Importance Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations of injectable and peptide-based agents for type 2 diabetes. Objective To evaluate the efficacy and safety of HRS-7535, an oral nonpeptide GLP-1 RA, as add-on therapy among adults with type 2 diabetes inadequately controlled with metformin. Design, Setting, and Participants This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial was conducted at 44 centers in China. Adults aged 18 to 75 years with type 2 diabetes, hemoglobin A 1c (HbA 1c ) levels ranging from 7.5% to 11.0%, and receiving stable metformin therapy were enrolled between May 10 and December 18, 2023. Data were analyzed from May 8 to 22, 2024. Interventions Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 (15, 30, 60, or 90 mg) or matching placebo. The 60- and 90-mg treatment groups used dose-escalation regimens. Main Outcomes and Measures The primary outcome was change in HbA 1c level from baseline to week 16. Secondary outcomes included changes in fasting plasma glucose level, 2-hour postprandial glucose level, body weight, and the proportion of patients achieving HbA 1c levels less than 7.0%. Safety outcomes included adverse events (AEs), hypoglycemia, and AEs of special interest. Results Of 194 randomized patients (mean [SD] age, 52.3 [11.0] years; 115 [59.3%] men; mean [SD] HbA 1c level, 8.5% [0.7]), 177 (91.2%) completed treatment. The mean changes in HbA 1c level at week 16 were −1.19% (95% CI, −1.54% to −0.84%) with the 15-mg dose, −1.59% (95% CI, −1.94% to −1.24%) with the 30-mg dose, −1.82% (95% CI, −2.16% to −1.48%) with the 60-mg dose, and −1.64% (95% CI, −1.97% to −1.30%) with the 90-mg dose compared with −0.25% (95% CI, −0.60% to 0.09%) with placebo; placebo-adjusted differences ranged from −0.94% (95% CI, −1.43% to −0.45%) to −1.57% (95% CI, −2.05% to −1.08%) (all P < .001). HbA 1c level less than 7.0% was achieved in proportions ranging from 48.7% (95% CI, 32.4%-65.2%) to 63.2% (95% CI, 46.0%-78.2%) of HRS-7535–treated patients vs 15.4% (95% CI, 5.9%-30.5%) with placebo. The 90-mg group had greater body weight reduction than placebo (−2.63% [95% CI, −3.72% to −1.54%] vs −1.30% [95% CI, −2.46% to −0.15%]). AEs occurred in 28 of 39 (71.8%) to 33 of 39 (84.6%) HRS-7535–treated patients and 28 of 39 (71.8%) placebo-treated patients and were predominantly mild to moderate gastrointestinal events. Level 1 hypoglycemia occurred in 9 HRS-7535–treated patients; no level 2 or 3 hypoglycemia, pancreatitis, or elevations of alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal occurred. Conclusions and Relevance In this randomized clinical trial of adults with type 2 diabetes inadequately controlled with metformin, oral HRS-7535 improved glycemic control and was associated with modest weight reduction, with a safety profile consistent with that of GLP-1 RAs. Because HRS-7535 is a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, it may be a viable treatment option, pending confirmation in phase 3 trials. Trial Registration ClinicalTrials.gov Identifier: NCT05759897

Importance:Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations of injectable and peptide-based agents for type 2 diabetes. Objective:To evaluate the efficacy and safety of HRS-7535, an oral nonpeptide GLP-1 RA, as add-on therapy among adults with type 2 diabetes inadequately controlled with metformin. Design, Setting, and Participants:This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial was conducted at 44 centers in China. Adults aged 18 to 75 years with type 2 diabetes, hemoglobin A1c (HbA1c) levels ranging from 7.5% to 11.0%, and receiving stable metformin therapy were enrolled between May 10 and December 18, 2023. Data were analyzed from May 8 to 22, 2024. Interventions:Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 (15, 30, 60, or 90 mg) or matching placebo. The 60- and 90-mg treatment groups used dose-escalation regimens. Main Outcomes and Measures:The primary outcome was change in HbA1c level from baseline to week 16. Secondary outcomes included changes in fasting plasma glucose level, 2-hour postprandial glucose level, body weight, and the proportion of patients achieving HbA1c levels less than 7.0%. Safety outcomes included adverse events (AEs), hypoglycemia, and AEs of special interest. Results:Of 194 randomized patients (mean [SD] age, 52.3 [11.0] years; 115 [59.3%] men; mean [SD] HbA1c level, 8.5% [0.7]), 177 (91.2%) completed treatment. The mean changes in HbA1c level at week 16 were -1.19% (95% CI, -1.54% to -0.84%) with the 15-mg dose, -1.59% (95% CI, -1.94% to -1.24%) with the 30-mg dose, -1.82% (95% CI, -2.16% to -1.48%) with the 60-mg dose, and -1.64% (95% CI, -1.97% to -1.30%) with the 90-mg dose compared with -0.25% (95% CI, -0.60% to 0.09%) with placebo; placebo-adjusted differences ranged from -0.94% (95% CI, -1.43% to -0.45%) to -1.57% (95% CI, -2.05% to -1.08%) (all P < .001). HbA1c level less than 7.0% was achieved in proportions ranging from 48.7% (95% CI, 32.4%-65.2%) to 63.2% (95% CI, 46.0%-78.2%) of HRS-7535-treated patients vs 15.4% (95% CI, 5.9%-30.5%) with placebo. The 90-mg group had greater body weight reduction than placebo (-2.63% [95% CI, -3.72% to -1.54%] vs -1.30% [95% CI, -2.46% to -0.15%]). AEs occurred in 28 of 39 (71.8%) to 33 of 39 (84.6%) HRS-7535-treated patients and 28 of 39 (71.8%) placebo-treated patients and were predominantly mild to moderate gastrointestinal events. Level 1 hypoglycemia occurred in 9 HRS-7535-treated patients; no level 2 or 3 hypoglycemia, pancreatitis, or elevations of alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal occurred. Conclusions and Relevance:In this randomized clinical trial of adults with type 2 diabetes inadequately controlled with metformin, oral HRS-7535 improved glycemic control and was associated with modest weight reduction, with a safety profile consistent with that of GLP-1 RAs. Because HRS-7535 is a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, it may be a viable treatment option, pending confirmation in phase 3 trials. Trial Registration:ClinicalTrials.gov Identifier: NCT05759897.

Efsubaglutide alfa, a long-acting humanised GLP-1 receptor agonist, was evaluated as add-on therapy to metformin in adults with type 2 diabetes. In an operationally seamless adaptive phase 2b/3, randomised, double-blind, placebo-controlled trial, phase 2b randomised participants 1:1:1 to Efsubaglutide 1 mg, 3 mg, or placebo for 12 weeks; based on phase 2b efficacy and safety, an independent committee selected 3 mg as the recommended phase 3 dose. Phase 3 randomised new participants 1:1 to Efsubaglutide 3 mg or placebo for 24-week double-blind treatment, followed by a 28-week open-label extension. At week 12 in phase 2b, HbA1c decreased by 1.10% with 1 mg and 1.43% with 3 mg (both p < 0.0001). At week 24 in phase 3, HbA1c decreased by 1.80% with Efsubaglutide 3 mg versus 0.74% with placebo (estimated treatment difference, -1.06%; p < 0.001). Adverse events were predominantly mild to moderate gastrointestinal events. Trial registration: ClinicalTrials.gov NCT04998032.

BackgroundHemodialysis (HD) can significantly lower blood glucose levels, increasing the risk of hypoglycemia. The contributing factors are not fully understood. This study aimed to identify key risk factors for hypoglycemia during HD and develop a predictive model.MethodsA retrospective nested case-control study was conducted at the Third Hospital of Shandong Province from January 2020 to December 2023. Clinical and laboratory data were collected from electronic medical records and patient questionnaires. Univariate and multivariate analyses identified independent risk factors, and a predictive model was developed using stepwise logistic regression. Internal validation was performed using 10-fold stratified cross-validation, with model performance evaluated by mean area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity.ResultsAmong 114 HD patients (57 cases, 57 controls), six independent risk factors were identified: afternoon HD session, presence of cardiovascular disease, and low levels of albumin (<37.35 g/L), creatinine (<828.65 μmol/L), urea (<28.05 mmol/L), and pre-dialysis blood glucose (<5.75 mmol/L). The predictive model demonstrated good internal validity with mean AUC 0.79, accuracy 0.71, sensitivity 0.64, and specificity 0.78, indicating stable discriminative performance.ConclusionSix key risk factors for hypoglycemia during HD were identified, and a predictive model integrating disease status, HD timing, and laboratory markers was developed. Early identification of high-risk patients may help prevent hypoglycemic events and improve HD outcomes. Future studies should externally validate and refine this model for broader clinical application.

Aim:The aim of this study was to compare the efficacy and safety of fixed-dose combination (FDC) of pioglitazone and metformin supplemented with dapagliflozin (test group) with those of basal insulin supplemented with metformin (control group) in patients with inadequately controlled type 2 diabetes mellitus (T2DM). Methods:This 16-week, prospective, randomized, open-label study enrolled patients aged 18-75 years with glycated hemoglobin (HbA1c) levels between ≥ 8% and ≤ 11%. The primary endpoint was the proportion of patients who achieved HbA1c < 7% at week 16 without hypoglycemia or weight gain. The secondary endpoints included blood glucose, lipid profile, body weight, body mass index, inflammatory markers, bone Gla-protein, liver enzymes, and patient satisfaction. Results:Among the full analysis set of 147 participants, no significant difference was observed in the primary endpoint between the test group and the control group. However, the test group had a higher percentage of patients who achieved HbA1c <7% at week 16 without hypoglycemia and experienced a weight loss of ≥3% (31.51% vs 13.51%, P=0.009). Patients in the test group whose BMI≥24 kg/m2 also achieved a substantial achievement rate (36.73% vs 15.79%, P=0.014). The test group also exhibited a greater reduction in body weight and improvements in 2-hour postprandial glucose level, systolic blood pressure, and lipid profile. Notably, combination therapy did not increase the risk of hypoglycemia or weight gain. Patients in the test group were more satisfied than those in the control group with continuing to accept pioglitazone/metformin FDC combined with dapagliflozin. Conclusion:In the absence of contraindications, pioglitazone/metformin FDC supplemented with dapagliflozin may serve as a safe and effective alternative to basal insulin combined with metformin for rectifying inadequate glucose control, as the former enables metabolic improvements without compromising safety. Chinese Clinical Trial Registry Number:CHiCTR2000036076. https://www.chictr.org.cn/showproj.html?proj=58825.

Objective Diabetes presenting at younger age has more aggressive nature. We aimed to explore the association of age at type 2 diabetes mellitus (T2DM) diagnosis with subsequent cancer incidence in a large Chinese population. Research design and methods The prospective population-based longitudinal cohort included 428,568 newly diagnosed T2DM patients from 2011 to 2018. Participants were divided into six groups according to their age at diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, ≥75. The incidence of overall and 14 site-specific cancers were compared to Shanghai general population including 100,649,346 person-years. Results A total of 18,853 and 582,643 overall cancer cases were recorded in the T2DM cohort and the general population. The age-standardized rate of overall cancer in T2DM patients was 501 (95% CI: 491, 511) per 100,000 person years and the standardized incidence ratio (SIR) was 1.10 (1.09, 1.12). Younger age at T2DM diagnosis was associated with higher incidence of overall and site-specific cancers. SIRs for overall cancer with T2DM diagnosis at ages 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years were 1.48 (1.41, 1.54), 1.30 (1.25, 1.35), 1.19 (1.15, 1.23), 1.16 (1.12, 1.20), 1.06 (1.02, 1.10) and 0.86 (0.84, 0.89) respectively. Similar trends were observed for site-specific cancers including respiratory, colorectum, stomach, liver, pancreatic, bladder, CNS, kidney, gallbladder cancer, and lymphoma among both males and females. Conclusions Our findings highlight the necessity of stratifying management for T2DM according to age of diagnosis. As with a range of vascular outcomes, age-standardised cancer risks are greater in younger compared to later onset T2DM.

BACKGROUND Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have been used to reduce the level of low-density lipoprotein cholesterol (LDL-C), but require either biweekly or monthly dosing frequency. Recaticimab is a new humanized monoclonal antibody selectively targeting PCSK9, with long-acting characteristic. OBJECTIVES The purpose of this study was to assess the efficacy and safety of recaticimab monotherapy in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk, and to explore different dosing strategies to provide patients with flexible administration options. METHODS This was a randomized, double-blind, placebo-controlled, phase 3 study conducted at 59 sites in China. Patients with fasting LDL-C >= 2.6 to <4.9 mmol/L, fasting triglyceride <= 5.6 mmol/L, and 10-year ASCVD risk score <10% were randomly assigned (2:2:2:1:1:1) to receive subcutaneous injections of recaticimab at 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg every 12 weeks (Q12W), or matching placebo, on background lipid-lowering diet. Primary endpoint was percentage change in LDL-C from baseline to week 12 for 150 mg Q4W and 450 mg Q12W and to week 16 for 300 mg Q8W. RESULTS A total of 703 patients underwent randomization and received recaticimab (n = 157, 156, and 155 for 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W, respectively) or placebo (n = 78, 79, and 78, respectively). Compared with placebo, recaticimab further reduced LDL-C by 49.6% (95% CI: 44.2%-54.9%) at 150 mg Q4W, 52.8% (95% CI: 48.3%57.2%) at 300 mg Q8W, and 45.0% (95% CI: 41.0%-49.0%) at 450 mg Q12W (P < 0.0001 for all comparisons). Safety with recaticimab was comparable to placebo. After 12 or 16 weeks of treatment, patients who received recaticimab continued treatment until week 24, whereas those allocated to placebo were switched to recaticimab treatment with the same dosing strategy. Both 24-week recaticimab and 12- or 8-week recaticimab switched from placebo were effective. With 24 weeks of recaticimab treatment, the most common treatment-related adverse event was injection site reaction (n = 23 [4.9%]). CONCLUSIONS Recaticimab monotherapy yielded significant LDL-C reductions and showed comparable safety vs placebo in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate ASCVD risk, even with an infrequent dosing interval up to Q12W.

Background Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have been used to reduce the level of low-density lipoprotein cholesterol (LDL-C), but require either biweekly or monthly dosing frequency. Recaticimab is a new humanized monoclonal antibody selectively targeting PCSK9, with long-acting characteristic. Objectives The purpose of this study was to assess the efficacy and safety of recaticimab monotherapy in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk, and to explore different dosing strategies to provide patients with flexible administration options. Methods This was a randomized, double-blind, placebo-controlled, phase 3 study conducted at 59 sites in China. Patients with fasting LDL-C ≥2.6 to <4.9 mmol/L, fasting triglyceride ≤5.6 mmol/L, and 10-year ASCVD risk score <10% were randomly assigned (2:2:2:1:1:1) to receive subcutaneous injections of recaticimab at 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg every 12 weeks (Q12W), or matching placebo, on background lipid-lowering diet. Primary endpoint was percentage change in LDL-C from baseline to week 12 for 150 mg Q4W and 450 mg Q12W and to week 16 for 300 mg Q8W. Results A total of 703 patients underwent randomization and received recaticimab (n = 157, 156, and 155 for 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W, respectively) or placebo (n = 78, 79, and 78, respectively). Compared with placebo, recaticimab further reduced LDL-C by 49.6% (95% CI: 44.2%-54.9%) at 150 mg Q4W, 52.8% (95% CI: 48.3%-57.2%) at 300 mg Q8W, and 45.0% (95% CI: 41.0%-49.0%) at 450 mg Q12W (P < 0.0001 for all comparisons). Safety with recaticimab was comparable to placebo. After 12 or 16 weeks of treatment, patients who received recaticimab continued treatment until week 24, whereas those allocated to placebo were switched to recaticimab treatment with the same dosing strategy. Both 24-week recaticimab and 12- or 8-week recaticimab switched from placebo were effective. With 24 weeks of recaticimab treatment, the most common treatment-related adverse event was injection site reaction (n = 23 [4.9%]). Conclusions Recaticimab monotherapy yielded significant LDL-C reductions and showed comparable safety vs placebo in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate ASCVD risk, even with an infrequent dosing interval up to Q12W.

Objective:To explore the efficacy and safety of biphasic insulin aspart 50 (Ruisulin ?50) in treatment of patients with type 2 diabetes mellitus (T2DM). Methods:A multicenter, randomized, open-labeled, parallel-controlled and positive control and the phase Ⅲ of clinical trial included the 542 T2DM patients having poor glucose control after using oral hypoglycemic drugs from July 29, 2016 to September 12, 2019. All patients were assigned to Ruisulin ?50 group or NovoMix ?50 group for 24 weeks by a ratio of 2∶1 based on block randomization. The decreased value and qualification rates of glycated hemoglobin A 1c (HbA 1c), fasting plasma glucose (FPG), 2 h postprandial blood glucose (2hPG), the incidence of hypoglycemic and adverse events, and the positive rate of aspartic islet specific antibody were compared at the end of 24 weeks. The full analysis set (FAS) and per-protocol dataset (PPS) were used for the effectiveness index analysis, and the safety set (SS) was used for the security index analysis. Analyses of matched samples t-test, t-test, and chi-square test were used. Results:All of 542 cases were included in the trial (364 cases received Ruisulin ?50 therapy and 178 cases received NovoMix ?50 therapy). There were 532 cases in FAS (356 cases received Ruisulin ?50 therapy and 176 cases received NovoMix ?50 therapy), 485 cases in PPS (325 cases received Ruisulin ?50 therapy and 160 cases received NovoMix ?50 therapy), and 533 cases in SS (357 cases received Ruisulin ?50 therapy and 176 cases received NovoMix ?50 therapy). At the end of 24-week treatment period, HbA 1c in Ruisulin ?50 group and NovoMix ?50 group decreased by 1.56%±1.42% and 1.54%±1.27%, respectively. FPG decreased by (1.94±3.08) and (1.43±2.53) mmol/L, and 2hPG decreased by (4.66±5.40) and (4.21±5.36) mmol/L, respectively. The decrease of the above indexes within the group was statistically significant ( P<0.001), and there was no statistically significant difference between the two groups ( P>0.05). Moreover, the incidence of hypoglycemic events was 65.27% (233/357) and 68.18% (120/176), the incidence of adverse events was 79.55% (284/357) and 72.73% (128/176), and after 24 weeks treatment, anti-insulin aspart antibody was 55.03% (186/338) and 57.83% (96/166) in Ruisulin ?50 group and NovoMix ?50 group, respectively. There were no significant differences in above parameters between the two groups ( P>0.05). Conclusion:Ruisulin ?50 provides similar glycemic control and safety profiles to NovoMix ?50, indicating that Ruisulin ?50 is a suitable therapeutic option in clinical practice.

What is Known and Objective . To explore the effects of traditional Chinese medicine (TCM) combined with levothyroxine (L-T4) on thyroid autoantibodies, inflammation, and sleep quality in Hashimoto’s thyroiditis patients. Methods . Patients were randomly divided into group A and group B. Group A was treated with L-T4 alone, while group B was treated with integrated TCM and L-T4. TCM symptoms were quantified before and after treatment as well as PSQI. Blood samples were taken to detect clinical indicators and thyroid autoantibodies. Cytokines in serum and thyroid tissues were analyzed by ELISA and RT-PCR. Results and Discussion . Totally, 196 patients were enrolled in the study, and there were no differences between group A and group B at the baseline. TCM treatment effectively reduced the levels of TGAb and TPOAb and was a protective factor for the improvement of Hashimoto’s thyroiditis antibody titers, p   <  0.05. The serum expressions of IL-17A, IL-6, and IFN- γ in group B after treatment were lower than those in group A and before, while the IL-10 level was raised from the baseline, p   <  0.05. Similar results were found in the comparison of IL-17A, IFN- γ , and IL-10 in thyroid tissues of group A, B, and control, p   <  0.05. Besides, with integrated treatment, all TCM symptoms except for poor memory were improved as well as sleep quality and mood, p   <  0.05. However, these changes were not observed before and after treatment with L-T4 in group A. What is New and Conclusion . The integrated treatment with TCM had a significant effect on thyroid autoantibodies, inflammation, and sleep quality in Hashimoto’s thyroiditis patients and provided a new and effective method for future treatment.

To assess the efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control.

目的 通过连续血糖监测方法,分析不同体质量指数(BMI)的老年2 型糖尿病患者血糖波动特点.方法 回顾性分析2021 年于复旦大学附属华东医院内分泌科住院、65 岁及以上并行动态血糖监测的146 例2 型糖尿病患者,所有患者均记录人口统计学及实验室指标等数据.按照BMI将患者分为 3 组,体重正常组BMI＜24 kg/m2,超重组BMI 24～28 kg/m2之间,肥胖组的BMI≥28 kg/m2.比较不同BMI患者在年龄、性别、化验指标、血糖波动、用药及病程等方面的差异.在亚组中检测体重正常和超重组+肥胖组患者血清成纤维细胞生长因子19(FGF19)水平.结果 (1)3 组患者病程、年龄、糖化血红蛋白、空腹血糖及餐后2h血糖差异无统计学意义.体重正常组空腹及餐后2hC肽水平低于超重及肥胖组,最低血糖从体重正常组到超重组再到肥胖组,逐渐递增.在血糖波动的参数上,平均血糖水平、葡萄糖目标范围内时间在3 组之间差异无统计学意义;而日内血糖波动最大幅度从体重正常组到超重组再到肥胖组,逐渐递减.体重正常组黎明现象发生率高于另外2 组.BMI与最低血糖呈正相关(r =0.187,P =0.024)、与日内血糖波动最大幅度呈负相关(r = -0.222,P =0.007).(2)易发生低血糖风险的药物如胰岛素、磺脲类使用率在3 组之间差异无统计学意义,而二甲双胍及DPP4-i使用率在3 组间差异有统计学意义,超重组及肥胖组二甲双胍及DPP4-i使用率均高于体重正常组.(3)在亚组中检测体重正常组和超重+肥胖组血清FGF19 水平,发现体重正常组FGF19 水平较超重+肥胖组显著升高.结论 体重正常的老年2 型糖尿病患者夜间血糖偏低、血糖波动大,偏低的血糖受降糖药物影响小,可能受FGF19 影响.

Aim Gastrointestinal discomfort is the most common adverse event in metformin treatment for type 2 diabetes. The mechanism of action of metformin is associated with gut microbiota. However, the gut microbial community structure related to metformin-induced gastrointestinal adverse events remains unclear. This study aimed to investigate it. Methods 50 patients with newly diagnosed diabetes were treated with metformin 1500mg/d for 12 weeks. The patients were divided into two groups according to whether gastrointestinal adverse events occurred (group B) or did not occur (group A) after treatment. The fecal bacterial communities and short-chain fatty acids (SCFAs) were sequenced and compared. 70 diabetes mice were randomly divided into 8 groups and treated with metformin (Met), clindamycin (Clin) and/or SCFA, which were the Met+/Clin+, Met+/Clin-, Met-/Clin+, Met-/Clin-, Met+/SCFA+, Met+/SCFA-, Met-/SCFA+ and Met-/SCFA- group. After 4 weeks of metformin treatment, blood glucose, food intake, fecal SCFAs, gut microbiota and gut hormones were measured. Results Metformin increased the abundance of Phascolarctobacterium , Intestinimonas and Clostridium III . Functional prediction analysis showed that the propanoate metabolism pathway was significantly up-regulated. The concentrations of acetic acid and propanoic acid in feces were significantly increased. The abundance of Clostridium sensu stricto, Streptococcus and Akkermansia induced by metformin in group B was higher than that in group A. The propanoate metabolism pathway and propanoic acid in feces were significantly up-regulated in group B. In the animal experiments, the food intake decreased and glucose control increased in metformin groups compared with those in the control groups. The total GLP-1 level in the Met+/Clin- group was significantly higher than that in the Met-/Clin- group, while there was no statistical difference between the Met-/Clin- and Met+/Clin+ group. The total GLP-1 level in the Met-/SCFA+ group was significantly higher than that in the Met-/SCFA-group, while the levels of total GLP-1 and active GLP-1 in the Met+/SCFA- group and the Met+/SCFA+ group were significantly higher than those in the Met-/SCFA-group. Conclusions Our data suggest that metformin promotes the secretion of intestinal hormones such as GLP-1 by increasing the abundance of SCFA-producing bacteria, which not only plays an anti-diabetic role, but also may causes gastrointestinal adverse events.

报道1例在上海华东医院内分泌科住院使用胰岛素泵联合二甲双胍强化治疗的2型糖尿病（T2DM）合并肌少症患者，血糖控制后转换为利拉鲁肽联合二甲双胍治疗的诊疗过程并进行文献复习。患者为56岁男性，因“发现血糖升高1年，控制不佳1个月”入院，入院后完善各项检查，诊断为2型糖尿病合并肌少症。予胰岛素泵联合二甲双胍降糖，因患者合并有动脉硬化性心血管疾病（ASCVD），血糖下降后予换为利拉鲁肽（1.2 mg，1次/d）联合二甲双胍（0.5 g，3次/d）治疗，26周后复查时发现血糖控制良好，进行身体成分分析发现脂肪含量减少，瘦体重无明显减少，患者治疗满意。T2DM合并肌少症患者使用利拉鲁肽联合二甲双胍治疗可平稳降糖，减轻体重、体脂，不减少瘦体重、肌力，不良反应小，安全可靠。

Skin wound healing tends to slow down with aging, which is detrimental to both minor wound recovery in daily life and the recovery after surgery. The aim of current study was to explore the effect of histone deacetylase 6 (HDAC6) on wound healing during aging. Cultured human dermal fibroblasts (HDFs) and mouse full-thickness skin wound model were used to explore the functional changes of replicative senescent dermal fibroblasts and the effect of aging on skin wound healing. Scratch wound healing assay revealed significantly decreased migration speed of senescent HDFs, and BrdU incorporation assay indicated their considerably retardant proliferation. The protein expression levels of collagen and HDAC6 were significantly decreased in both senescent HDFs and skin tissues from aged mice. HDAC6 activity inhibition with highly selective inhibitor tubastatin A (TsA) or HDAC6 knockdown with siRNA decreased the migration speed of HDFs and considerably suppressed fibroblast differentiation induced by transforming growth factor-β1 (TGF-β1), which suggests the involvement of HDAC6 in regulating fundamental physiological activities of dermal fibroblasts. In vivo full-thickness skin wound healing was significantly delayed in young HDAC6 knockout mice when compared with young wild type mice. In addition, the wound healing was significantly slower in aged wild type mice than that in young wild type mice, and became even worse in aged HDAC6 knockout aged mice. Compared to the aged wild type mice, aged HDAC6 knockout mice exhibited delayed angiogenesis, reduced collagen synthesis, and decreased collagen deposition in skin wounds. Together, these results suggest that delayed skin wound healing in aged mice is associated with impaired fibroblast function. Adequate expression and activity of HDAC6 are required for fibroblasts migration and differentiation.

Objective:To investigate the effects of once-weekly dulaglutide 1.5 mg treatment on glucose variability and glucose control in type 2 diabetes patients using 24 h continuous glucose monitoring (CGM) technology.Methods:A multi-center, prospective study was carried out. A total of 149 type 2 diabetes patients were recruited, who were treated with dulaglutide for 2 to 4 weeks, wearing CGM devices to monitor the glucose level. The primary evaluation indicators included mean amplitude of glycemic excursions (MAGE), mean daily glucose (MDG), time in target glucose range (TIR), time above range and time below range (TAR, TBR). Secondary indicators included change of concomitant medication dosages, treatment-related adverse events and change of blood pressure. Mixed effects model (MEM) of repeated measurement data or paired Mann-Whitney rank-sum test was used to analysis the differences between CGM parameters in each week during the treatment period.Results:MDG and MAGE of patients decreased by (0.76±0.31) and (0.50±0.13) mmol/L ( P<0.05), respectively, after the 4-week dulaglutide treatment. When compared with the first week, time in range (TIR) in week 2 increased from 73.91% (IQR 25.20%) to 7.49% (IQR 24.89%), and the mean difference was 3.58% ( P<0.01). Time in hyperglycemia decreased from 2.95% (IQR 10.76%) to 1.94% (IQR 7.24%), and the median difference was 1.01% ( P<0.001), while the time in hypoglycemia did not change ( P>0.05). Mean systolic pressure of patients decreased by (5.2±1.5) mmHg (1 mmHg=0.133 kPa) after the first-week treatment. Furthermore, 14 patients reported treatment-related adverse events including gastrointestinal reaction and hypoglycemia. Conclusions:Treatment with dulaglutide 1.5 mg weekly for 2 to 4 weeks could significantly reduce glycemic variability, improve short-term glucose control and lower blood pressure in type 2 diabetes patients without significantly increasing the risk of hypoglycemic events.

Background:The Somogyi effect is defined as fasting hyperglycemia secondary to nocturnal hypoglycemia. In past decades, this effect proved to be rare or absent. However, many endocrinologists still believe in this phenomenon in clinical practice. Does the Somogyi effect truly exist? We aimed to answer this question with a study based on a larger sample size.Methods:We collected retrospective CGMs data from 2,600 patients with type 2 diabetes with stable treatment of insulin. Nocturnal hypoglycemia was defined as a CGMs sensor glucose of less than 3.9 mmol/L for at least 15 min between 24:00 and 06:00. Morning fasting glucose was compared between people with nocturnal hypoglycemia and without nocturnal hypoglycemia.Results:Valid CGMs data were obtained on 4,705 of 5,200 nights. Morning fasting glucose was observed lower after nights with nocturnal hypoglycemia compared with nights without hypoglycemia (P < 0.001). 84 cases presented fasting glucose of more than 7 mmol/L after nocturnal glucose of less than 3.9 mmol/L. Only 27 cases presented fasting glucose of more than 7 mmol/L after nocturnal glucose of less than 3.0 mmol/L. Fasting glucose values below 3.9 mmol/l in the morning were associated with a 100% risk of nocturnal hypoglycemia, while fasting glucose values over 9.6 mmol/l in the morning were associated with no risk of nocturnal hypoglycemia. Correlation analysis showed that the nocturnal glucose nadir was significantly correlated with fasting glucose levels (r = 0.613, P < 0.001).Conclusions:Our data provided no support for the existence of the Somogyi effect. If fasting glucose exceeds 9.6 mmol/L, we do not have to worry about asymptomatic nocturnal hypoglycemia in patients with type 2 diabetes.

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24-weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was -1.02% (-1.11, -0.93) in the dorzagliatin group and -0.36% (-0.45, -0.26) in the placebo group (estimated treatment difference, -0.66%; 95% CI: -0.79, -0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile (NCT03141073).

目的 探索社会经济地位与喀什地区糖尿病足严重程度的相关性,为更好地防治糖尿病足提供依据.方法 回顾分析2015年1月—2019年12月,新疆喀什地区第二人民医院内分泌代谢科出院并诊断为糖尿病足的50岁以上患者304例.录入Wagner分级、人口统计学、社会经济学和实验室检查等数据.分析不同Wagner分级患者的受教育程度、居住地、职业记录,以及体质量指数、化验指标、吸烟饮酒史等的差异.进一步使用回归分析探索与糖尿病足严重程度相关的社会经济因素.结果(1)304例患者中,男性200例(占65.8％),维吾尔族254例(占83.6％),平均年龄(62.9±8.5)岁,糖尿病病程(13.8±7.2)年.(2)随着Wagner分级的升高,白蛋白和血红蛋白等营养性指标下降,白细胞和D二聚体等炎症性指标升高(P<0.05);年龄、性别、民族、病程和糖化血红蛋白等组间差异无统计学意义(P>0.05).(3)在不同的Wagner分级患者中(1级,2级,3级,4级以上),小学及以下学历比例为31.4％,46.7％,57.5％和63.6％,农民比例20.4％,31.4％,42.5％和60.6％,居住于乡村比例35.2％,46.0％,65.0％和69.7％,组间差异有统计学意义(P<0.05).(4)多因素回归分析显示低受教育程度、居住乡村和农民职业均是糖尿病足严重程度的独立危险因素(P<0.05).结论 在喀什地区,受教育程度、居住于乡村、农民与糖尿病足的严重程度有关,需加大对相关群体的糖尿病足宣教、筛查和早期干预等工作.

Vemurafenib (VEM) is a commonly used inhibitor of papillary thyroid cancer (PTC) and melanoma with the BRAFV600E mutation; however, acquired resistance is unavoidable. The present study aimed to identify a potential target to reverse resistance. A VEM-resistant PTC cell line (B-CPAP/VR) was established by gradually increasing the drug concentration, and a VEM-resistant BRAFV600E melanoma cell line (A375/VR) was also established. RNA sequencing and bioinformatics analyses were conducted to identify dysregulated genes and construct a transcription factor (TF) network. The role of a potential TF, forkhead box P2 (FOXP2), verified by qRT-PCR, was selected for further confirmation. The two resistant cell lines were tolerant of VEM and displayed higher migration and colony formation abilities (p < 0.05). RNA sequencing identified 9177 dysregulated genes in the resistant cell lines, and a TF network consisting of 13 TFs and 44 target genes was constructed. Alterations in FOXP2 expression were determined to be consistent between the two VEM-resistant cell lines. Finally, silencing FOXP2 resulted in an increase in drug sensitivity and significant suppression of the migration and colony formation abilities of the two resistant cell lines (p < 0.05). The present study successfully established two VEM-resistant cell lines and identified a potential target for VEM-resistant PTC or melanoma.