significantly in 0.4 to ≤ 1.2 nmol/L group with LS mean difference (SE) of 0.16 (0.01) U/kg/day (p = 0.008) compared to FCP ≤ 0.4 nmol/L group. When combined with Diabetes Treatment Satisfaction Questionnaire (DTSQ) score, participants with a C-peptide level of 0.4 to ≤1.2 nmol/L (OR, 4.05; 95% CI, 1.08 to 15.22; p = 0.039) had significantly higher odds of achieving HbA1c <7%. The number of participants experiencing documented symptomatic hypoglycaemia (≤3.9 mmol/L) was higher in the FCP ≤0.4 nmol/L group compared to those in 0.4 to ≤1.2 nmol/L FCP group at any time of the day (31.6 vs. 17.1%) and during night (00:00 ∼ 05:59) (17.1 vs. 7.5%). CONCLUSION: The findings from this study proposed that FCP is an important biomarker to identify T2DM participants who experience improved glucose control without compromising on hypoglycemia levels during switch from premixed insulin to BI. Participants especially with FCP levels >1.2 nmol/L may respond better in terms of HbA1c reduction without increased hypoglycemia risk compared to those with lower FCP values.

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

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

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.