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Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus

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Signal Transduction and Targeted Therapy 2023年第5期8卷 2278-2290页

作者： Junjie Wang Ziping Qi Yun Wu Aoli Wang Qingwang Liu Fengming Zou Beilei Wang Shuang Qi Jiangyan Cao Chen Hu Chenliang Shi Qianmao Liang Li Wang Jing Liu Wenchao Wang Qingsong Liu Anhui Province Key Laboratory of Medical Physics and Technology Institute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhui230031P.R.China University of Science and Technology of China HefeiAnhui230026P.R.China Hefei Cancer Hospital Chinese Academy of SciencesHefeiAnhui230031P.R.China Precision Medicine Research Laboratory of Anhui Province HefeiAnhui230088P.R.China

Insulin-producing pancreaticβcell death is the fundamental cause of type 1 diabetes(T1D)and a contributing factor to type 2 diabetes(T2D).Moreover,metabolic disorder is another hallmark of *** sterile 20-like kinase 1(MST1)contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreaticβcell ***-activated protein kinase(AMPK)is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic ***,pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes ***,we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39,which exhibits anti-apoptosis efficacy and improves the survival of pancreaticβcells under diabetogenic conditions,as well as primary pancreatic islets in an ex vivo disease ***,IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro,combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic *** together,IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.

关键词： diabetes mellitus treatment

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Prolonging dual antiplatelet therapy improves the long-term prognosis in patients with diabetes mellitus undergoing complex percutaneous coronary intervention

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Journal of Geriatric Cardiology 2023年第8期20卷 586-595页

作者： Jing-Jing XU Si-Da JIA Pei ZHU Ying SONG De-Shan YUAN Xue-Yan ZHAO Yi YAO Lin JIANG Jian-Xin LI Yin ZHANG Lei SONG Run-Lin GAO Ya-Ling HAN Jin-Qing YUAN Department of Cardiology National Clinical Research Center for Cardiovascular DiseasesNational Center for Cardiovascular DiseasesState Key Laboratory of Cardiovascular DiseaseFuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Cardiology General Hospital of Northern Theater CommandShenyangChina

OBJECTIVE To investigate the optimal duration of dual antiplatelet therapy(DAPT)in patients with diabetes mellitus(DM)requiring complex percutaneous coronary intervention(PCI).METHODS A total of 2403 patients with DM who underwent complex PCI from January to December 2013 were consecutively enrolled in this observational cohort study and divided according to DAPT duration into a standard group(11-13 months,n=689)and two prolonged groups(13-24 months,n=1133;>24 months,n=581).RESULTS Baseline characteristics,angiographic findings,and complexity of PCI were comparable regardless of DAPT *** incidence of major adverse cardiac and cerebrovascular event was lower when DAPT was 13-24 months than when it was 11-13 months or>24 months(4.6%vs.8.1%vs.6.0%,P=0.008),as was the incidence of all-cause death(1.9%vs.4.6%vs.2.2%,P=0.002)and cardiac death(1.0%vs.3.0%vs.1.2%,P=0.002).After adjustment for confounders,DAPT for 13-24 months was associated with a lower risk of major adverse cardiac and cerebrovascular event[hazard ratio(HR)=0.544,95%CI:0.373-0.795]and all-cause death(HR=0.605,95%CI:0.387-0.944).DAPT for>24 months was associated with a lower risk of all-cause death(HR=0.681,95%CI:0.493-0.942)and cardiac death(HR=0.620,95%CI:0.403-0.952).The risk of major bleeding was not increased by prolonging DAPT to 13-24 months(HR=1.356,95%CI:0.766-2.401)or>24 months(HR=0.967,95%CI:0.682-1.371).CONCLUSIONS For patients with DM undergoing complex PCI,prolonging DAPT might improve the long-term prognosis by reducing the risk of adverse ischemic events without increasing the bleeding risk.

关键词： patients coronary mellitus

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Effect of Astragalus polysaccharide in treatment of diabetes mellitus: a narrative review

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Journal of Traditional Chinese Medicine 2019年第1期39卷 133-138页

作者： Zhang Zexi Zhang Lei Xu Hansong Department of endocrinology Guiyang College of Traditional Chinese MedicineGuiyang 550000China First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Tianjin 300100China NO.2 Hospital Affiliated to Traditional Chinese Medicine College of Guiyang Guiyang 550000China

Diabetes mellitus is a chronic endocrine/metabolism disease characterized by hyperglycemia arising from defects in insulin action, insulin secretion,or both. Diabetes mellitus is often complicated by visceral lesions, which can lead to serious complications and death. A variety of new agents are in development for the treatment of the disease. Astragalus polysaccharides are monomer components extracted from the Traditional Chinese Medicine,Huangqi(Radix Astragali Mongolici), which have been studied widely for treating diabetes mellitus with promising effects in recent years. This paper reviews recent advances in experimental studies on the effects of Astragalus polysaccharides in treating diabetes mellitus. The effects of Astragalus polysaccharides on the etiology and complication of diabetes mellitus including insulin resistance and secretion, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, diabetic foot, and infection complicated by diabetes mellitus are discussed.

关键词： Diabetes mellitus Astragalus polysaccharide Review

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Preventive effects of ophiopogon-polysaccharide on apiponectin in gestational diabetes mellitus rat

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Asian Pacific Journal of Tropical Medicine 2013年第4期6卷 296-299页

作者： Hong Wang Obstetrical Department Shandong Provincial Hospital

Objective:To investigate the effect of ophiopogon-polysaccharide on adiponectin(APN) in gestational diabetic mellitus ***:The model of gestational diabeties mellitus rat were established with streptozotocin by intraperitoneal *** rats were randomly divided into ophiopogon-polysaccharide 125 mg/kg group,250 mg/kg group,500 mg/kg group,GDM group and normal pregnancy group(n=10).Ophiopogon-polysaccharide was given by intragastric administration for 14 *** fasting blood glucose levels of rats at the 0,7,14 day were detected *** serum insulin level and APN in fat tissue and placenta were detected at the 14 ***:The fasting blood glucose level,serum insulin level and APN mRNA in fat tissue and placenta were significantly decreased in gestational diabetes rats treated by ophiopogon-polysaccharide compared with model group(P<0.05).Conclusions:Ophiopogon-polysaccharide could decrease the fasting blood glucose level and serum insulin level,and improve APN mRNA in fat tissue and placenta.

关键词： Ophiopogon-polysaccharide Gestational diabetes mellitus Adiponectin

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The relationship of Imp2 and DR3 genes with susceptibility to type Ⅰ diabetes mellitus in south China Han population

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World Journal of Gastroenterology 2000年第1期6卷 111-114页

作者： Ding HL Cheng H Fu ZZ Deng QL Yan L Yan T Department of Endocrinology Sun Yat-Sen Memorial HospitalSun Yat-Sen University of Medical SciencesGuangzhou 510120China

AIN To study the relationship of Imp2 and DR3genes with type Ⅰ diabetes *** Imp2 genotypes and DR3 wereidentified in 68 patients with type Ⅰ diabetesmellitus(Ⅰ-DM)and 71 healthy ***,Ⅰ-DM patients and controls were respectivelyallocated into DR3-positive and *** frequencies of Imp2 and DR3 genein random subjects,and Imp2 genotypes in DR3-matched subjects were compared between Ⅰ-DMpatients and *** the same time,Ⅰ-DMpatients were divided into 3 groups based on theonset age of diabetics:group A≤14 years,group B 15-30 years and group C≥31 *** The frequency of DR3 in Ⅰ-DMpatients was significantly higher than that incontrols(47% vs 21%,P<0.005),and it wassignificantly higher in group A than that in groupB+C(70% vs 36%,x^2=7.07,P<0.01).Therewas a significant difference among groups withdifferent onset age of diabetics(x^2=8.19,rp=0.33,P<0.05).In random subjects,thefrequency of Imp2.R/R in Ⅰ-DM patients waslower(43% vs 61%,P<0.05)and Imp2.R/Hhigher(53% vs 28%,P<0.05)than that incontrols,and there was no significant differenceamong groups with different onset age *** DR3-positive subjects,thefrequency of Imp2.R/R in Ⅰ-DM patients waslower(47% vs 87%,P<0.05)and Imp2-R/H higher(47% vs 13%,P<0.05)than that *** DR3-negative subjects,thefrequency of Imp2.R/H in Ⅰ-DM patients washigher than that in controls(58% vs 32%,P<0.01),but the frequency of Imp2-R/R and Imp2H/H was not significantly different betweenthese two *** DR3 gene may be one of thesusceptible genes of Ⅰ-DM,and significantlyrelated to the onset age of diabetics,and thepersons with DR3 may have an younger onsetage of *** Imp2-R/R may be theprotective genotype of Ⅰ-DM,and Imp2-R/H thesusceptible *** were not affectedby DR3 ***-2 genotypes were not relatedwith the onset age of diabetics.

关键词： Subject headings diabetes mellitus Imp2 genes DR3 genes polymerase chain reaction restriction fragment length polymorphism genetic susceptibility

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Calcium channel blocker monotherapy versus combination with reninangiotensin system inhibitors on the development of new-onset diabetes mellitus in hypertensive Korean patients

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Journal of Geriatric Cardiology 2019年第6期16卷 439-447页

作者： Yong Hoon Kim Ae-Young Her Seung-Woon Rha Byoung Geol Choi Se Yeon Choi Jae Kyeong Byun Yoonjee Park Dong Oh Kang Won Young Jang Woohyeun Kim Woong Gil Choi Tae Soo Kang Jihun Ahn Sang-Ho Park Ji Young Park Min-Ho Lee Cheol Ung Choi Chang Gyu Park Hong Seog Seo Division of Cardiology Department of Internal Medicine Kangwon National University School of Medicine Chuncheon South Korea Cardiovascular Center Korea University Guro Hospital Seoul South Korea Department of Medicine Korea University Graduate School Seoul South Korea Cardiology Department Konkuk University Chungju Hospital Chungju South Korea Department of Internal Medicine Cardiovascular Division Dankook University Hospital Cheonan South Korea Department of Cardiology Soonchunhyang University Gumi Hospital Gumi South Korea Cardiology Department Soonchunhyang University Cheonan Hospital Cheonan South Korea Division of Cardiology Department of Internal Medicine Cardiovascular Center Nowon Eulji Medical Center Eulji University Seoul South Korea Department of Cardiology Soonchunhyang University College of Medicine Seoul South Korea

Background In real practice, two or more antihypertensive drugs are needed to achieve target blood pressure. We investigated the comparative beneficial actions of combination therapy of renin-angiotensin system inhibitors (RASI), with calcium channel blockers (CCB) over CCB monotherapy on the development of new-onset diabetes mellitus (NODM) in Korean patients during four-year follow-up periods. Methods A total of 3208 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled from January 2004 to December 2012. These patients were divided into the two groups according to the additional use of RASI (the RASI group, n = 1221 and the no RASI group, n = 1987). Primary endpoint was NODM, defined as a fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, myocardial infarction (MI) and percutaneous coronary intervention (PCI). Results After propensity score-matched (PSM) analysis, two propensity- matched groups (939 pairs, n = 1878, C-statistic = 0.743) were generated. The incidences of NODM (HR = 1.009, 95% CI: 0.700–1.452, P = 0.962), MACE (HR = 0.877, 95% CI: 0.544–1.413, P = 0.589), total death, MI, PCI were similar between the two groups after PSM during four years. Conclusions The use of RASI in addition to CCB showed comparable incidences of NODM and MACE compared to CCB monotherapy in non-diabetic hypertensive Korean patients during four-year follow-up period. However, large-scaled randomized controlled clinical trials will be required for a more definitive conclusion.

关键词： Calcium channel blocker Diabetes mellitus Renin-angiotensin system inhibitors

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Effect of type 2 diabetes mellitus on flavonoid pharmacokinetics and tissue distribution after oral administration of Radix Scutellaria extract in rats

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Chinese Journal of Natural Medicines 2018年第6期16卷 418-427页

作者： ZHANG Xue-Ju LIU Shu XING Jun-Peng LIU Zhi-Qiang SONG Feng-Rui National Center of Mass Spectrometry in Changchun Jilin Province Key Laboratory of Chinese Medicine Chemistry and Mass SpectrometryChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China University of Chinese Academy of Sciences Beijing 100039China

Radix Scutellaria is widely applied to the treatment of diabetes mellitus in China. Its main bioactive constituents contain baicalin, wogonoside, oroxyloside, and their aglycones. To investigate the effect of type 2 diabetes mellitus on both pharmacokinetics and tissue distribution of these flavonoid compounds, the six flavonoids in plasma and tissues from the normal and type 2 diabetic rats after oral administration of Radix Scutellaria extract were simultaneously measured by ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method. The results showed that baicalin, wogonoside, and oroxyloside had higher Cmax and AUC values(P < 0.05) in type 2 diabetic rats than that in normal rats and the tissue-distribution behaviors of the six flavonoid compounds in hearts, livers, spleens, lungs, kidneys, brains, pancreas, fat and muscle of the type 2 diabetic rats showed obviously differences from the normal rats(P < 0.05). In conclusion, the differences in the pharmacokinetics of oroxyloside and tissue distribution of the six flavanoids in Radix Scutellaria extract between diabetic and normal rats were found for the first time. The results from the present study provided a crucial basis for a better understanding of in vivo anti-diabetic mechanism of action of the six flavonoids from Radix Scutellaria.

关键词： Radix Scutellaria Diabetes mellitus Flavonoid Pharmacokinetics Tissue distribution

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Association between diabetes mellitus and gastroesophageal reflux disease:A meta-analysis

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World Journal of Gastroenterology 2015年第10期21卷 3085-3092页

作者： Xiao-Meng Sun Jia-Cheng Tan Ying Zhu Lin Lin Department of Gastroenterology First Affiliated Hospital of Nanjing Medical University

AIM:To investigate whether there is a link between diabetes mellitus(DM) and gastroesophageal reflux disease(GERD).METHODS:We conducted a systematic search of Pub Med and Web of Science databases,from their respective inceptions until December 31,2013,for articles evaluating the relationship between DM *** were selected for analysis based on certain inclusion and exclusion *** were extracted from each study on the basis of predefined items.A meta-analysis was performed to compare the odds ratio(OR)in DM between individuals with and without GERD using a fixed effect or random effect model,depending on the absence or presence of significant *** analyses were used to identify sources of *** bias was assessed by Begg’s *** evaluate the results,we also performed a sensitivity ***:When the electronic database and hand searches were combined,a total of nine eligible articles involving 9067 cases and 81 968 controls were included in our *** on the randomeffects model,these studies identified a significant association between DM and the risk of GERD(overall OR=1.61;95%CI:1.36-1.91;P=0.003).Subgroup analyses indicated that this result persisted in studies on populations from Eastern countries(OR=1.71;9 5%C I:1.3 8-2.1 2;P=0.0 0 3)a n d i n y o u n g e r patients(mean age<50 years)(OR=1.70;95%CI:1.22-2.37;P=0.001).No significant publication bias was observed in this meta-analysis using Begg’s test(P=0.175).The sensitivity analysis also confirmed the stability of our ***:This meta-analysis suggests that patients with DM are at greater risk of GERD than those who do not have DM.

关键词： Diabetes mellitus Gastroesophageal reflux disease

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Therapeutic potential of human embryonic stem cells in type 2 diabetes mellitus

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World Journal of Stem Cells 2016年第7期8卷 223-230页

作者： Geeta Shroff Nutech Mediworld New Delhi 110016 India

AIM:To evaluate the safety and efficacy of human embryonic stem cells(h ESCs)for the management of type 2 diabetes mellitus(T2DM).METHODS:Patients with a previous history of diabetes and its associated complications were enrolled and injected with hE SC lines as per the defined *** patients were assessed using Nutech functional score(NFS),a numeric scoring scale to evaluate the patients for 11 diagnostic *** were evaluated at baseline and at the end of treatment period 1(T1).All the parameters were graded on the NFS scale from 1to *** possible grade(HPG)of 5 was considered as the grade of best ***:Overall,94.8%of the patients showed improvement by at least one grade of NFS at the end of *** all the 11 parameters evaluated,54%of patients achieved HPG after *** four essential parameters(improvement in glycated hemoglobin(HbA 1c)and insulin level,and fall in number of other oral hypoglycemic drugs with and without insulin)are presented in *** Hb A1c,72.6%of patients at the end of T1 met the World Health Organization cut off value,i.e.,6.5%of HbA *** insulin level,65.9%of patients at the end of T1 were able to achieve *** treatment,the improvement was seen in 16.3%of patients who required no more than two medications along with ***,21.5%of patients were improved as their dosage regimen for using oral drugs was reduced to 1-2 from ***:hE SC therapy is beneficial in patients with diabetes and helps in reducing their dependence on insulin and other medicines.

关键词： Type 2 diabetes mellitus Human embryonic stem cells Insulin Glycated hemoglobin Nutech functional scoring scale

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Diabetes mellitus carries a risk of gastric cancer:A metaanalysis

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World Journal of Gastroenterology 2013年第40期19卷 6902-6910页

作者： Shouji Shimoyama Gastrointestinal Unit Settlement ClinicTokyo 120-0003Japan

AIM:To investigate the association and quantify the relationship between diabetes mellitus(DM) and gastric cancer(GC) by an updated ***:The initial PubMed search identified 1233publications. Studies not reporting GC or those not reporting actual number of GC were excluded. Twelve pertinent studies were retrieved from the PubMed database or from a manual search and considered for the meta-analysis. Pooled risk ratios and 95%CI were estimated by a random-effects model. Subgroup analysis was performed according to gender or geographical regions. Heterogeneity and publication bias were evaluated by I2and funnel plot analysis,***:DM was significantly associated with GC with a RR of 1.41(P = 0.006)(95%CI:1.10-1.81).Subgroup analyses revealed that both sexes showed a significant association with GC,with a greater magnitude of risk in females(RR = 1.90; 95%CI:1.27-2.85;P = 0.002) than in males(RR = 1.24; 95%CI:1.08-1.43;P = 0.002). In addition,the link between DM and GC was significant in East Asian DM patients(RR = 1.77;95%CI:1.38-2.26; P < 0.00001) but not in Western DM patients(RR = 1.23; 95%CI:0.90-1.68; P = 0.2).There was no evidence of publication bias,but the results indicated significant ***:This updated meta-analysis has provided evidence of positive DM-GC associations. The limited information on potentially important clinical confounding factors in each study deserves further investigation.

关键词： Gastric cancer Diabetes mellitus Metaanalysis Hyperglycemia Hyperinsulinemia

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