sirolimus and Diabetes-Mellitus--Type-2

Percutaneous coronary intervention with the new generation drug eluting stents (DES) is 1 among the revascularization procedures required to treat patients with coronary artery disease (CAD). Since late stent thrombosis and silent myocardial infarction are highly associated with type 2 diabetes mellitus (T2DM), an analysis comparing the newer generation DES in this specific subgroup of patients would be scientifically relevant.In this analysis, we aimed to systematically compare the cardiovascular outcomes observed with the ultrathin bioresorbable polymer sirolimus eluting stents (SES) versus thin, durable polymer everolimus eluting stents (EES) following percutaneous coronary intervention in patients with T2DM.. Through online databases, relevant studies comparing ultrathin bioresorbable polymer SES versus the durable polymer EES were carefully searched. The cardiovascular outcomes were assessed during a follow-up time period of 1 year and more than 1 year (1-5 years) respectively. This meta-analysis was carried out by the latest version of the RevMan software. Following analysis, the results were represented by odds ratios (OR) with 95% confidence intervals (CI).. A total number of 1967 patients with T2DM were included in this analysis. During a 1 year follow-up time period, target lesion failure (TLF) (OR: 0.59, 95% CI: 0.34-1.02; P = .06, target vessel revascularization (TVR) (OR: 0.97, 95% CI: 0.55-1.70; P = .91) and target lesion revascularization (TLR) (OR: 0.91, 95% CI: 0.44-1.87; P = .79) were similarly observed with ultrathin bioresorbable polymer SES versus the thin, durable polymer EES in these patients with T2DM. Other cardiovascular outcomes including myocardial infarction (MI), major adverse cardiac events, all-cause mortality (OR: 0.72, 95% CI: 0.37-1.40; P = .34), cardiac death and stent thrombosis (OR: 0.85, 95% CI: 0.45-1.62; P = .63) were also similarly observed with these 2 types of new stents. During a follow-up time period above 1 year (1-5 years), still no significant difference was observed in TLF, TVR, TLR, major adverse cardiac events, MI, all-cause mortality, cardiac death and stent thrombosis (OR: 0.62, 95% CI: 0.33-1.16; P = .14).. The ultrathin bioresorbable polymer SES were similar to the durable polymer EES in these patients with T2DM. These 2 types of new generation stents were comparable in terms of cardiovascular outcomes. Hence, they might be recommended in patients with T2DM. Upcoming trials should be able to confirm this hypothesis.

Topics: Absorbable Implants; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Everolimus; Humans; Immunosuppressive Agents; Outcome Assessment, Health Care; Percutaneous Coronary Intervention; Sirolimus

The mammalian targets of rapamycin (mTOR) inhibitors are potent immunosuppressors used for prevention of acute rejection after transplantation and have been more recently used as anticancer drugs. mTOR inhibitors have a significant impact on glucose metabolism and frequently induce diabetes. mTOR inhibitors, when used as immunosuppressive agents (sirolimus, everolimus), can induce diabetes with an incidence which is low when used without calcineurin inhibitors but high when used in combination with calcineurin inhibitors (from 11.0% to 38.1%). mTOR inhibitors used as anticancer agents (everolimus, temsirolimus) increase significantly the risk for new-onset diabetes and induce a 5-fold increase in the risk for severe hyperglycemia. The deleterious effect of mTOR inhibitors on glucose metabolism is due to an increased insulin resistance secondary to a reduction of the insulin signaling pathway within the cell and a reduction of insulin secretion via a direct effect on the pancreatic beta cells. Because of the risk for diabetes, it is recommended, when starting a treatment with an mTOR inhibitor, to check fasting blood glucose every 2 weeks during the first month of treatment then every month and HbA1c every 3 months and to intensify self-monitoring of blood glucose in patients with known diabetes. When fasting blood glucose is more than 126 mg/dL (7.0 mmol/L), when plasma glucose is more than 200 mg/dL at any time, or when HbA1c is more than 6.5%, it is recommended to start antidiabetic treatment.

Topics: Diabetes Mellitus, Type 2; Everolimus; Humans; Hyperglycemia; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

The prevalence of obesity, of type 2 diabetes mellitus (T2DM), and of cancer are all increasing globally. The relationships between these diseases are complex, and thus difficult to elucidate; nevertheless, evidence supports the hypothesis that obesity increases the risks of both T2DM and certain cancers. Further complexity arises from controversial evidence that specific drugs used in the treatment of T2DM increase or decrease cancer risk or influence cancer prognosis. Herein, we review the current evidence from studies that have addressed these relationships, and summarize the methodological challenges that are frequently encountered in such research. We also outline the physiology that links obesity, T2DM, and neoplasia. Finally, we outline the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer.

Topics: Androgen Antagonists; Antineoplastic Agents; Diabetes Mellitus, Type 2; Global Health; Glucocorticoids; Humans; Hypoglycemic Agents; Incidence; Insulin; Neoplasms; Obesity; Prevalence; Prognosis; Risk Factors; Signal Transduction; Sirolimus; Survivors

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; 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Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; 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Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

This study aimed to compare 6 months to 5 years stent thrombosis (ST) and adverse cardiovascular outcomes associated with sirolimus-eluting stents (SES) and other drug-eluting stents (DES) in patients with type 2 diabetes mellitus (T2DM).Electronic databases were searched for studies comparing SES with other DES in patients with T2DM. Total ST, definite ST, probable ST, and other adverse cardiovascular outcomes reported between 6 months and 5 years were considered as the clinical end points in this study. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for categorical variables and the pooled analyses were performed with RevMan 5.3 software.Twenty-nine studies involving a total number of 25,729 patients with diabetes were included in this meta-analysis. SES were not associated with significantly higher total, definite, and probable STs with OR: 0.95, 95% CI: 0.77-1.17, P = 0.62; OR: 0.94, 95% CI: 0.65-1.37, P = 0.76; and OR: 1.05, 95% CI: 0.77-1.45, P = 0.74, respectively. SES were also noninferior to the other non-sirolimus eluting drug eluting stents (non-SE DES) in terms of all-cause mortality, cardiac death, myocardial infarction, and stroke with OR: 0.92, 95% CI: 0.82-1.03, P = 0.16; OR: 1.09, 95% CI: 0.88-1.35, P = 0.44; OR: 0.92, 95% CI: 0.80-1.06, P = 0.26; and OR: 0.79, 95% CI: 0.49-1.28, P = 0.43, respectively. Target vessel revascularization, target lesion revascularization, and major adverse cardiac events were also similarly reported between SES and non-SE DES with OR: 1.04, 95% CI: 0.83-1.31, P = 0.72; OR: 1.25, 95% CI: 0.95-1.64, P = 0.11; and OR: 1.06, 95% CI: 0.90-1.25, P = 0.49, respectively.During this particular follow-up period, SES were not associated with any increase in ST among these patients with T2DM. Mortality and other adverse cardiovascular outcomes were also not significantly different between these 2 groups. Hence, SES should be considered neither superior nor inferior to other DES. They are expected to be equally effective and safe to use in patients with T2DM.

Topics: Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Humans; Sirolimus; Thrombosis; Time Factors; Treatment Outcome

The main approach to obesity and type-II diabetes is to unravel the mechanisms involved in nutrient absorption and fuel allocation. In conditions of over-nutrition, cells must cope with a multitude of extracellular signals generated by changes in nutrient load, hormonal milieu, adverse cytokine/adipokine profile, and apoptosis/anti-apoptosis processes. To date studies have demonstrate that among all nutrients, lipids and carbohydrates play a major regulatory role in the gene transcription of glycolytic and lipogenic enzymes, insulin, and adipokines. These nutrients mainly exert their effects through the gene expression of sterol responsive binding protein 1 and 2 (SREBP) and the mammalian target of rapamycin (mTOR). Excess of adipose tissue is known to confer a significantly higher risk of coronary artery disease. Administration of rapamycin effectively attenuated inflammation, inhibited progression, and enhanced stability of atherosclerotic plaques in animal models. Herein we discuss the mTOR pathway and the molecular mechanisms of mTOR inhibitors, hypothesizing a possible protective role in atherosclerosis, taking into account also previous clinical studies emphasizing their opposite role.

Topics: Adipose Tissue; Animals; Coronary Artery Disease; Diabetes Mellitus, Type 2; Humans; Obesity; Sirolimus; TOR Serine-Threonine Kinases

The target of rapamycin (TOR) is a highly conserved serine/threonine kinase that is part of two structurally and functionally distinct complexes, TORC1 and TORC2. In multicellular organisms, TOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy. Deregulation of TOR signaling alters whole body metabolism and causes age-related disease. This review describes the most recent advances in TOR signaling with a particular focus on mammalian TOR (mTOR) in metabolic tissues vis-a-vis aging, obesity, type 2 diabetes, and cancer.

Topics: Aging; Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Gene Deletion; Gene Expression Regulation; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Neoplasms; Obesity; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Pancreas-kidney transplant is an effective treatment for patients with insulin-dependent dabetes and chronic renal failure. Reduction in technical failure loss and early acute rejection rates contributed to prolong pancreas graft survival. However, drug toxicity affects negatively both short- and long-term follow-ups.. This article reviews the existing literature and knowledge of the immunosuppressive drugs that are frequently used in pancreas transplant, including calcineurin inhibitors, sirolimus, corticosteroids, and mycophenolate. The article also discusses the short- and long-term adverse effects of these drugs. The article also reports and discusses the most relevant in vitro studies, providing additional information to in vivo findings. Some clinically relevant drug interactions with immunosuppressive drugs are also highlighted. Over- and underimmunosuppression effects will not be addressed.. Immunosuppressive regimen after pancreas transplant is very effective and contributed to pancreas allograft survival. However, they present several side effects that are potentiated when drugs are combined. Modifiable and non-modifiable risk factors can aggravate metabolic and toxicological effects of immunosuppressive drugs. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

Topics: Adrenal Cortex Hormones; Bone Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Hematologic Diseases; Humans; Hyperkalemia; Hyperuricemia; Immunosuppressive Agents; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Pneumonia; Renal Insufficiency, Chronic; Sirolimus

Calcineurin inhibitor drugs (CNI) are the mainstay of modern immunosuppression in renal transplantation. However, they contribute significantly to the chronic loss of renal grafts and the high morbidity and mortality in this population due to their deleterious effects on the renal graft, cardiovascular profile and tumour pathology. Anti-mTOR drugs, sirolimus (SRL) and everolimus (EVE) are potent immunosuppressants with antiproliferative and anti-migratory capacities. These properties mean that they have a potential protective role in graft dysfunction, in renal function optimisation and the appearance of malignant tumours. Indeed, clinical trials and observational studies have demonstrated that conversion from CNI to anti-mTOR-based maintenance therapy has beneficial effects on transplant outcomes in terms of renal function, without significant increase in acute rejection rates. This review article examines the evidence of the use of anti-mTOR in the following clinical situations following renal transplantation: 1) prevention of immune dysfunction and renal function preservation in de novo renal transplantation and after early or late CNI withdrawal; 2) chronic dysfunction of the renal graft; 3) cardiovascular effects; 4) de novo post-transplant diabetes, and 5) de novo tumour pathology.

Topics: Animals; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Dyslipidemias; Everolimus; Evidence-Based Medicine; Graft Rejection; Graft vs Host Disease; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney; Kidney Transplantation; Models, Animal; Multicenter Studies as Topic; Neoplasms; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

Coronary stent thrombosis is a serious problem in the drug-eluting stent era. Despite aggressive antiplatelet therapy during and after percutaneous coronary intervention (PCI), the incidence of sub-acute stent thrombosis remains approximately 0.5%-2%, which may represent a catastrophic clinical situation. Both procedural factors and discontinuation of antiplatelet therapy are normally associated with this event. We report on simultaneous stent thromboses of two drug-eluting stents implanted in two different vessels, which resulted in a life-threatening clinical condition. Possible contributing factors that led to synergistic thrombotic effects are discussed.

Topics: Angioplasty, Balloon, Coronary; Aspirin; Cardiovascular Agents; Clopidogrel; Coronary Angiography; Coronary Stenosis; Coronary Thrombosis; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Humans; Medication Adherence; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk Factors; Sirolimus; Ticlopidine; Treatment Outcome

The insulin resistance of type 2 diabetes mellitus (T2DM), although important for its pathophysiology, is not sufficient to establish the disease unless major deficiency of beta-cell function coexists. This is demonstrated by the fact that near-physiological administration of insulin (CSII) achieved excellent blood glucose control with doses similar to those used in insulin-deficient type 1 diabetics. The normal beta-cell adapts well to the demands of insulin resistance. Also in hyperglycaemic states some degree of adaptation does exist and helps limit the severity of disease. We demonstrate here that the mammalian target of rapamycin (mTOR) system might play an important role in this adaptation, because blocking mTORC1 (complex 1) by rapamycin in the nutritional diabetes model Psammomys obesus caused severe impairment of beta-cell function, increased beta-cell apoptosis and progression of diabetes. On the other hand, under exposure to high glucose and FFA (gluco-lipotoxicity), blocking mTORC1 in vitro reduced endoplasmic reticulum (ER) stress and beta-cell death. Thus, according to the conditions of stress, mTOR may have beneficial or deleterious effects on the beta-cell. beta-Cell function in man can be reduced without T2DM/impaired glucose tolerance (IGT). Prospective studies have shown subjects with reduced insulin response to present, several decades later, an increased incidence of IGT/T2DM. From these and other studies we conclude that T2DM develops on the grounds of beta-cells whose adaptation capacity to increased nutrient intake and/or insulin resistance is in the lower end of the normal variation. Inborn and acquired factors that limit beta-cell function are diabetogenic only in a nutritional/metabolic environment that requires high functional capabilities from the beta-cell.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Genetic Variation; Gerbillinae; Insulin Resistance; Insulin-Secreting Cells; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Proteins; Sirolimus; TOR Serine-Threonine Kinases

What is the relationship between stem cell aging and organismal aging? Does stem cell aging cause organismal aging or vice versa? Will stem cell aging aggravate age-related diseases? And what is stem cell aging? As suggested herein, hyperstimulation of signal transduction pathways can render cells compensatorily irresponsive. And the hallmark of stem cell aging is poor responsiveness to activating stimuli. On the basis of the hypothesis that insensitivity to stimuli is in part due to hyperactivation of the target of rapamycin (TOR), this article suggests a means of pharmacologic rejuvenation of stem cells and wound-healing cells.

Topics: Aging; Animals; Cellular Senescence; Diabetes Mellitus, Type 2; Feedback, Physiological; Humans; Models, Biological; Protein Kinases; Rejuvenation; Sirolimus; Stem Cells; TOR Serine-Threonine Kinases; Wound Healing

Diabetes mellitus is a major risk factor for restenosis in patients undergoing percutaneous coronary intervention. Randomized controlled trials comparing drug-eluting stents (DESs) with bare metal stents (BMSs) showed a marked decrease in in-stent restenosis and target lesion revascularization with DESs in the total patient population enrolled in the studies, including patients with diabetes. However, it remains unclear whether the antirestenotic benefit of DESs is preserved in the high-risk diabetic subgroup. MEDLINE, EMBASE, ISI Web of Knowledge, Current Contents, International Pharmaceutical Abstracts, and recent Scientific Sessions databases were searched to identify relevant clinical trials comparing DESs with BMSs. A randomized controlled trial was included if it provided outcome data for patients with diabetes for > or =1 of the following: late lumen loss, in-stent restenosis, or target lesion revascularization. Data were combined using fixed-effects models, and standard tests for heterogeneity were performed. Eight studies with 1,520 patients with diabetes were identified that reported > or =1 outcome of interest. Mean late lumen losses (7 studies) were 0.93 mm (95% confidence interval [CI] 0.510 to 1.348) with BMSs and 0.18 mm (95% CI -0.088 to +0.446) with DESs. For patients receiving a DES, this translated into a marked decrease in in-stent restenosis (7 studies, RR 0.14, 95% CI 0.10 to 0.22, p <0.001) and target lesion revascularization (8 studies, RR 0.34, 95% CI 0.26 to 0.45, p <0.001). DES use is associated with a marked decrease in in-stent restenosis and target lesion revascularization in patients with diabetes. In conclusion, the analysis supports the current widespread use of DESs in these high-risk patients.

Topics: Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Coronary Artery Disease; Coronary Restenosis; Databases, Factual; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Paclitaxel; Prosthesis Design; Randomized Controlled Trials as Topic; Sirolimus; Stents; Treatment Outcome

The diabetic patient is at high risk for coronary artery disease. Incidence as well as severity of the disease is highly increased in comparison to non-diabetic patients. The revascularization of the diabetic patient is a great challenge, since the longterm results are disappointing when compared to non-diabetic patients. The success of coronary artery bypass grafting is limited by increased perioperative mortality and a faster occlusion of especially venous bypass grafts. In percutaneous interventions the excessive high restenosis rates worsen longterm results. Several clinical trials investigated the outcome of the two revascularization strategies and could demonstrate at least a tendency towards better results when the operative approach was chosen. Particularly, the BARI trial showed reduced mortality for surgery when compared to percutaneous coronary interventions. However, in this trial, in 87% of patients undergoing bypass surgery all stenoses were successfully treated, whereas in patients undergoing percutaneous coronary intervention only 76% of all stenoses were primarily successfully treated. In addition, no stents were used in this trial.Furthermore, the enrollment of the previous trials dates one decade ago. These trials do therefore not necessarily represent the current standard therapy, especially for percutaneous coronary interventions. The restenosis rate could be decreased in recent years by means of drug-eluting stents and an aggressive antiplatelet therapy from more than 50% to less than 10% leading to considerably improved long-term results. Therefore, percutaneous coronary interventions have developed to be a reasonable alternative to bypass surgery. Different clinical trials are currently underway (BARI 2D, CarDIA, FREEDOM) comparing the outcome of the two approaches.

Topics: Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Artery Bypass; Coronary Artery Disease; Diabetes Complications; Diabetes Mellitus, Type 2; Humans; Myocardial Revascularization; Paclitaxel; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Sirolimus; Stents

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Administration Schedule; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Postoperative Complications; Sirolimus

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; 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The DIABETES (DIABETes and sirolimus-Eluting Stent) trial is a prospective, multicentre, randomised, controlled trial aimed at demonstrating the efficacy of sirolimus-eluting stent (SES) as compared to bare metal stent (BMS) implantation in diabetic patients. The aim of the present analysis was to assess the five-year clinical follow-up of the patients included in this trial.. One hundred and sixty patients (222 lesions) were included: 80 patients were randomised to SES and 80 patients to BMS. Patients were eligible for the study if they were identified as non-insulin-dependent diabetics (NIDDM) or insulin-dependent diabetics (IDDM), with significant native coronary stenoses in ≥1 vessel. There was a sub-randomisation according to diabetes status. Clinical follow-up was extended up to five years. Five-year clinical follow-up was obtained in 96.2%. Overall, MACE at five years was significantly lower in the SES group as compared with the BMS arm, mainly due to a significant reduction in TLR. There were no significant differences in cardiac death or myocardial infarction (MI). This was also observed in both prespecified subgroups IDDM and NIDDM. In the SES group, the incidence density of definite/probable stent thrombosis was 0.53 per 100 person-years, whereas in the BMS group it was 0.8 per 100 person-years. Independent predictors of MACE were: SES implantation (p<0.001), multivessel stent implantation (p=0.04), and creatinine levels (p=0.001).. Five-year follow-up of the DIABETES trial suggests the effect of SES in reducing TLR is similar in both IDDM and NIDDM. No major safety concerns in terms of ST, MI or mortality were observed.

Topics: Aged; Cardiovascular Agents; Coronary Angiography; Coronary Stenosis; Coronary Thrombosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Drug-Eluting Stents; Female; Humans; Kaplan-Meier Estimate; Male; Metals; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Proportional Hazards Models; Prospective Studies; Prosthesis Design; Risk Factors; Severity of Illness Index; Sirolimus; Spain; Stents; Time Factors; Treatment Outcome

Because a delayed arterial healing response after drug-eluting stent implantation has raised concerns about safety in diabetic patients, long-term effects of treatment with sirolimus-eluting stent (SES), as compared with bare-metal stent (BMS), have to be established. The aim of the 5-year follow-up of the randomized, controlled, open-label multicenter SCORPIUS study was to assess long-term safety and efficacy of the CYPHER (Cordis, Johnson & Johnson, Bridgewater, NJ) SES in percutaneous coronary intervention of diabetic patients.. A total of 190 patients with type 2 diabetes mellitus were randomized to receive either a SES (n = 95) or a BMS (n = 95). Dual-antiplatelet therapy (aspirin plus clopidogrel) was prescribed for at least 6 months. Clinical follow-up data were scheduled at 1, 8, and 12 months and 5 years.. Treatment with SES resulted in a 16% decrease in the rate of major adverse cardiac events (36% vs 52%; hazard ratio 0.6, 95% CI 0.4-0.9; P = .02). This reduction in major adverse cardiac events with SES at 5 years was mostly attributable to a lower number of repeat target lesion revascularization (13% vs 29%; hazard ratio 0.4, 95% CI 0.2-0.7; P = .003). No differences between groups were observed for safety end points (all-cause mortality 21% vs 21%, cardiac death 15% vs 13%, repeat myocardial infarction 8% vs 9%, and stent thrombosis 5% vs 6%) at 5 years.. The 5-year follow-up of the SCORPIUS trial demonstrates the long-term antirestenotic efficacy of SES in diabetic patients with significantly reduced target lesion revascularization and comparable rates of mortality, myocardial infarction, and stent thrombosis compared with BMS.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Stenosis; Diabetes Mellitus, Type 2; Double-Blind Method; Drug-Eluting Stents; Female; Follow-Up Studies; Germany; Humans; Immunosuppressive Agents; Male; Prospective Studies; Prosthesis Design; Sirolimus; Time Factors; Treatment Outcome

Diabetic patients respond less favorably to revascularization and have poorer long-term outcomes. Our main aim was to evaluate the angiographic efficacy of XIENCE V (everolimus-eluting stent, or EES) in diabetic patients compared with TAXUS Liberté (paclitaxel-eluting stent, or PES).. The SPIRIT V Diabetic Study was a prospective, single-blind, randomized study that enrolled 324 diabetic (insulin and non-insulin dependent) patients at 28 sites in Europe and Asia Pacific. Randomization was 2:1 between EES (n = 218) and PES (n = 106). The primary end point was sequential noninferiority and superiority of EES for in-stent late loss at 9 months. Secondary clinical end points included stent thrombosis, death, myocardial infarction, and revascularization rates up to 1 year.. Everolimus-eluting stent was superior to PES for in-stent late loss at 9 months (0.19 mm vs 0.39 mm, respectively; P(superiority) = .0001). The composite rate of death, myocardial infarction, and target vessel revascularization was the same in the 2 groups at 1 year (16.3% vs 16.4%). No stent thromboses (Academic Research Consortium definite and probable) were seen through 1 year with EES compared with 2 of 104 (2%) with PES (P = .11).. In this prospective, randomized trial in a high-risk group of diabetic patients, implantation of EES compared with PES resulted in significantly better inhibition of intimal hyperplasia with a comparable safety outcome.

Topics: Aged; Angioplasty, Balloon, Coronary; Asia; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Europe; Evaluation Studies as Topic; Everolimus; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Prospective Studies; Risk Assessment; Single-Blind Method; Sirolimus; Statistics, Nonparametric; Survival Analysis; Taxus; Treatment Outcome

To expand the paucity of data on the efficacy of various drug-eluting stents in diabetic patients.. Type 2 diabetic patients treated in our institution from October 2005 to January 2007 presenting with of de novo lesions in native coronary arteries were randomly assigned to sirolimus-eluting stents (Cypher group; n=76); paclitaxel-eluting stents (Taxus group; n=75); and everolimus-eluting stents (Endeavor group; n=75). Poor metabolic control (HbA1c >7% and low-density lipoprotein cholesterol >100 mg/dL) and microvascular complications (retinopathy and/or nephropathy) were assessed. The primary end point was the 3-year composite of major adverse cardiac events (MACE), including death of any cause, myocardial infarction, and clinically driven target vessel revascularization. MACE-free survival was 86.8% in the Cypher group, 82.5% in the Taxus group, and 64.4% in the Endeavor group (P=0.006 by log-rank test). The post hoc comparisons showed no significant difference between Cypher versus Taxus groups (adjusted P=1.0) but a higher MACE rate in the Endeavor group versus both the Cypher group (adjusted P=0.012) and the Taxus group (adjusted P=0.075). Independent predictors of 3-year MACE at Cox analysis were treatment by Endeavor versus Cypher stent (2.35 [95% confidence interval, 1.07 to 5.41]; P=0.030), multivessel disease (hazard ratio, 1.78 [95% confidence interval, 1.06 to 2.66]; P=0.031), diabetic retinopathy (hazard ratio, 1.60; [95% confidence interval, 1.03 to 2.76]; P=0.038), and poor metabolic control (hazard ratio, 1.60; [95% confidence interval, 1.02 to 2.52]; P=0.048).. The present pilot study suggests that in diabetic patients, the Endeavor stent is associated with a higher 3-year MACE rate when compared with Cypher and Taxus stents.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Retinopathy; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Paclitaxel; Pilot Projects; Sirolimus

Telmisartan is a peroxisome proliferator-activated receptor-γ activator with potent anti-inflammatory and antiatherogenic effects. The authors compared the effects of telmisartan and valsartan on neointima volume, atherosclerosis progression and brachial-ankle pulse wave velocity (baPWV) after stenting in hypertensive type 2 diabetes.. This was a prospective, randomised, 8-month follow-up study that included patients with significant coronary stenosis who received telmisartan (n=36) or valsartan (n=37).. University hospital.. Neointima volume and atherosclerosis progression 10 mm proximal and distal to the stented segment were analysed using repeat intravascular ultrasonography. baPWV and inflammatory markers such as interleukin 6, tumour necrosis factor α, C-reactive protein and adiponectin were compared.. Neointima volume at 8 months was significantly lower in the telmisartan group than the valsartan group (1.9±1.0 vs 2.6±1.4 mm(3)/1 mm, p=0.007, respectively). Total plaque volumes 10 mm proximal (7.1±1.5 vs 7.8±1.6 mm(3)/1 mm, p=0.032, respectively) and distal (3.5±1.4 vs 4.1±1.3 mm(3)/1 mm, p=0.028, respectively) to the stent were significantly lower in the telmisartan group than the valsartan group at 8 months. The decrease from baseline in baPWV was significantly greater in the telmisartan group than the valsartan group (-52±104 vs 30±113 cm/s, p=0.002, respectively). The increase from baseline in adiponectin levels and the decreases from baseline in interleukin 6 and tumour necrosis factor α levels were significantly greater in the telmisartan group at 8 months. Retinol-binding protein-4, homeostasis model of assessment index, hemoglobin A(1c) and low-density lipoprotein cholesterol levels decreased significantly in both groups without differences in changes from baseline between the two groups.. Telmisartan reduced neointima volume; atherosclerosis progression 10 mm proximal and distal to the stented segment and baPWV independent of blood pressure, glucose and lipid control in hypertensive type 2 diabetes. Clinical trial no NCT00599885 (clinicaltrials.gov.).

Topics: Adiponectin; Aged; Ankle Brachial Index; Anti-Inflammatory Agents; Benzimidazoles; Benzoates; C-Reactive Protein; Coronary Stenosis; Diabetes Mellitus, Type 2; Disease Progression; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Hypertension; Interleukin-6; Male; Middle Aged; Neointima; Prospective Studies; Single-Blind Method; Sirolimus; Telmisartan; Tetrazoles; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Ultrasonography, Interventional; Valine; Valsartan

Kidney transplantation is the best replacement therapy of type 2 diabetic patients and recently similar graft and patient survival between diabetic and nondiabetic recipients has been reported. However, standard immunosuppressive protocols are lacking. We present our experience with sirolimus-based immunosuppression in a population of 24 type 2 diabetic patients who underwent a kidney transplantation.. From January 2001 to December 2006, 396 kidney transplantations were performed. Twenty-four patients had type 2 diabetes mellitus as a cause of end-stage renal disease. They were randomized in two groups: thirteen patients (group A) received an immunosuppressive treatment with sirolimus, low-dose tacrolimus and steroids, while 11 patients (group B) received sirolimus, mycophenolate mofetil and steroids.. Clinical characteristics were similar between the two groups. A slightly better kidney functionality was observed in group B patients. There were neither acute rejection episodes nor severe infectious complications in both groups. One patient in each group underwent a foot amputation. Graft and patient survival was 100% for both groups at a median follow-up of 29 months.. Sirolimus-based immunosuppression is safe and efficacious in type 2 diabetic patients who underwent a kidney transplantation, allowing a better glucose metabolism control.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Retrospective Studies; Sirolimus

To investigate the mechanistic basis underlying antirestenosis and the antiatherogenic effect of pioglitazone in patients with type 2 diabetes mellitus who were undergoing zotarolimus-eluting stent implantation.. Recent studies highlight the beneficial effect of pioglitazone in attenuating neointimal growth after stent implantation. Patients with coronary artery diseases were randomly assigned to pioglitazone (n=47) or placebo (n=47) after stent implantation. Pioglitazone significantly reduced neointimal hyperplasia within the stented lesion and attenuated total plaque burden in the in-segment regions of the stent, as assessed by intravascular ultrasonography at the 8-month follow-up. These changes were preceded by reduced circulating natural killer (NK) cells, diminished interleukin 6 and monocyte chemoattractant protein-1 levels, and downregulation of chemokine receptor 2 at 2 days after stent implantation; and an elevated interleukin 10 level at 10 days after implantation. Furthermore, the proliferation and migration of vascular smooth muscle cells were inhibited in the presence of pioglitazone-treated patient serum, demonstrating that the antiproliferative effects of pioglitazone occurred concurrently with its antiinflammatory action.. Our data present early cellular and immunologic changes by pioglitazone that might have been associated with antirestenotic and antiatherogenic effects in diabetic patients. Inhibiting proinflammatory responses while promoting antiinflammatory circuits, together with an antiproliferative action, may, in part, account for the antirestenotic effect of pioglitazone by altering vascular remodeling processes in the early phase.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Biomarkers; Blood Glucose; Cardiovascular Agents; Cell Movement; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug-Eluting Stents; Female; Glycated Hemoglobin; Humans; Hyperplasia; Hypoglycemic Agents; Inflammation Mediators; Insulin; Interleukin-6; Killer Cells, Natural; Lipids; Male; Middle Aged; Myocytes, Smooth Muscle; Pioglitazone; Prospective Studies; Prosthesis Design; Receptors, CCR2; Republic of Korea; Single-Blind Method; Sirolimus; Thiazolidinediones; Time Factors; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional

To study long-term results of 3-42-month (mean 18.1 +/- 1.2 month) of a prospective clinically and angiologically controlled follow-up after coronary endovascular revascularisation with sirolimus-eluting stents (SES) in patients with coronary heart disease (CHD) comorbid with type 2 diabetes mellitus (DM).. A total of 108 CHD patients with angina pectoris resistant to antianginal therapy were divided into 2 groups: 51 CHD patients with mild and moderate type-2 DM (group 1); 57 CHD patients free of diabetes (group 2). All the patients have undergone successful coronary endovascular revascularisation with SES. Anti-ischemic efficacy and safety of stenting were studied in the course of 18-month prospective follow-up.. An anti-ischemic effect of stenting in hospital setting was achieved in all the patients. 18 months after stenting frequency and severity of anginal attacks reduced in group 1 by 70.6%, daily need in nitroglycerine--by 71.9%, in group 2--by 87.1 and 93.1%, respectively. As a result, exercise tolerance improved in group 1 by 38.3%, in group 2--by 40.8%. Quality of life improved by 22.7 and 25.1%, respectively. Most of the patients showed no deterioration of carbohydrate and lipid metabolism compensation. Recurrent angina and symptoms of painless myocardial ischemia occurred in 39.3 and 14% patients of group 1 and 2, respectively. More frequent causes of the recurrence were progression of coronary artery atherosclerosis de novo and Cypher stent restenosis (11.8 and 3.5% in group 1 and 2, respectively).. SES implantation provided good anti-ischemic efficacy in 60.7 and 86% CHD patients with and without DM, respectively. It significantly improved exercise tolerance and quality of life.

Topics: Coronary Angiography; Coronary Restenosis; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Revascularization; Prospective Studies; Quality of Life; Sirolimus; Time Factors; Treatment Outcome

It is still controversial whether sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) are equally effective in patients with diabetes. In these patients, multiple individual variables may be responsible for neointimal hyperplasia, thus making difficult the comparison of the two drug-eluting stents (DES).. We designed a prospective, randomized study to compare the efficacy in prevention of restenosis of SES and PES, both implanted in the same diabetic patient with multiple de novo coronary artery lesions undergoing elective percutaneous coronary intervention. We enrolled 60 patients with diabetes with at least two significant de novo angiographic stenoses in different coronary segments. The primary end point was in-stent late luminal loss (LLL) at 8-month angiographic follow-up.. A total of 120 lesions were successfully treated with the randomly assigned DES (SES, n = 60; PES, n = 60). In-stent LLL was lower in the SES than in the PES group (0.26 +/- 0.4 vs. 0.50 +/- 0.6 mm; P = 0.01). Coronary lesions treated with SES presented a reduced in-stent LLL in 40 (68%) patients, while PES resulted in a lower in-stent LLL in 19 (32%) patients (P = 0.0002). At multivariable analysis, the type of DES implanted was the only independent predictor of in-stent LLL (odds ratio 2.3 [95% CI 1.1-5.0]; P = 0.03).. SES directly compared with PES in the same diabetic patient is associated with a decrease in the extent of in-stent LLL at 8 months, suggesting a reduced risk of restenosis.

Topics: Aged; Anti-Bacterial Agents; Antineoplastic Agents; Coronary Angiography; Coronary Disease; Coronary Restenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Paclitaxel; Prospective Studies; Sirolimus

Few studies directly compared drug-eluting stents and bare-metal stents (BMSs) in diabetic patients. DESSERT was an Italian multicenter randomized trial to show the efficacy of sirolimus-eluting stents (SESs) compared with BMSs in de novo lesions of diabetic patients treated with insulin and/or oral antidiabetics for > or =3 months on top of glycoprotein IIb/IIIa inhibitors. The primary end point was in-stent late lumen loss, assessed using centralized quantitative coronary angiography at 8-month follow-up. Centrally adjudicated composite major adverse cardiac events (MACEs) and target-vessel failure (TVF; death, treated vessel-related acute myocardial infarction, and target-vessel revascularization) at 30 days and 9 and 12 months were secondary end points. Seventy-five patients were randomly assigned to an SES (109 lesions), and 75 (109 lesions), to a BMS. The 2 groups were well balanced for clinical, anatomic, and procedural characteristics. In-stent late lumen loss decreased from 0.96 +/- 0.61 mm for BMSs to 0.14 +/- 0.33 for SESs (p <0.001), and in-segment binary restenosis was 38.8% versus 3.6%, respectively (p <0.001). Twelve-month clinical events were significantly lower in the sirolimus group: MACEs 22.1% versus 40% (p = 0.023), target-lesion revascularization 5.9% versus 30% (p <0.001), and TVF 14.7% versus 34.3% (p = 0.008). At multivariate analysis, stent type was confirmed as an independent predictor of in-segment late loss (p <0.001), binary restenosis (p <0.001), 12-month TVF (p = 0.010), and 12-month MACEs (p = 0.037). In conclusion, the randomized DESSERT showed SESs to be safe and effective in decreasing both angiographic parameters of restenosis and incidence of MACEs compared with BMSs in diabetic patients with de novo 1- or 2-vessel coronary stenoses.

Topics: Aged; Coated Materials, Biocompatible; Coronary Angiography; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electrocardiography; Female; Follow-Up Studies; Humans; Incidence; Italy; Male; Metals; Myocardial Infarction; Myocardial Revascularization; Prospective Studies; Risk Factors; Single-Blind Method; Sirolimus; Stents; Survival Rate; Time Factors; Treatment Outcome

Outcomes after percutaneous coronary interventions in diabetic patients are shadowed by the increased rate of recurrence compared with nondiabetic patients.. We conducted a multicenter, randomized trial to demonstrate the efficacy of sirolimus-eluting stents compared with standard stents to prevent restenosis in diabetic patients with de novo lesions in native coronary arteries. The primary end point of the trial was in-segment late lumen loss as assessed by quantitative coronary angiography at 9-month follow-up. The trial was stratified by diabetes treatment status. One hundred sixty patients were randomized to sirolimus-eluting stents (80 patients; 111 lesions) or standard stent implantation (80 patients; 110 lesions). On average, reference diameter was 2.34+/-0.6 mm, lesion length was 15.0+/-8 mm, and 13.1% of lesions were chronic total occlusions. In-segment late lumen loss was reduced from 0.47+/-0.5 mm for standard stents to 0.06+/-0.4 mm for sirolimus stents (P<0.001). Target-lesion revascularization and major adverse cardiac event rates were significantly lower in the sirolimus group (31.3% versus 7.3% and 36.3% versus 11.3%, respectively; both P<0.001). Non-insulin- and insulin-requiring patients demonstrated similar reductions in angiographic and clinical parameters of restenosis after sirolimus-eluting stent implantation. During the 9-month follow-up, stent thrombosis occurred in 2 patients after standard stent implantation. Conversely, this phenomenon was not seen in the sirolimus stent group.. This randomized trial demonstrated that sirolimus stent implantation is safe and efficacious in reducing both angiographic and clinical parameters of restenosis compared with standard stents in diabetic patients with de novo coronary stenoses.

Topics: Aged; Angioplasty, Balloon, Coronary; Anti-Bacterial Agents; Coronary Restenosis; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Equipment Design; Female; Humans; Male; Middle Aged; Sirolimus; Stents

Randomized clinical trials have shown that sirolimus-eluting stents (SESs) decrease restenosis rates compared with bare metal stents (BMSs), but their efficacy among patients who have diabetes mellitus remains to be established. This study investigated the effect of SES implantation in a high-risk population (i.e., patients who had diabetes and small coronary vessel disease). For this purpose, we analyzed outcomes of the subset of patients who had diabetes and were enrolled in the SES-SMART, a randomized trial that compared the results of implantation of SESs and BMSs in small coronary arteries. Twenty-nine patients who had diabetes were originally randomized to receive SESs and 45 patients received BMSs. The use of SESs was associated with approximately 60% decreases in the relative incidence of in-segment angiographic restenosis (63% vs 25%, p = 0.003) and in-segment late loss (0.76 vs 0.28 mm, p <0.002). Angiographic patterns of restenosis were more favorable in the SES group. SES implantation was associated with a 15% absolute decrease in adverse clinical events. In patients who had insulin-dependent diabetes mellitus, SESs showed a high in-segment restenosis rate (40%) that was principally due to persistent restenosis. In conclusion, in diabetics with small coronary arteries, SES implantation significantly reduces the incidence of the 8-month angiographic restenosis rate compared with BMSs.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Single-Blind Method; Sirolimus; Stents; Survival Rate; Treatment Outcome

Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis.. By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus.. ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.

Topics: Animals; Clusterin; Diabetes Mellitus, Type 2; Humans; Lipid Metabolism; Lipids; Liver; Mammals; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitins

Pentadecanoic acid (C15:0) is an essential odd-chain saturated fatty acid with broad activities relevant to protecting cardiometabolic, immune, and liver health. C15:0 activates AMPK and inhibits mTOR, both of which are core components of the human longevity pathway. To assess the potential for C15:0 to enhance processes associated with longevity and healthspan, we used human cell-based molecular phenotyping assays to compare C15:0 with three longevity-enhancing candidates: acarbose, metformin, and rapamycin. C15:0 (n = 36 activities in 10 of 12 cell systems) and rapamycin (n = 32 activities in 12 of 12 systems) had the most clinically relevant, dose-dependent activities. At their optimal doses, C15:0 (17 µM) and rapamycin (9 µM) shared 24 activities across 10 cell systems, including anti-inflammatory (e.g., lowered MCP-1, TNFα, IL-10, IL-17A/F), antifibrotic, and anticancer activities, which are further supported by previously published in vitro and in vivo studies. Paired with prior demonstrated abilities for C15:0 to target longevity pathways, hallmarks of aging, aging rate biomarkers, and core components of type 2 diabetes, heart disease, cancer, and nonalcoholic fatty liver disease, our results support C15:0 as an essential nutrient with activities equivalent to, or surpassing, leading longevity-enhancing candidate compounds.

Topics: Diabetes Mellitus, Type 2; Fatty Acids, Essential; Humans; Longevity; Sirolimus

An alteration in extracellular matrix (ECM) production by vascular smooth muscle cells is a crucial event in the pathogenesis of vascular diseases such as aging-related, atherosclerosis and allograft vasculopathy. The human target of rapamycin (TOR) is involved in the synthesis of ECM by vascular smooth muscle cells. TOR inhibitors reduce arterial stiffness, blood pressure, and left ventricle hypertrophy and decrease cardiovascular risk in kidney graft recipients and patients with coronary artery disease and heart allograft vasculopathy. Other drugs that modulate ECM production such as cilostazol and colchicine have also demonstrated a beneficial cardiovascular effect. Clinical studies have consistently shown that cilostazol confers cardiovascular protection in peripheral vascular disease, coronary artery disease, and cerebrovascular disease. In patients with type 2 diabetes, cilostazol prevents the progression of subclinical coronary atherosclerosis. Colchicine reduces arterial stiffness in patients with familial Mediterranean fever and patients with coronary artery disease. Pathophysiological mechanisms underlying the cardioprotective effect of these drugs may be related to interactions between the cytoskeleton, TOR signaling, and cyclic adenosine monophosphate (cAMP) synthesis that remain to be fully elucidated. Adult vascular smooth muscle cells exhibit a contractile phenotype and produce little ECM. Conditions that upregulate ECM synthesis induce a phenotypic switch toward a synthetic phenotype. TOR inhibition with rapamycin reduces ECM production by promoting the change to the contractile phenotype. Cilostazol increases the cytosolic level of cAMP, which in turn leads to a reduction in ECM synthesis. Colchicine is a microtubule-destabilizing agent that may enhance the synthesis of cAMP.

Topics: Cilostazol; Colchicine; Coronary Artery Disease; Cyclic AMP; Diabetes Mellitus, Type 2; Humans; Muscle, Smooth, Vascular; Sirolimus; Tetrazoles; Vascular Diseases

Objective To investigate the effect of saxagliptin (Sax) against kidney injury in diabetic rats and its mechanisms. Methods SD male rats were fed for 2 weeks, among which 14 rats were selected randomly and given intraperitoneal injection of streptozotocin (STZ) to establish the type 2 diabetes mellitus (T2DM) model, and then were randomly divided into T2DM group and Sax group after the model was successfully established; 6 rats were selected as normal control (NC) group randomly. The rats of Sax group were given the saxagliptin solution. The rats of NC and T2DM groups were injected with the same amount of sodium carboxymethyl cellulose solution. After 8 weeks of continuous gastric administration, the rats were sacrificed and their blood and kidney tissues were collected. Glucose (G1u), albumin (ALB), aspartate transaminase (AST), alanine transaminase (ALT), serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), serum total cholesterol (TC), triglycerides (TG) were detected by automatic biochemical analyzer. HE, PAS, Masson staining and transmission electron microscopy were performed to observe the morphological changes of renal. Immunohistochemical staining was used to detect the protein expression level of mammalian target of rapamycin (mTOR), interleukin 1 (IL-1), IL-6, tumor necrosis factor α (TNF-α) in renal tissues. Results Compared with the NC group, the levels of biochemical indicators such as G1u, ALB, AST, ALT, Scr, BUN, UA, TC, and TG showed significant increase; the number of glomerular mesangial cells also increased, and the mesangial matrix hyperplasia, mTOR, IL-1, IL-6, TNF-α protein expression levels exhibited significant increase in T2DM group. Compared with T2DM group, Sax group showed decreased levels of biochemical indicators such as G1u, ALB, AST, ALT, Scr, BUN, UA, TC, and TG and improved renal pathological damage performance, together with a profound reduction in mTOR, IL-1, IL-6, TNF-α protein expression level. Conclusion Sax may suppress inflammatory response and reduce renal injury in diabetic rats by down-regulating mTOR expression.

Topics: Adamantane; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptides; Interleukin-1; Interleukin-6; Kidney; Male; Mammals; Rats; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

Rapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/LtJ (NcZ10). Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30 weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA-IR, and inflammation, and prevented hyperinsulinemia and pre-steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c-reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulin-resistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (Mest, Gpam), inflammation (Itgam, Itgax, Hmox1, Lbp), and cell senescence (Serpine1). In liver, the addition of metformin counteracted rapamycin-induced alterations of G6pc, Ppara, and Ldlr expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic Fasn expression, potentially preventing lipidosis. These results delineate a state of "insulin signaling restriction" that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the development of its comorbidities. Our results are relevant for the treatment of T2D, the optimization of current rapamycin-based treatments for posttransplant rejection and various cancers, and for the development of treatments for healthy aging.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fatty Liver; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Metformin; Mice; Sirolimus

To investigate the effectiveness of metformin and atorvastatin in preventing in-stent restenosis (ISR) on coronary patients with type 2 diabetes mellitus with percutaneous coronary intervention within 8 to 12 months after rapamycin-eluting stent implantation. A total of 1278 consecutive patients implanted with rapamycin-eluting stent from January 2012 to December 2019, who underwent coronary computed tomography or coronary angiography within 8 to 12 months. The patients were categorized into atorvastatin 20 mg, or atorvastatin 20 mg + metformin 1.5/d, or atorvastatin 40 mg + metformin 1.5/d groups. The clinical characteristics of the 3 groups were compared. The correlation between variables and ISR was analyzed. A total of 701 patients participated in the study. The ratio of ISR/nonstenosis (P = .039) and fasting blood sugar (P = .001) differed significantly in the 3 groups. Logistic regression showed that d, L, different therapeutic agents, and dosage groups were independent risk factors of ISR. The longer L and smaller d may increase ISR incidence with 8 to 12 months after percutaneous coronary intervention. Both metformin and atorvastatin are beneficial in reducing stent restenosis by a dose-dependent manner. An increasing dose of atorvastatin and a combination of metformin decreases the incidence of ISR in patients.

Topics: Atorvastatin; Blood Glucose; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Humans; Metformin; Percutaneous Coronary Intervention; Risk Factors; Sirolimus; Stents; Treatment Outcome

Patients with diabetes mellitus (DM) represents a challenging subset of population as they experience worse outcomes after percutaneous coronary intervention than patients without diabetes. We evaluated the 2-year efficacy and safety profile of the Abluminus DES+ in patients with diabetes within the population enrolled in the large multicenter en-ABL e-registry.. Multicenter, prospective, all-comers registry performed in 31 centers in India. We analyze patients according to the diagnosis of DM and insulin dependency (ID or Non-ID): non-DM (1641 patients), NIDDM (721 patients), IDDM (138 patients). The primary endpoint was a composite of device-oriented major adverse cardiac events (MACE): cardiac death, target vessel-related myocardial infarction (MI), and ischemia-driven target lesion revascularization (TLR)/ target vessel revascularization (TVR) at 2-year. Stent thrombosis (ST) at any time point was also recorded.. The MACE rate at 2-year follow-up was 3.0% in the overall population with DM patients showing a higher rate of primary endpoint compared to non-DM (4.4% vs. 2.4%, P=0.025). Rate of cardiac death was actually low and consistent between the 2 groups (1.7% vs. 0.9%, P=0.100). At 2-year follow-up, the rate of ST was 0.9% in DM patients versus 0.5% in non-DM, P=0.213.. At 2-year follow-up, the Abluminus DES+ technology that merges the features of a sirolimus coated balloon with those of a bioresorbable polymer drug eluting stent appears to be safe and effective. This safety/efficacy profile was consistent in patients with or without DM.

Topics: Coronary Artery Disease; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Humans; Prospective Studies; Sirolimus

An accumulating body of evidence supports the role of autophagy in the pathophysiology of T2DM. Also, abnormal endoplasmic reticulum (ER) stress response that has been implicated as a cause of insulin resistance (IR) could also be affected by the autophagic status in β-cells. The present study was designed to investigate whether autophagy is regulated in T2DM as well as to investigate the modulatory effect of the ER stress inhibitor 4-phenylbutyric acid (4-PBA) and the autophagy inducer rapamycin (Rapa) on the autophagic and diabetic status using type 2 diabetic animal model with IR. Treatment of diabetic rats with either 4-PBA or Rapa improved significantly the states of hyperglycaemia and dyslipidaemia, increased the antioxidant capacity, reduced the levels of lipid peroxidation and ER stress and increased the autophagic flux. The obtained improvements were attributed mainly to the induction of autophagy with subsequent regulation of ER stress-oxidative activation and prevention of β-cell apoptosis.

Topics: Animals; Autophagy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Endoplasmic Reticulum Stress; Phenylbutyrates; Sirolimus

Diabetes mellitus (DM) plays an important role in restenosis and late in-stent thrombosis (ST). The current study using optical coherence tomography (OCT) aims to compare target lesion neointima in patients with or without diabetes after zotarolimus-eluting stent (ZES) treatment.. OCT images of 90,212 struts and quantitative coronary angiography (QCA) in 62 patients (32 with DM and 30 without DM) with 69 de novo coronary lesions (34 DM and 35 non-DM) both after ZES implantation and 12 ± 1 month angiographic follow-up were recorded. Patient characteristics, lesion characteristics, clinical outcomes, and OCT findings including neointimal thickness, coverage, malapposition, and intimal morphology were analyzed.. Baseline patient characteristics and lesion characteristics data were similar between the two groups. Higher neointimal thickness (0.14 ± 0.09 mm vs. 0.09 ± 0.04 mm, p = 0.021), more neovascularization (3.03 ± 6.24 vs. 0.52 ± 1.87, p = 0.017) and higher incidence of layered signal pattern (12.19 ± 19.91% vs. 4.28 ± 9.02%, p = 0.049) were observed in diabetic lesions comparing with non-diabetic lesions. No differences were found in malapposition, uncovered percentage, and thrombus between the two groups (all p > 0.05). Occurrence of clinical adverse events was also similar during the follow-up period (p > 0.05).. Although more neointimal proliferation and more neovascularization were found in diabetic coronary lesions when compared with non-diabetic lesions, treatment with ZES showed similar stent malapposition rate at 1-year follow-up. The data indicated that ZES treatment could possibly be effective in treating diabetic coronary lesions.. ClinicalTrials.gov identifier, NCT01747356.

Topics: Aged; Case-Control Studies; Coronary Angiography; Coronary Vessels; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Sirolimus; Tomography, Optical Coherence; Treatment Outcome

The present study examined the potential of Zingiber officinale-Terminalia chebula extract alone (ZO and TC) and in combination (ZOTC) against type 2 diabetes via downregulation of mechanistic target of rapamycin (mTOR). The 1:4 (ZOTC) ratio showed high cell survival percentage against the rat insulinoma cell line (RIN-5F) when compared to other possible ratios of ZOTC. Oral administration of ZO alone, TC alone, combined ZOTC (1:4), and the positive control metformin (Met) in fructose-streptozotocin (STZ) -induced diabetic rats showed reduced blood glucose levels, reduced insulin resistance (HOMA-IR), increased insulin levels, and increased pancreatic beta cell function (HOMA-β). ZOTC treatment in diabetic rats ameliorated the antioxidant status without affecting liver and serum parameters. Histological evaluation of the pancreas was performed to find pathological changes; the transcriptional and immunohistochemistry results showed reduced mTOR expression in the pancreas during ZOTC treatment. Conclusively, the results obtained suggest that ZOTC treatment against fructose-STZ-induced type 2 diabetes rat models can help regulate blood glucose, insulin levels, and normalize pancreatic β cell damage. PRACTICAL APPLICATIONS: Type 2 diabetes is a chronic metabolic disorder that affects a large number of populations worldwide. Zingiber officinale (ZO) and Terminalia chebula (TC) has been used in traditional medicine since ancient times against various ailments, including diabetes. In this study, we reported the effect of the combined ZOTC that showed significant blood glucose reduction and increased insulin levels via mTOR when compared to individual treatments. This finding is valuable for food technologists and alternative medicine practitioners to know the antidiabetic effect of the ZOTC combination.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Plant Extracts; Rats; Rats, Wistar; Sirolimus; Terminalia; TOR Serine-Threonine Kinases; Zingiber officinale

Type 2 diabetes mellitus (T2DM) is strongly correlated with Alzheimer's disease (AD). Rapamycin has important uses in oncology, cardiology and transplantation medicine. This study aims to investigate effects of rapamycin on AD in hippocampus of T2DM rat by AMPK/mTOR signaling pathway.. Morris water maze test was applied to evaluate the learning and memory abilities. The fasting plasma glucose (FBG), glycosylated haemoglobin, total cholesterol, triglyceride and serum insulin level were measured. RT-qPCR and Western blot analysis were performed to test expression of AMPK and mTOR. Immunohistochemistry was used to detect the Aβ deposition and immunoblotting to test the total tau, p-tau and Aβ precursor APP expressions.. After treated with rapamycin, T2DM rats and rats with T2DM and AD showed increased learning-memory ability, and decreased levels of FBG, glycosylated hemoglobin, total cholesterol, triglyceride and serum insulin, decreased expression of APP and p-tau, increased AMPK mRNA expression and p-AMPK and decreased Aβ deposition, mTOR mRNA expression and p-mTOR.. The study demonstrated that rapamycin reduces the risk of AD in T2DM rats and inhibits activation of AMPK-mTOR signaling pathway, thereby improving AD lesion in hippocampus of T2DM rats.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Hippocampus; Male; Maze Learning; Phosphorylation; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; tau Proteins; TOR Serine-Threonine Kinases

The RESOLUTE-DIABETES CHINA study was specifically designed to investigate the safety and efficacy of Resolute zotarolimus-eluting stents (ZES; Medtronic, Santa Rosa, CA, USA) in the treatment of diabetic coronary lesions in the Chinese population.. In all, 945 patients with de novo native coronary lesions and type 2 diabetes mellitus were recruited at 32 cardiac centers across the Chinese mainland and were implanted with Resolute ZES. The primary endpoint was target vessel failure (TVF); secondary endpoints were clinical outcomes, namely all-cause death, stroke, bleeding, target lesion revascularization (TLR), target vessel revascularization (TVR), non-TVR, and stent thrombosis (ST). The follow-up period for all endpoints was 12 months after the procedure.. In all, 933 patients (98.73%) had clinical follow-up at 12 months. The rate of TVF was 11.60%, whereas the rate of occurrence of secondary endpoints was 5.47%, with four patients (0.43%) having subacute or late ST. There were no significant differences in TVF rates comparing patients with different HbA1c levels or receiving different glucose control treatments (all P > 0.05). Patients with multivessel lesions had higher TVF rates (95% confidence intervals) than those with single-vessel lesions (16.76% [12.10%-22.97%) vs 9.72% [7.79%-12.11%], respectively; P = 0.006). There were no significant differences in TVF rates in patients with or without small vessels, bifurcated lesions, or chronic total occlusions (all P > 0.05). [Correction added on 17 January 2019, after first online publication: in the second sentence of Results section, "TLF" was changed to "TVF".].. Resolute ZES may perform well in the Chinese diabetic population, especially in those with poor glucose control, complex lesions, and certain unfavorable clinical features. Further studies are needed to determine why ZES perform well in this population.

Topics: Coronary Artery Disease; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Prospective Studies; Safety; Sirolimus; Treatment Outcome

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.

Topics: Adult; Allografts; Animals; Calcineurin Inhibitors; Cells, Cultured; Deafness; Diabetes Mellitus, Type 2; Disease Progression; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; MELAS Syndrome; Membrane Potential, Mitochondrial; Mice; Middle Aged; Mitochondria; Mitochondrial Diseases; Primary Cell Culture; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and cardiovascular risk in type 2 diabetes, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. Utilizing an integrated transcriptomic-metabolomics approach, we demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5' AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Given that these phenotypes mirror the effects of FGF21 to promote lipid oxidation, ketogenesis, and reduction in adiposity, we hypothesized that FGF21 is required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for SGLT2i-mediated induction of lipid oxidation and ketogenesis but is required for reduction in fat mass and activation of lipolysis. Taken together, these data demonstrate that SGLT2 inhibition triggers a fasting-like transcriptional and metabolic paradigm but requires FGF21 for reduction in adiposity.

Topics: Adiposity; AMP-Activated Protein Kinases; Animals; Blood Glucose; Canagliflozin; Cellular Reprogramming; Diabetes Mellitus, Type 2; Diglycerides; Energy Metabolism; Fasting; Fatty Liver; Fibroblast Growth Factors; Insulin; Ketones; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Signal Transduction; Sirolimus; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Podocyte injury, characterized by podocyte hypertrophy, apoptosis, and epithelial-mesenchymal transition (EMT), is the major causative factor of diabetic nephropathy (DN). Autophagy dysfunction is regarded as the major risk factor for podocyte injury including EMT and apoptosis. High mobility group box 1 (HMGB1) is involved in the progression of DN through the induction of autophagy. However, the underlying mechanism remains unknown.. Plasma HMGB1 concentrations were determined in DN patients using ELISA. Apoptosis of DN serum-treated podocytes was evaluated by flow cytometry. Podocyte autophagy flux was measured using immunofluorescence. Western blotting analysis was used to investigate HMGB1 expression, EMT, and autophagy-related signaling pathways.. Upregulation of HMGB1 was found in DN patients and DN serum-treated podocytes. Removal of HMGB1 inhibited DN serum-mediated podocyte apoptosis by inhibiting autophagy and activating AKT/mammalian target of rapamycin (mTOR) signaling. In addition, HMGB1 depletion repressed the progression of podocyte EMT by inhibiting transforming growth factor (TGF)-β/smad1 signaling in vitro and in vivo. The combination of HMGB1 short interference (si) RNA and the autophagy activator rapamycin protected against podocyte apoptosis and EMT progression by inhibiting the AKT/mTOR and TGF-β/smad signaling pathway, respectively.. Although HMGB1 siRNA and rapamycin treatment had opposite effects on autophagy and AKT/mTOR signaling, there was no contradiction about the role of HMGB1 siRNA and rapamycin on AKT/mTOR pathway because autophagy and AKT/mTOR signaling play dual roles in intracellular biological processes. Based on the findings of this study, we may assume that HMGB1-initiated autophagy is harmful, whereas rapamycin is beneficial to podocyte survival. Possibly combined treatment with HMGB1 siRNA and rapamycin improved podocyte damage and EMT by regulating autophagy homeostasis.. 摘要: 背景 以肥大、凋亡、上皮-间充质转化(EMT)为特征的足细胞损伤是糖尿病肾病(DN)的主要病因。自噬功能障碍被认为是包括EMT和凋亡在内的足细胞损伤的主要危险因素。HMGB1 (High mobility group box 1) 也通过自噬参与DN的发展进程，但具体机制尚未明确。 方法:采用ELISA法测定DN患者血浆HMGB1浓度。采用流式细胞术检测经DN患者血清处理后的足细胞的凋亡情况。用免疫荧光法测定足细胞自噬流。采用Western blotting分析HMGB1表达、EMT和自噬相关信号通路。 结果 在DN患者和经过DN患者血清处理的足细胞中均发现HMGB1表达量上升。通过抑制HMGB1可抑制自噬和激活AKT/mTOR信号通路，进而抑制DN患者血清介导的足细胞凋亡。此外，HMGB1的损耗可通过抑制体内、外的转化生长因子(TGF) -β/ smad1信号，抑制足细胞的EMT进程。HMGB1 siRNA和自噬激活剂雷帕霉素的结合可分别通过抑制 AKT/mTOR和TGF-β/smad信号通路而起到抑制足细胞凋亡和EMT进程的作用。 结论 虽然HMGB1 siRNA和雷帕霉素处理对自噬和AKT/mTOR信号通路有相反的作用，但因自噬和AKT/mTOR信号通路在细胞内的生物进程中起双重作用，所以二者对AKT/mTOR通路的作用并不矛盾。基于此项研究发现，我们可以推测HMGB1启动的自噬是有害的，而雷帕霉素对足细胞的存活有益。HMGB1 siRNA联合雷帕霉素可能通过调节自噬稳态而改善足细胞损伤和EMT。.

Topics: Animals; Apoptosis; Autophagy; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Female; Follow-Up Studies; HMGB1 Protein; Humans; Male; Mice, Inbred C57BL; Middle Aged; Podocytes; Prognosis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Recently, a malfunction of the autophagic pathway has been implicated with impaired glucose metabolism and progression from prediabetes to type 2 diabetes. The aims of this study were to investigate the effect of exercise and rapamycin (RAPA) treatment on the autophagic process in peripheral blood mononuclear cells (PBMCs) from people with prediabetes compared with control subjects.. Two groups matched for age and sex served as participants and included 6 participants with prediabetes (42.4±11.7 years) and 6 control subjects (44.4±11.9 years). Participants exercised at 50% of maximal oxygen consumption for 60 min with 5 min of rest interspersed every 20 min. PBMCs were isolated pre-exercise, immediately postexercise and 4 h after exercise recovery. Additional PBMCs were incubated for 24 h and either exposed to bafilomycin, rapamycin with bafilomycin (RAPA), or no treatment with vehicle (dimethyl sulfoxide). Proteins and mRNA were analyzed via western blot and quantitative real-time polymerase chain reaction, respectively.. Exercise increased autophagy immediately postexercise and recovered 4 h after exercise in control participants but not in participants with prediabetes. Autophagy increased in PBMCs from people with prediabetes and control participants after RAPA treatment; however, a significantly impaired autophagic response was observed in people with prediabetes when compared with control subjects.. Our results indicate an impairment in autophagic flux in PBMCs from people with prediabetes when compared with control subjects in response to both exercise and RAPA treatment. Future methods of autophagic upregulation should be investigated to spare malfunctions in autophagy in people with prediabetes.

Topics: Adult; Autophagy; Case-Control Studies; Diabetes Mellitus, Type 2; Exercise; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Male; Middle Aged; Oxygen Consumption; Prediabetic State; Prognosis; Sirolimus

Designed a century ago to treat epilepsy, the ketogenic diet (KD) is also effective against obesity and diabetes. Paradoxically, some studies in rodents have found that the KD seemingly causes diabetes, contradicting solid clinical data in humans. This paradox can be resolved by applying the concept of starvation pseudo-diabetes, which was discovered in starved animals almost two centuries ago, and has also been observed in some rapamycin-treated rodents. Intriguingly, use of the KD and rapamycin is indicated for a similar spectrum of diseases, including Alzheimer's disease and cancer. Even more intriguingly, benevolent (starvation) pseudo-diabetes may counteract type 2 diabetes or its complications.

Topics: Aging; Animals; Diabetes Mellitus, Type 2; Diet, Ketogenic; Fasting; Humans; Insulin Resistance; Ketosis; Mice; Obesity; Sirolimus; Starvation

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cardiomyopathies; Cardiotonic Agents; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Echocardiography; Female; Insulin; Insulin Resistance; Longevity; Male; Mice; Mice, Inbred C57BL; Sirolimus; Weight Gain

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction of autophagy. In the following studies, we have examined the effects of metformin in the presence of various chemotherapeutic drugs, signal transduction inhibitors and natural products on the growth of three different PDAC lines. Metformin, by itself, was not effective at suppressing growth of the pancreatic cancer cell lines at concentration less than 1000 nM, however, in certain PDAC lines, a suboptimal dose of metformin (250 nM) potentiated the effects of various chemotherapeutic drugs used to treat pancreatic cancer (e.g., gemcitabine, cisplatin, 5-fluorouracil) and other cancer types (e.g., doxorubicin, docetaxel). Furthermore, metformin could increase anti-proliferative effects of mTORC1 and PI3K/mTOR inhibitors as well as natural products such as berberine and the anti-malarial drug chloroquine in certain PDAC lines. Thus, metformin can enhance the effects of certain drugs and signal transduction inhibitors which are used to treat pancreatic and various other cancers.

Topics: Animals; Carcinoma, Pancreatic Ductal; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Metformin; Pancreatic Neoplasms; Signal Transduction; Sirolimus

Patients with diabetes mellitus (DM) have poorer outcomes after percutaneous coronary intervention than patients without diabetes. The Abluminus DES+™ drug-eluting stent (DES) features a novel technology of fusion coating of PLLA bioresorbable polymer on both the abluminal surface of the stent and exposed parts of the balloon. The aim of this study was to evaluate the efficacy/safety profile of the Abluminus DES+ in an all-comers population with minimal exclusion criteria and with a specific focus on diabetic patients.. Multicenter, prospective, all-comers registry performed in 31 centers in India. Patients were analyzed according to the diagnosis of DM and insulin dependency (ID or Non ID): non-DM (1256 patients), NIDDM (498 patients), IDDM (99 patients). The primary endpoint was a composite of device-oriented major adverse cardiac events (MACE): cardiac death, target vessel-related myocardial infarction (MI), and ischemia-driven target lesion revascularization (TLR)/ target vessel revascularization (TVR) at 1 year. Stent thrombosis (ST) at any time point was also recorded.. The MACE rate at 1 year in the overall population was 2.3% and it was mainly driven by a 1.57% rate of TLR/TVR. Although patients with IDDM showed slightly higher figures for MACE (non-DM 2.3%, NIDDM 2.8%, IDDM 4%, P=0.09), as well as for single end-points, none of them reached statistical significance. The rate of ST was 0.56%, 0.4%, 1% for non-DM, NIDDM and IDDM group, respectively (P=0.6).. The performance of the Abluminus DES+ is consistent among patients with or without diabetes, regardless the insulin dependency.

Topics: Absorbable Implants; Adult; Aged; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Humans; India; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Percutaneous Coronary Intervention; Polymers; Prospective Studies; Registries; Sirolimus; Treatment Outcome

Insulin resistance (IR) is a hallmark of type 2 diabetes mellitus (T2DM). This study aimed to explore the effects of rapamycin, a specific inhibitor of kinase mammalian target of rapamycin (mTOR), on IR in T2DM rats, and to validate whether the underlying mechanism was associated with autophagy. In this study, the model of T2DM rats was established by feeding the animals with a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). Diabetic rats were randomly divided into model of T2DM control group (DM-C, n = 15), metformin group (DM-M, n = 15), rapamycin group (DM-Rapa, n = 15), 3-methyladenine (3-MA) group (DM-3-MA, n = 15), and rapamycin + 3-MA group (DM-Rapa-3-MA, n = 15). Rats in different treatment groups were given by corresponding therapy from gastric tube. Meanwhile, normal control group was established (n = 10). As expected, HFD- and STZ- induced T2DM rats exhibited significantly impaired glucose tolerance, reduced insulin sensitivity, dysglycemia and dyslipidemia, aggravated hepatic steatosis, enhanced hepatic inflammation, elevated p-mTOR, and suppressed hepatic autophagy. Importantly, rapamycin and metformin significantly ameliorated IR, relieved disorders of glucose and lipid metabolism, reduced inflammatory level, inhibited mTOR, and promoted autophagy. Importantly, the autophagy inhibitor 3-MA significantly reversed the effects exerted by rapamycin. Collectively, our study suggests that rapamycin improved IR and hepatic steatosis in T2DM rats via activation of autophagy.

Topics: Animals; Autophagy; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Glucose; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Rats; Rats, Sprague-Dawley; Sirolimus

We report here a simple and global strategy to map out gene functions and target pathways of drugs, toxins, or other small molecules based on "homomer dynamics" protein-fragment complementation assays (hdPCA). hdPCA measures changes in self-association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating the confounding effects of gene ablation. We demonstrate that hdPCA accurately predicts the effects of two longevity and health span-affecting drugs, the immunosuppressant rapamycin and the type 2 diabetes drug metformin, on cellular pathways. We also discovered an unsuspected global cellular response to metformin that resembles iron deficiency and includes a change in protein-bound iron levels. This discovery opens a new avenue to investigate molecular mechanisms for the prevention or treatment of diabetes, cancers, and other chronic diseases of aging.

Topics: Diabetes Mellitus, Type 2; Genetic Complementation Test; Humans; Iron; Metalloproteins; Metformin; Saccharomyces cerevisiae; Sirolimus

Roux-en-Y Gastric Bypass, RYGB, is the most effective strategy to control body weight in morbid obesity. RYGB leads to rapid improvement of glycemic status and weight loss, which are largely attributed to the alteration of gastrointestinal hormones including ghrelin. The current study examined potential mechanisms of altered ghrelin synthesis after RYGB.. Gastric mammalian target of rapamycin (mTOR) signaling, ghrelin synthesis and secretion were determined in lean or obese male mice with or without RYGB operation, as well as in obese patients pre- and post-RYGB surgery. Ghrelin expression and mTOR signaling were investigated by western blotting and immunohistochemistry. Ghrelin mRNA levels were detected by real-time PCR. Plasma ghrelin was measured by enzyme immunoassay.. mTOR activity in the gastric fundus was significantly lower than in the forestomachs. Both of them were decreased after 24h fasting. A significant negative correlation was found between gastric levels of phospho-S6 (phospho-S6 ribosomal protein) and proghrelin during changes of energy status. mTOR activity was activated, whereas ghrelin expression was inhibited by Roux-en-Y Gastric Bypass in both rodents and human beings. Increment of ghrelin synthesis and decline of mTOR signaling induced by rapamycin were significantly reversed by RYGB in both lean and obese mice. Administration of Ad-S6K1 (adenovirus-mediated p70 ribosomal protein subunit 6 kinase 1) from tail vein suppressed the expression of ghrelin in RYGB-operated mice relative to control animals.. mTOR is therefore a gastric fuel sensor whose activity is linked to the regulation of ghrelin after Roux-en-Y Gastric Bypass.

Topics: Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Gastric Bypass; Gastric Fundus; Gastric Mucosa; Ghrelin; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Middle Aged; Obesity, Morbid; Signal Transduction; Sirolimus

The hypothalamus regulates metabolism and feeding behavior by perceiving the levels of peripheral insulin. However, little is known about the hypothalamic changes after aberrant metabolism. In this study, we investigated the changes of insulin and autophagy relevant signals of hypothalamus under diabetes mellitus.. C57B/L mice were injected with low-dose streptozotocin (STZ) and fed with high-fat diet to induce type 2 diabetes mellitus. In vitro, PC12 cells were treated with oleic acid to mimic lipotoxicity.. Results showed that the cholesterol level in the hypothalamus of the diabetic mice was higher than that of the normal mice. The expression of insulin receptors and insulin receptor substrate-1 were downregulated and the number of Fluoro-Jade C positive cells significantly increased in the hypothalamic arcuate nucleus of the diabetic mice. Furthermore, Upregulation of mammalian target of rapamycin (mTOR) and downregulation of LC 3II were obvious in the hypothalamus of the diabetic mice. In vitro, results showed that high-lipid caused PC12 cell damage and upregulated LC3 II expression. Pretreatment of cells with 3-methyladenine evidently downregulated LC3 II expression and aggravated PC12 cell death under high lipid conditions. By contrast, pretreatment of cells with rapamycin upregulated LC3 II expression and ameliorated PC12 cell death caused by lipotoxicity.. These results demonstrate that autophagy activation confers protection to neurons under aberrant metabolism and that autophagy dysfunction in the hypothalamus occurs in the chronic metabolic disorder such as T2DM.

Topics: Adenine; Animals; Arcuate Nucleus of Hypothalamus; Autophagy; Blotting, Western; Brain Diseases; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Down-Regulation; Glucose Tolerance Test; Hypothalamus; Immunosuppressive Agents; In Vitro Techniques; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Lipid Metabolism; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neurons; Oleic Acid; PC12 Cells; Rats; Receptor, Insulin; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation; Ventromedial Hypothalamic Nucleus

Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency. Rapamycin and metformin improved proteinuria, and rapamycin also reduced urinary gamma glutamyl transferase (GGT) indicating improvement of tubular health. Metformin reduced food and water intake, and urinary sodium and potassium, whereas rapamycin increased urinary sodium. Metformin reduced plasma alkaline phosphatase, but induced transaminitis as evidenced by significant increases in plasma AST and ALT. Metformin also induced hyperinsulinemia, but did not suppress fasting plasma glucose after ZDF rats reached 17 weeks of age, and worsened lipid profile. Rapamycin also induced mild transaminitis. Additionally, both rapamycin and metformin increased plasma uric acid and creatinine, biomarkers for cardiovascular and renal disease. These observations define how rapamycin and metformin differentially modulate metabolic profiles that regulate cardiorenal pathology in conditions of severe type 2 diabetes.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Mechanistic Target of Rapamycin Complex 1; Metformin; Multiprotein Complexes; Protein Kinase Inhibitors; Proteinuria; Rats, Zucker; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment.

Topics: Animals; Cause of Death; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Immunosuppressive Agents; Inflammation; Longevity; Male; Mice; Mice, Inbred C57BL; Mortality; Sex Factors; Sirolimus; Treatment Outcome

Autophagy, a key homeostasis mechanism, is defective in Osteoarthritis (OA) and Type 2 Diabetes (T2D). T2D has been proposed as a risk factor for OA. We hypothesized that diabetes impairs articular cartilage integrity by decreasing autophagy. Our objective was to investigate the effects of high glucose and insulin, characteristics of T2D, on cartilage homeostasis.. Immortalized human chondrocytes (TC28a2) and primary human chondrocytes (HC) were cultured in 25 mM or 0 mM glucose and treated with insulin (10, 100, 500 nM) for 2, 6 or 24 h. Activity of LC3-II, Akt and rpS6 was evaluated by Western blotting (WB). Human cartilage explants were cultivated with 25 mM glucose and insulin (100,1000 nM) for 24 h to evaluate histopathology. MMP-13 and IL-1β expression was determined by immunohistochemistry and WB. Effects of Rapamycin (10 μM) were analyzed by WB. LC3 and rpS6 expression was determined by WB in chondrocytes from Healthy, Non Diabetic-OA and Diabetic-OA patients.. Insulin downregulates autophagy by reducing LC3 II expression and increasing Akt and rpS6 phosphorylation. Loss of proteoglycans and increased MMP-13 and IL-1β expression was observed after insulin treatment. Autophagy activation by rapamycin reversed insulin effects. Importantly, chondrocytes from diabetic-OA patients showed decreased LC3 and increased p-rpS6 expression compared to Healthy and Non-Diabetic OA patients.. These results suggest that decreased autophagy might be a mechanism by which diabetes influences cartilage degradation. Pharmacological activation of autophagy may be an effective therapeutic approach to prevent T2D-induced cartilage damage.

Topics: Aged; Aged, 80 and over; Autophagy; Cartilage, Articular; Cells, Cultured; Chondrocytes; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glucose; Humans; Insulin; Interleukin-1beta; Matrix Metalloproteinase 13; Middle Aged; Osteoarthritis; Proteoglycans; Proto-Oncogene Proteins c-akt; Sirolimus; Tissue Culture Techniques; TOR Serine-Threonine Kinases; Up-Regulation

Numerous studies suggest that rapamycin treatment promotes insulin resistance, implying that rapamycin could have negative effects on patients with, or at risk for, type 2 diabetes (T2D). New evidence, however, indicates that rapamycin treatment produces some

Topics: Adiposity; Aging; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Sirolimus; TOR Serine-Threonine Kinases

1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1α/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1α or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1α/Stra13 (DEC1) pathway.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Carboxylic Ester Hydrolases; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Knockdown Techniques; Glucose; Hep G2 Cells; Hepatocytes; Homeodomain Proteins; Humans; Hydrolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Intestines; Liver; Male; Mice, Inbred C57BL; Overweight; Phosphorylcholine; Proto-Oncogene Proteins c-akt; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) and decreased activation of STAT3 are implicated in diabetic complications. Considering the potent cardioprotective effect of mTOR inhibitor, rapamycin, we hypothesized that reperfusion therapy with rapamycin would reduce infarct size in the diabetic hearts through STAT3 signaling. Hearts from adult male db/db or wild type (WT) C57 mice were isolated and subjected to 30 min of normothermic global ischemia and 60 min of reperfusion in Langendorff mode. Rapamycin (100 nM) was infused at the onset of reperfusion. Myocardial infarct size (IS) was significantly reduced in rapamycin-treated mice (13.3 ± 2.4 %) compared to DMSO vehicle control (35.9 ± 0.9 %) or WT mice (27.7 ± 1.1 %). Rapamycin treatment restored phosphorylation of STAT3 and enhanced AKT phosphorylation (target of mTORC2), but significantly reduced ribosomal protein S6 phosphorylation (target of mTORC1) in the diabetic heart. To determine the cause and effect relationship of STAT3 in cardioprotection, inducible cardiac-specific STAT3-deficient (MCM TG:STAT3(flox/flox)) and WT mice (MCM TG:STAT3(flox/flox)) were made diabetic by feeding high fat diet (HFD). Rapamycin given at reperfusion reduced IS in WT mice but not in STAT3-deficient mice following I/R. Moreover, cardiomyocytes isolated from HFD-fed WT mice showed resistance against necrosis (trypan blue staining) and apoptosis (TUNEL assay) when treated with rapamycin during reoxygenation following simulated ischemia. Such protection was absent in cardiomyocytes from HFD-fed STAT3-deficient mice. STAT3 signaling plays critical role in reducing IS and attenuates cardiomyocyte death following reperfusion therapy with rapamycin in diabetic heart.

Topics: Animals; Apoptosis; Blotting, Western; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Immunosuppressive Agents; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Reperfusion Injury; Signal Transduction; Sirolimus; STAT3 Transcription Factor; TOR Serine-Threonine Kinases

Elevated mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes, with increased morbidity and mortality, mainly because of cardiovascular complications. Because mTOR inhibition with rapamycin protects against ischemia/reperfusion injury, we hypothesized that rapamycin would prevent cardiac dysfunction associated with type 2 diabetes (T2D). We also investigated the possible mechanisms and novel protein targets involved in rapamycin-induced preservation of cardiac function in T2D mice. Adult male leptin receptor null, homozygous db/db, or wild type mice were treated daily for 28 days with vehicle (5% DMSO) or rapamycin (0.25 mg/kg, intraperitoneally). Cardiac function was monitored by echocardiography, and protein targets were identified by proteomics analysis. Rapamycin treatment significantly reduced body weight, heart weight, plasma glucose, triglyceride, and insulin levels in db/db mice. Fractional shortening was improved by rapamycin treatment in db/db mice. Oxidative stress as measured by glutathione levels and lipid peroxidation was significantly reduced in rapamycin-treated db/db hearts. Rapamycin blocked the enhanced phosphorylation of mTOR and S6, but not AKT in db/db hearts. Proteomic (by two-dimensional gel and mass spectrometry) and Western blot analyses identified significant changes in several cytoskeletal/contractile proteins (myosin light chain MLY2, myosin heavy chain 6, myosin-binding protein C), glucose metabolism proteins (pyruvate dehydrogenase E1, PYGB, Pgm2), and antioxidant proteins (peroxiredoxin 5, ferritin heavy chain 1) following rapamycin treatment in db/db heart. These results show that chronic rapamycin treatment prevents cardiac dysfunction in T2D mice, possibly through attenuation of oxidative stress and alteration of antioxidants and contractile as well as glucose metabolic protein expression.

Topics: Animals; Anti-Bacterial Agents; Contractile Proteins; Diabetes Mellitus, Type 2; Gene Expression Regulation; Glucose; Male; Mice; Mice, Mutant Strains; Myocardial Contraction; Myocardium; Oxidative Stress; Proteomics; Sirolimus; TOR Serine-Threonine Kinases

This study sought to compare everolimus-eluting stents (EES) versus Resolute zotarolimus-eluting stents (ZES) in terms of patient- or stent-related clinical outcomes in an "all-comer" group of patients with diabetes mellitus (DM) who underwent percutaneous coronary intervention.. DM significantly increases the risk of adverse events after percutaneous coronary intervention. The efficacy and safety of second-generation drug-eluting stents, in particular EES versus ZES, in patients with DM have not been extensively evaluated.. Patients with DM (1,855 of 5,054 patients, 36.7%) from 2 prospective registries (the EXCELLENT [Efficacy of Xience/Promus Versus Cypher in Reducing Late Loss After Stenting] registry and RESOLUTE-Korea [Registry to Evaluate the Efficacy of Zotarolimus-Eluting Stent]) who were treated with EES (n = 1,149) or ZES (n = 706) were compared. Stent-related outcome was target lesion failure (TLF), and patient-oriented composite events were a composite of all-cause mortality, any myocardial infarction, and any revascularization.. Despite a higher risk patient profile in the ZES group, both TLF (43 of 1,149 [3.7%] vs. 25 of 706 [3.5%], p = 0.899) and patient-oriented composite events (104 of 1,149 [9.1%] vs. 72 of 706 [10.2%], p = 0.416) were similar between the EES and ZES in patients with DM at 1 year. In those without DM, EES and ZES also showed comparable incidence of TLF (39 of 1,882 [2.1%] vs. 33 of 1,292 [2.6%], p = 0.370) and patient-oriented composite events (119 of 1,882 [6.3%] vs. 81 of 1,292 [6.3%], p = 0.951), which were all significantly lower than in the DM patients. These results were corroborated by similar findings from the propensity score-matched cohort. Upon multivariate analysis, chronic renal failure was the most powerful predictor of TLF in DM patients (hazard ratio: 4.39, 95% confidence interval: 1.91 to 10.09, p < 0.001).. After unrestricted use of second-generation drug-eluting stents in all-comers receiving percutaneous coronary intervention, both EES and ZES showed comparable clinical outcomes in the patients with DM up to 1 year of follow-up. DM compared with non-DM patients showed significantly worse patient- and stent-related outcomes. Nonetheless, overall incidences of TLF were low, even in the patients with DM, suggesting excellent safety and efficacy of both types of second-generation drug-eluting stents in this high-risk subgroup of patients.

Topics: Aged; Cardiovascular Agents; Chi-Square Distribution; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Everolimus; Female; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Patient Selection; Percutaneous Coronary Intervention; Propensity Score; Proportional Hazards Models; Prosthesis Design; Registries; Republic of Korea; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

Topics: Absorbable Implants; Cardiovascular Agents; Coronary Artery Disease; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Everolimus; Female; Humans; Male; Percutaneous Coronary Intervention; Sirolimus

We included into this study 112 patients with ischemic heart disease (IHD) and concomitant type 2 diabetes mellitus (DM) subjected to percutaneous coronary interventions with stenting. Everolimus and sirolimus eluting stents (EES and SES) were implanted in 54 (group 1) and 58 (group 2) patients, respectively. After 12 months in groups 1 and 2 rates of repeat target lesion revascularizations (TLR) were 5.5 and 8.6% (odds ratio - OR - 0.62, 95% confidence interval - CI - 0.14- 2.74, p = 0.72); acute myocardial infarctions (MI) - 3.7 and 5.2% (OR 0.71, 95% CI 0.11- 4.4, p = 0.94); deaths - 1.85 and 1.7% (OR 1.1, 95% CI 0.1- 17.6, p = 1.0), respectively. There was no significant difference between groups by rate of unfavorable cardiac events (composite of cardiac death, nonfatal MI, and clinically indicated TLR) - 11.1 and 15.5% in groups 1 and 2, respectively (OR 0.68, 95% CI 0.225- 2.059, p = 0.69). Rates of stent thrombosis also did not differ (1.85 and 3.4% in groups 1 and 2, respectively; OR 0.53, 95% CI 0.05- 6.0; p = 0.94). Thus the use of EES and SES in patients with IHD and type-2 DM was equally effective.

Topics: Aged; Coronary Restenosis; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Heart Function Tests; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Moscow; Myocardial Ischemia; Percutaneous Coronary Intervention; Postoperative Complications; Severity of Illness Index; Sirolimus; Treatment Outcome

While rapamycin treatment has been reported to have a putatively negative effect on glucose homeostasis in mammals, it has not been tested in polygenic models of type 2 diabetes. One such mouse model, NONcNZO10/LtJ, was treated chronically with rapamycin (14 ppm encapsulated in diet) and monitored for the development of diabetes. As expected, rapamycin treatment accelerated the onset and severity of hyperglycemia. However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced. Insulin production and secretion appeared to be inhibited, suppressing the developing hyperinsulinemia present in untreated controls. Rapamycin treatment also reduced body weight gain. Thus, rapamycin reduced some of the complications of diabetes despite elevating hyperglycemia. These results suggest that multiple factors must be evaluated when assessing the benefit vs. hazard of rapamycin treatment in patients that have overt, or are at risk for, type 2 diabetes. Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Female; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Male; Mice; Sirolimus

BRS-3 KO-mice developed obesity and unbalanced glucose metabolism, suggesting an important role of BRS-3 receptor in glucose homeostasis. We explored BRS-3 expression in skeletal muscle from normal, obese or type-2 diabetic (T2D) patients, and the effect of [D-Phe(6), β-Ala(11),Phe(13),Nle(14)]bombesin(6-14)-BRS-3-agonist-peptide (BRS-3-AP) - on glucose-related effects, before or after BRS-3 gene silencing. In muscle tissue and primary cultured myocytes from altered metabolic states, BRS-3 gene/protein expressions were down-regulated. In normal, obese and T2D cells: A) BRS-3-AP as insulin enhanced BRS-3 and GLUT-4 mRNA/protein levels; improving glucotransporter translocation to plasma membrane, and B) BRS-3-AP caused a concentration-related-stimulation of glucose transport, being obese and T2D myocytes more sensitive to the ligand than normal. Wortmannin and PD98059, but not rapamycin, abolished the stimulatory action of BRS-3-AP on glucose transport. BRS-3 plays an important role in glucose metabolism, and could be use as a molecular target, and/or its ligand, as a therapeutic agent for obesity and diabetes treatments.

Topics: Adult; Aged; Androstadienes; Animals; Biological Transport; Cells, Cultured; Diabetes Mellitus, Type 2; Female; Flavonoids; Gene Expression Regulation; Glucose; Glucose Transporter Type 4; Humans; Insulin; Male; Mice; Mice, Knockout; Middle Aged; Molecular Targeted Therapy; Muscle Cells; Muscle, Skeletal; Obesity; Peptides; Receptors, Bombesin; Sirolimus; Wortmannin

To evaluate the efficacy and safety of conversion from calcineurin inhibitors to sirolimus among liver transplant recipients with calcineurin inhibitor-induced complications.. After receiving liver transplants, 25 patients with calcineurin inhibitor-induced complications (22 renal dysfunction and 3 new-onset diabetes mellitus) were converted from sirolimus to tacrolimus. The serum creatinine, sirolimus trough level, liver function, acute rejection episodes, and drug-related adverse effects were monitored.. The patients were followed for 12 to 50 months (median, 25 months). The renal function of the 22 patients with renal dysfunction improved after sirolimus conversion. The serum creatinine levels were significantly lower at 3 months after conversion versus before conversion (113.2 ± 21.8 μmol/L vs 163.2 ± 45.3 μmol/L; P < .05). At the end of the follow-up, the average serum creatinine level was 101.9 ± 23.4 μmol/L among the 20 living recipients. Diabetes also was under control in 3 diabetic recipients after the conversion. Four patients experienced episodes of acute rejection, and intravenous steroid bolus therapy was administered in 2 of them. No graft was lost because of acute rejection. The adverse effects of sirolimus included hyperlipidemia (7/25), anemia (8/25), and mouth ulcers (9/25). All these adverse effects were relieved after a short-term symptomatic therapy, and no patient was withdrawn from the conversion trial.. Sirolimus monotherapy is effective and safe in liver transplant recipients. Conversion to sirolimus was associated with a sustained improvement in renal function and diabetes mellitus without an increased incidence of acute rejection episodes.

Topics: Acute Disease; Anemia; Calcineurin Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Follow-Up Studies; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Oral Ulcer; Retrospective Studies; Sirolimus; Tacrolimus

Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition-like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN.

Topics: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Cell Differentiation; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Endoplasmic Reticulum; Enzyme Activation; Glomerular Basement Membrane; Glomerular Mesangium; Male; Mechanistic Target of Rapamycin Complex 1; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Multiprotein Complexes; Phosphorylation; Podocytes; Protein Processing, Post-Translational; Proteins; Regulatory-Associated Protein of mTOR; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins

Rapamycin prolongs healthy lifespan in yeast, flies and mammals and delays age-related diseases, including cancer and atherosclerosis. Rapamycin is considered for prevention of diabetic complications, such as retinopathy and nephropathy, and acute treatment with rapamycin decreases insulin resistance. However, under certain conditions, chronic administration of rapamycin may cause glucose intolerance and even provoke type II diabetes. This does not fit logically with its potential effects against diabetic complications. This also seems puzzling, because calorie restriction (CR) can prevent type II diabetes and its complications, and rapamycin mimics CR. It was somehow forgotten that almost two centuries ago, Claude Bernard discovered "starvation diabetes," as shown later, characterized by glucose intolerance, decreased insulin, increased lipoproteins and ketones, gluconeogenesis and hepatic resistance to insulin. This reversible condition is not true diabetes: it does not lead to diabetic complications, and CR extends healthy lifespan. If rapamycin is a CR-mimetic, no wonder it may, in certain models, induce "hunger diabetes." But will rapamycin prevent true type II diabetes? Here are some answers.

Topics: Caloric Restriction; Diabetes Complications; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Insulin Resistance; Insulin-Secreting Cells; Models, Biological; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases

This study aimed to evaluate the impact of angiographic and intravascular ultrasound (IVUS) features on clinical outcome in nondiabetic and type 2 diabetic patients after percutaneous coronary intervention (PCI) with sirolimus-eluting stent (SES) implantation.. Repeat coronary angiography with IVUS imaging was performed after SES-based PCI for de-novo lesions in 128 diabetic and 327 nondiabetic patients (189 lesions and 504 lesions, respectively). The rate of major adverse cardiac events including cardiac death, non fatal myocardial infarction (MI), and target lesion revascularization during clinical follow-up was recorded.. In-stent and in-segment late loss, intimal hyperplasia volume, and percentage volumetric obstruction were similar, but stented external elastic membrane cross-sectional area and reference/stented segment ratio were lower in diabetic than in nondiabetic patients. Incomplete stent apposition (ISA) was less frequent, but occurrence of new coronary lesions was higher in diabetic than in nondiabetic patients. Despite similar target lesion revascularization, cumulative survival rates freedom from composite cardiac death and nonfatal MI or major adverse cardiac events were reduced in diabetic patients. Cox proportional hazards model identified diabetes, left ventricular ejection fraction, minimal stent CSA, maximal ISA area, atherosclerotic progression and lesion length as independent predictors of non fatal MI or mortality at follow-up.. In diabetic patients, PCI with SES implantation neutralizes the excess risk of intimal hyperplasia and decreases occurrence of ISA, but could not modify the propensity of increased adverse clinical outcomes at follow-up.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Chi-Square Distribution; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Heart Diseases; Humans; Hyperplasia; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Blood Glucose; Body Weight; Breast Neoplasms; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Female; Insulin; Mice; Mice, Transgenic; Sirolimus; TOR Serine-Threonine Kinases; Triglycerides

Drug-eluting stents have been effective in randomized controlled trials, but their safety and efficacy in patients with insulin-dependent diabetes has not been well studied. Baseline clinical and angiographic characteristics and in-hospital and follow-up events were recorded for enrolled patients. From October 2005 and October 2006, 581 patients with insulin-dependent diabetes and 1,078 with non-insulin-dependent diabetes treated with sirolimus- and paclitaxel-eluting stents were enrolled at 98 sites. The composite of death, myocardial infarction, and stroke, defined as major adverse cardiac and cerebrovascular events, as well as target vessel revascularization was used as the primary end point. Multiple logistic regression analysis was used to adjust for confounding parameters. Baseline clinical characteristics were more severe in patients with insulin-dependent diabetes, whereas descriptive characteristics were not unique. At 1-year follow-up, the comparison between the 2 groups revealed significantly higher rates of overall death (7.4% vs 4.6%, p <0.05), target vessel revascularization (15.1% vs 10.4%, p <0.05), and overall stent thrombosis (6.5% vs 4.1%, p <0.05) for insulin-dependent patients, while rates of major adverse cardiac and cerebrovascular events were not significantly different (12.8% vs 9.9%, p = 0.09). These results persisted even after risk adjustment for heterogenous baseline characteristics of the 2 groups. In conclusion, the data generated from the German Drug-Eluting Stent (DES.DE) registry revealed that even with drug-eluting stents, the annual risk for death, target vessel revascularization, and thrombotic events remains higher in patients with insulin-dependent diabetes compared to those with non-insulin-dependent diabetes.

Topics: Aged; Coronary Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Germany; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Logistic Models; Male; Paclitaxel; Prospective Studies; Registries; Sirolimus; Survival Rate; Treatment Outcome; Tubulin Modulators

Topics: Carcinoma, Squamous Cell; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Everolimus; Humans; Liver Transplantation; Male; Middle Aged; Proteinuria; Sirolimus

Clinical studies of drug-eluting stents delivering the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (Sirolimus), have demonstrated a reduced efficacy for these devices in patients with diabetes, which suggests that the mTOR pathway may cease to be dominant in mediating the vascular response to injury under diabetic conditions. We hypothesized that changes in serum composition accompanying diabetes may reduce the role of mTOR in mediating the vascular response to injury. We measured the ability of a median dose of rapamycin (10 nM) to inhibit the proliferation of human coronary artery smooth muscle cells (huCASMCs) stimulated with serum obtained from donors with diabetes (n = 14) and without diabetes (n = 16). In an additional analysis, we compared the effects of rapamycin on huCASMCs stimulated with the serum of donors with metabolic syndrome (n = 15) versus those without (n = 7). There was no difference in the effect of rapamycin on huCASMC proliferation after stimulation with serum from either donors with diabetes or donors with metabolic syndrome compared with the respective controls. We conclude that the changes in the serum composition common to diabetes and metabolic syndrome are insufficient to diminish the role of mTOR in the progression of cardiovascular disease.

Topics: Aged; Animals; Cell Proliferation; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Female; Humans; Male; Mammals; Middle Aged; Muscle, Smooth; Myocytes, Smooth Muscle; Sirolimus

Palmitate is a potent inducer of endoplasmic reticulum (ER) stress in beta-cells. In type 2 diabetes, glucose amplifies fatty-acid toxicity for pancreatic beta-cells, leading to beta-cell dysfunction and death. Why glucose exacerbates beta-cell lipotoxicity is largely unknown. Glucose stimulates mTORC1, an important nutrient sensor involved in the regulation of cellular stress. Our study tested the hypothesis that glucose augments lipotoxicity by stimulating mTORC1 leading to increased beta-cell ER stress.. We found that glucose amplifies palmitate-induced ER stress by increasing IRE1alpha protein levels and activating the JNK pathway, leading to increased beta-cell apoptosis. Moreover, glucose increased mTORC1 activity and its inhibition by rapamycin decreased beta-cell apoptosis under conditions of glucolipotoxicity. Inhibition of mTORC1 by rapamycin did not affect proinsulin and total protein synthesis in beta-cells incubated at high glucose with palmitate. However, it decreased IRE1alpha expression and signaling and inhibited JNK pathway activation. In TSC2-deficient mouse embryonic fibroblasts, in which mTORC1 is constitutively active, mTORC1 regulated the stimulation of JNK by ER stressors, but not in response to anisomycin, which activates JNK independent of ER stress. Finally, we found that JNK inhibition decreased beta-cell apoptosis under conditions of glucolipotoxicity.. Collectively, our findings suggest that mTORC1 mediates glucose amplification of lipotoxicity, acting through activation of ER stress and JNK. Thus, mTORC1 is an important transducer of ER stress in beta-cell glucolipotoxicity. Moreover, in stressed beta-cells mTORC1 inhibition decreases IRE1alpha protein expression and JNK activity without affecting ER protein load, suggesting that mTORC1 regulates the beta-cell stress response to glucose and fatty acids by modulating the synthesis and activity of specific proteins involved in the execution of the ER stress response. This novel paradigm may have important implications for understanding beta-cell failure in type 2 diabetes.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Line; Cycloheximide; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Enzyme Activation; Gerbillinae; Glucose; Insulin-Secreting Cells; JNK Mitogen-Activated Protein Kinases; Male; Mechanistic Target of Rapamycin Complex 1; Membrane Proteins; Mice; Multiprotein Complexes; Oxidative Stress; Palmitates; Protein Serine-Threonine Kinases; Protein Synthesis Inhibitors; Proteins; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

Diabetic nephropathy (DN) associated with type 2 diabetes is the most common cause of end-stage renal disease (ESRD) and a serious health issue in the world. Currently, molecular basis for DN has not been established and only limited clinical treatments are effective in abating the progression to ESRD associated with DN. Here we found that diabetic db/db mice which lack the leptin receptor signaling can be used as a model of ESRD associated with DN. We demonstrated that p70S6-kinase was highly activated in mesangial cells in diabetic obese db/db mice. Furthermore, systemic administration of rapamycin, a specific and potent inhibitor of mTOR, markedly ameliorated pathological changes and renal dysfunctions. Moreover, rapamycin treatment shows a significant reduction in fat deposits and attenuates hyperinsulinemia with few side effects. These results indicate that mTOR activation plays a pivotal role in the development of ESRD and that rapamycin could be an effective therapeutic agent for DN.

Topics: Animals; Carrier Proteins; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Kidney; Kidney Failure, Chronic; Mice; Mice, Inbred Strains; Phosphotransferases (Alcohol Group Acceptor); Restriction Mapping; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases

Topics: Diabetes Complications; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Immunosuppressive Agents; Sirolimus; Stents; Thromboembolism

It is now emerging that, in patients who are at high risk for cardiovascular complications and, in particular, those with diabetes, the occurrence of late restenosis and thrombosis after treatment of coronary artery disease with drug-eluting stents is higher than earlier reports have suggested. Therefore, the aim of this study was to assess the prevalence of in-stent restenosis in a cohort of consecutive patients with diabetes treated for coronary disease in 2005 with drug-eluting stents [either sirolimus (58%) or paclitaxel (42%)]. The duration of follow-up was 9.0+/-3.4 months [mean+/-1 standard deviation (S.D.)]. A total of 154 patients (type 2 diabetes: 91%) were included in the study (age: 66+/-10 years), and the total number of implanted stents was 184. Two subjects died from cardiac causes, while myocardial infarction and (un)stable angina were observed in 3 (2%) and 39 (25%) patients, respectively. In-stent restenosis, appraised by angiography, was observed in 17 individuals (11%) after a mean follow-up of five months. Mean HbA(1c) in patients with restenosis was 7.6+/-1.8%. There was no difference in the rate of restenosis with sirolimus-(n=8) compared with paclitaxel-(n=9) eluting stents. Male gender, oral therapy for diabetes and stent diameter were predictors of in-stent restenosis. In conclusion, even over a medium-term period, in-stent restenosis remains a potential risk for coronary diabetic patients treated with drug-eluting devices.

Topics: Aged; Cohort Studies; Coronary Restenosis; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Sirolimus; Survival Analysis; Treatment Outcome

Mammalian target of rapamycin (mTOR) and its downstream target S6 kinase 1 (S6K1) mediate nutrient-induced insulin resistance by downregulating insulin receptor substrate proteins with subsequent reduced Akt phosphorylation. Therefore, mTOR/S6K1 inhibition could become a therapeutic strategy in insulin-resistant states, including type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of nutrition-dependent type 2 diabetes, using the mTOR inhibitor rapamycin.. Normoglycemic and diabetic P. obesus were treated with 0.2 mg x kg(-1) x day(-1) i.p. rapamycin or vehicle, and the effects on insulin signaling in muscle, liver and islets, and on different metabolic parameters were analyzed.. Unexpectedly, rapamycin worsened hyperglycemia in diabetic P. obesus without affecting glycemia in normoglycemic controls. There was a 10-fold increase of serum insulin in diabetic P. obesus compared with controls; rapamycin completely abolished this increase. This was accompanied by weight loss and a robust increase of serum lipids and ketone bodies. Rapamycin decreased muscle insulin sensitivity paralleled by increased glycogen synthase kinase 3beta activity. In diabetic animals, rapamycin reduced beta-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive c-Jun NH(2)-terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and beta-cell apoptosis. Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin.. Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing beta-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating beta-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Gerbillinae; Insulin; Insulin Secretion; Insulin-Secreting Cells; Protein Kinases; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases

Alcohol intake is one of the important lifestyle factors for the risk of insulin resistance and type 2 diabetes. Acetaldehyde, the major ethanol metabolite which is far more reactive than ethanol, has been postulated to participate in alcohol-induced tissue injury although its direct impact on insulin signaling is unclear. This study was designed to examine the effect of acetaldehyde on glucose uptake and insulin signaling in human dopaminergic SH-SY5Y cells. Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. Glucose uptake and apoptosis were measured using [(3)H]-2-deoxyglucose uptake and caspase-3 assay, respectively. Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. Acetaldehyde inhibited mTOR phosphorylation without affecting total mTOR and insulin-elicited response on mTOR phosphorylation. Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation.

Topics: Acetaldehyde; Adaptor Proteins, Signal Transducing; Alcohol-Induced Disorders, Nervous System; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Diabetes Mellitus, Type 2; Dopamine; Glucose; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Metabolic Syndrome; Neurons; Phosphoproteins; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To investigate the outcome of a real world diabetic patient cohort treated with bare metal stents (BMS), sirolimus-, or paclitaxel-eluting stents (SES and PES, respectively). Due to the different mechanisms of action of both drugs it is currently unknown which device is the best option to treat these high-risk patients.. The study compares the 2-year clinical outcome of 708 consecutive diabetic patients (25% insulin treated) treated with either a BMS (n = 252), a SES (n = 206), or a PES (n = 250), as part of the RESEARCH and T-SEARCH registries. Target vessel revascularization was 19.5% in the BMS group, vs. 15.3% in the SES group and 9.7% in the PES group. PES (21.2%), but not SES (28.9%), were superior to BMS (29.7%) in reducing major adverse cardiac events. After propensity analyses, none of the differences remained significant. The incidence of stent thrombosis (ST) was high in both DES groups.. There was a trend towards a more favourable outcome associated with the use of PES over BMS. There was no significant difference between SES and PES in each of the clinical endpoints, and neither in the NIDDM patients, which are hypothesized to be better-off with PES.

Topics: Case-Control Studies; Coronary Restenosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Drug Implants; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Retrospective Studies; Sirolimus; Stents; Survival Analysis

This retrospective study of prospectively collected data compared coronary artery bypass graft (CABG) surgery to drug-eluting stenting (DES) in diabetic patients with multivessel coronary artery disease (CAD). Prior randomized trials and clinical studies have suggested that CABG may be the preferred revascularization strategy in diabetic patients with multivessel CAD. Data are limited regarding the impact of DES vs. CABG on clinical outcomes.. We included 205 consecutive diabetic patients who underwent either CABG (n=103) or DES (n=102). The primary clinical end points were freedom from major adverse cardiac events (MACE) at 30 days and 1 year.. Baseline characteristics were similar between both groups. At 1 year, the mortality rate was similar in the CABG and DES group (8% vs. 10%, p=0.6) but the MACE rate was lower in the CABG group (12% vs. 27%, p=0.006) due to less repeat revascularization with CABG (3% vs. 20%, p<0.001). Stroke occurred only in the CABG group (4% vs. 0%, p=0.04). Angiographically-documented stent thrombosis after DES occurred in 3%. Presentation with acute myocardial infarction (hazard ratio [HR], 2.26, 95% CI, 1.13 to 4.55) and DES (HR, 2.4, 95% CI, 1.23 to 4.77) were positive independent predictors, whereas therapy with a statin was a negative independent predictor of MACE (HR, 0.40, 95% CI, 0.21 to 0.76).. Bypass surgery was associated with less MACE primarily due to the higher repeat revascularization rate with DES and is therefore superior to DES despite more extensive CAD in CABG patients.

Topics: Aged; Antineoplastic Agents, Phytogenic; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Bypass; Coronary Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Paclitaxel; Retrospective Studies; Sirolimus; Stents; Time Factors; Treatment Outcome

Drug-eluting stents have been developed to reduce the rates of restenosis after coronary angioplasty. Several studies have demonstrated that rapamycin eluting stents are reliable and effective.. To report the experience in our Health Centre with rapamycin-eluting stents.. Forty two stents with rapamicine were implanted to 32 diabetic patients, between June 2002 and December 2004. After the procedure, subjects were clinically followed-up for an average period of 19.9+/-9.9 months, evaluating functional capacity, angina pectoris, dyspnea, need for hospital admission, acute coronary events and cardiac death. In those subjects clinically suspected to have restenosis, a coronary angiography was performed.. Twenty-nine subjects (90.6%) remained asymptomatic, two subjects (6.3%) developed angina pectoris but restenosis was ruled out, and one subject (3.1%) died.. The use of rapamycin-eluting stents in these patients was safe and successful with no evidence of clinic restenosis. These positive results are similar to those reported in the Diabetes Study.

Topics: Angioplasty; Chi-Square Distribution; Coronary Restenosis; Coronary Stenosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Reproducibility of Results; Sirolimus; Treatment Outcome

Chronic allograft nephropathy, cardiovascular mortality, and posttransplant malignancy are complications of conventional immunosuppression after kidney transplantation. We reported the feasibility of maintenance monotherapy with sirolimus (SRL) in a pilot experience. The aim was to study safety and feasibility of SRL maintenance monotherapy in 50 kidney transplant patients.. All patients from our center with at least 6 months follow-up on SRL monotherapy were included. During the first month after start of SRL monotherapy, follow-up visits were performed weekly, then each month for the following 2 months. Each follow-up visit included a physical exam and laboratory screening.. Mean follow-up on SRL monotherapy was 34.7 +/- 14.9 months. The time between transplantation until start of monotherapy was 7.7 +/- 3.3 years. No rejections occurred. During follow-up, two patients died of cardiovascular disease (already diagnosed before monotherapy); one, of previously diagnosed posttransplant malignancy and one, of hepatitis C-related liver failure. Glomerular filtration rate (GFR) was 53 mL/min x 1.73 m2 at start of monotherapy and 50 mL/min x 1.73 m2 after 4 years. Proteinuria was 632 +/- 562 mg/24 hours at 4 years. During the follow-up, no significant changes in the lipid profile, glycemia, or hemoglobin occurred.. Sirolimus monotherapy is safe in a selected group of immunological low-risk patients without increasing the risk of rejection.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Reoperation; Sirolimus; Time Factors

High glucose and high insulin, pathogenic factors in type 2 diabetes, induce rapid synthesis of the matrix protein laminin-beta1 in renal proximal tubular epithelial cells by stimulation of initiation phase of mRNA translation. We investigated if elongation phase of translation also contributes to high glucose and high insulin induction of laminin-beta1 synthesis in proximal tubular epithelial cells. High glucose or high insulin rapidly increased activating Thr56 dephosphorylation of eEF2 and inactivating Ser366 phosphorylation of eEF2 kinase, events that facilitate elongation. Studies with inhibitors showed that PI3 kinase-Akt-mTOR-p70S6 kinase pathway controlled changes in phosphorylation of eEF2 and eEF2 kinase induced by high glucose or high insulin. Renal cortical homogenates from db/db mice in early stage of type 2 diabetes showed decrease in eEF2 phosphorylation and increment in eEF2 kinase phosphorylation in association with renal hypertrophy and glomerular and tubular increase in laminin-beta1 content. Rapamycin, an inhibitor of mTOR, abolished diabetes-induced changes in phosphorylation of eEF2, eEF2 kinase, and p70S6 kinase and ameliorated renal hypertrophy and laminin-beta1 protein content, without affecting hyperglycemia. These data show that mTOR is an attractive target for amelioration of diabetes-induced renal injury.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Elongation Factor 2 Kinase; Glucose; Insulin; Kidney Cortex; Laminin; Mice; Mice, Mutant Strains; Phosphorylation; Protein Biosynthesis; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The objective of our study is to evaluate the long-term results of coronary angioplasty using active stents in a population of diabetic patients. This is a single-centre study on a consecutive series of 122 diabetic patients (40% of them insulin dependent) who between January 2003 and June 2004 underwent angioplasty with implantation of an active stent (sirolimus Cypher(R) or paclitaxel Taxus(R)) for one or more de novo coronary lesions. The mean age was 66 +/- 10 years and a total of 171 coronary segments were treated. The lesions treated were complex (type B2 + C) in 69% of the cases, with a mean stent length of 21 +/- 15 mm and a mean stent diameter of 2.7 +/- 0.3 mm. Follow-up at two years for 119 patients (3 lost to follow-up) revealed a mortality rate of 4.2%, and a myocardial infarction rate of 7.5%. The rates for revascularisation of the target lesion and the target vessel were 11.4% and 17.8% respectively, with a rate of major cardiac events of 22.5%. During this period, 25.2% of the patients underwent revascularisation of at least one vessel. This study confirms the benefits of using active stents for revascularisation of the target lesion in diabetic patients. However, it serves as a reminder that the progression of coronary atheroma is global, and that the prognosis for these patients depends essentially upon managing risk factors, and particularly on controlling their diabetes.

Topics: Aged; Coronary Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Paclitaxel; Sirolimus; Survival Analysis; Treatment Outcome

Endothelial dysfunction has been related both to progression of atherosclerotic disease and to future cardiovascular events. We assessed local epicardial endothelial function 6 months after sirolimus-eluting stent (SES) or bare metal stent (BS) implantation.. In 12 patients (seven SES, five BS), endothelium-dependent vasomotion of a coronary segment 15 mm in length, starting 2 mm distal to the stent, was assessed with quantitative coronary angiography immediately after the procedure and at 6 months follow-up, after intracoronary infusion of acetylcholine. Intravascular ultrasound (IVUS) was performed and coronary flow reserve (CFR) assessed in all patients. At follow-up significant vasoconstriction was seen in SES (median 32% diameter reduction from baseline) but not in BS (median 2% reduction) patients after acetylcholine infusion (P=0.03 for SES vs. BS); endothelium-independent vasodilatation to nitrates did not differ significantly between groups (20% SES, 5% BS, P=0.14). IVUS revealed no late unhealed dissections and CFR was comparable between groups (SES 3.1 vs. BS 3.2, n.s.).. SES implantation may have an adverse effect on local endothelium-dependent vasomotor responses compared with BS implantation at 6 months. Long-term clinical consequences of this observation are still unknown.

Topics: Aged; Coronary Angiography; Coronary Restenosis; Coronary Vasospasm; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Nitroglycerin; Prospective Studies; Sirolimus; Stents; Vasodilation; Vasodilator Agents

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Receptor Substrate Proteins; Leucine; Mice; Monomeric GTP-Binding Proteins; Mutation; Neuropeptides; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Protein Kinases; Proteins; Proto-Oncogene Proteins c-akt; Ras Homolog Enriched in Brain Protein; Rats; Regulatory-Associated Protein of mTOR; Serine; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The expanding indications for sirolimus-eluting stents (SES) include increasingly complex coronary lesions and populations with clinical profiles markedly different from those of early pivotal controlled studies. The e-Cypher registry monitored the safety and efficacy of SES currently implanted worldwide in daily practice.. Between April 2002 and September 2005, data were collected on 15,157 patients who underwent implantation of > or =1 SES at 279 medical centers from 41 countries. An independent endpoint review committee adjudicated all reported major adverse cardiovascular events, stent thromboses, and target-vessel revascularizations. Data were managed and analyzed by independent organizations. Predictors of adverse clinical events were identified by regression analysis. The mean age of the sample was 61.7+/-11.4 years; 77.7% were men, and 28.6% were diabetics. A total of 18,295 lesions were treated (20,503 SES) during the index procedure. The cumulative rates of major adverse cardiovascular events were 1.36% at 30 days, 3.38% at 6 months, and 5.80% at 1 year. The rates of acute, subacute, and late stent thrombosis were 0.13%, 0.56%, and 0.19% of patients, respectively, representing a 12-month actuarial incidence of 0.87%. Insulin-dependent diabetes, acute coronary syndrome at presentation, and advanced age were clinical predictors, whereas TIMI flow grade <3 after the index procedure, treatment of multiple lesions, a prominently calcified or totally occluded target lesion, and multivessel disease were the angiographic or procedural predictors of stent thrombosis at 12 months.. This analysis of 1-year data collected by the e-Cypher registry suggests a high degree of safety of SES, with a rate of stent thrombosis similar to that observed in randomized trials.

Topics: Aged; Angioplasty, Balloon, Coronary; Aspirin; Cause of Death; Clopidogrel; Comorbidity; Coronary Disease; Coronary Restenosis; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Implants; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Internet; Male; Middle Aged; Myocardial Infarction; Product Surveillance, Postmarketing; Registries; Risk Factors; Sirolimus; Stents; Thrombosis; Ticlopidine; United States

Topics: Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Restenosis; Cost-Benefit Analysis; Data Interpretation, Statistical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Delivery Systems; Female; Humans; Hypertension; Immunosuppressive Agents; Incidence; Male; Meta-Analysis as Topic; Myocardial Infarction; Paclitaxel; Randomized Controlled Trials as Topic; Registries; Risk Factors; Sirolimus; Stents; Treatment Outcome

Diabetics are at an increased risk of restenosis and adverse events after coronary stenting. Drug-eluting stents may, therefore, be useful in these patients. Our objective was to evaluate the use of sirolimus-eluting stents in diabetics with complex coronary lesions.. Between May 2002 and August 2003, we treated 231 patients with 260 complex coronary lesions using sirolimus-eluting stents. Of these patients, 56% did not have diabetes (ND), 22% had non-insulin-dependent diabetes (NIRD), and 20% had insulin-dependent diabetes (IRD). The primary clinical endpoint was target vessel failure at 1 year. The primary angiographic endpoints in the stent were late loss and binary restenosis at 6 months.. At 6 months, late loss was greater in the IRD group (0.35 [0.71] mm) than in the ND group (0,096 [0.54] mm; P =.016) or the NIRD group (0.058 [0.52] mm; P=.017), and restenosis was more frequent (IRD, 16.3%; ND, 6.3%; and NIRD 7.8%; P=.05 for linear trend). At one year, target vessel failure occurred more frequently in the IRD group (IRD, 17.4%; NIRD, 7.7%; ND, 7.7%; P=.07 for linear trend) and the rate of survival free of target vessel failure was lower in the IRD group (82.1%) compared with the ND group (92.3%, P=.06) or the NIRD group (92.3%, P=NS). The only independent predictor of restenosis and target vessel failure was female sex.. Despite IRD patients having greater late lumen loss and more frequent restenosis at six months and a trend towards a poorer clinical outcome at 1 year, no independent relationship was found between type of diabetes and clinical outcome.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Data Interpretation, Statistical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Myocardial Infarction; Prognosis; Sirolimus; Stents; Time Factors; Treatment Outcome

Diabetic patients frequently have small-diameter vessels, which increases their risk of restenosis. The aim of this study was to determine the efficacy of sirolimus-eluting stent implantation in these high-risk patients following percutaneous coronary intervention.. Our study population comprised a subset of 85 diabetic patients from the DIABETES (DIABETes and sirolimus Eluting Stent) trial who had very small vessels, defined as those with a reference diameter < or =2.25 mm. In the 100 lesions treated, 49 sirolimus-eluting stents and 51 bare-metal stents were used. Glycoprotein IIb/IIIa inhibitors were used as recommended by the protocol and dual antiplatelet therapy was administered for 1 year.. Baseline clinical and angiographic characteristics were comparable in the two groups. The patients' mean age was 66 (9) years, 42% were women, and 37% were insulin-dependent. On average, the lesion length was 15.0 (9.0) mm and the reference diameter was 1.9 (0.2) mm. At 9-month follow-up, both late lumen loss and the restenosis rate were significantly lower in the sirolimus-eluting stent group than in the bare-metal stent group, at -0.03 (0.3) mm vs 0.44 (0.5) mm (P< .001), and 9.1% vs 39.1% (P=.001), respectively. These differences were also observed in the subgroup of insulin-dependent patients. At 1-year follow-up, the stent thrombosis rate was 0% in the sirolimus-eluting stent group, whereas two patients in the bare-metal stent group presented with stent thrombosis.. Sirolimus-eluting stent implantation in diabetics with very small vessels is safe and effective, even in insulin-dependent patients.

Topics: Aged; Angioplasty, Balloon, Coronary; Anti-Bacterial Agents; Clinical Trials as Topic; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Data Interpretation, Statistical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Delivery Systems; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Patient Selection; Platelet Aggregation Inhibitors; Risk Factors; Sirolimus; Stents; Survival Analysis; Time Factors; Ultrasonography; Video Recording

Aim of the study was to determine the impact of sirolimus-eluting stents (SES) on clinical outcomes in patients with type 2 diabetes mellitus (DM) undergoing coronary revascularisation. The study enrolled 99 diabetic patients with de novo lesions in native coronary arteries. Medically treated DM was present in 61 patients (62%), 7 (7%) of whom required insulin. 53 patients received 78 SES and 46 patients received 57 bare metal stents. The differences in clinical outcomes between diabetic patients treated with SES and bare metal stents were assessed. Major adverse cardiac events (MACE) defined as death, myocardial infarction (MI), repeat revascularizations, and recurrences of angina were analyzed at 12-month follow-up. In the SES group the rate of recurrence of angina was 17%, the rate of coronary artery bypass surgery was 3,8%, the rate of repeat coronary angioplasty was 5,7%. In the bare metal stent group the rate of recurrence of angina was 37,8%, the rate of coronary artery bypass surgery was 2,2%, the rate of MI was 4,4%, the rate of repeat coronary angioplasty was 22,2%. Implantation of SES in patients with type 2 diabetes mellitus reduces recurrence of angina and major adverse cardiac events during first year after coronary angioplasty.

Topics: Coronary Angiography; Coronary Restenosis; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Follow-Up Studies; Humans; Sirolimus; Stents; Treatment Outcome

Insulin resistance is a primary characteristic of type 2 diabetes and likely causally related to the pathogenesis of the disease. It is a result of defects in signal transduction from the cell surface receptor of insulin to target effects. We found that insulin-stimulated phosphorylation of serine 307 (corresponding to serine 302 in the murine sequence) in the immediate downstream mediator protein of the insulin receptor, insulin receptor substrate-1 (IRS1), is required for efficient insulin signaling and that this phosphorylation is attenuated in adipocytes from patients with type 2 diabetes. Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. EC(50) for insulin-stimulated phosphorylation of serine 307 was about 0.2 nM with a t(1/2) of about 2 min. The amount of IRS1 was similar in cells from non-diabetic and diabetic subjects. These findings identify a molecular mechanism for insulin resistance in non-selected patients with type 2 diabetes.

Topics: Adipocytes; Aged; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Electrophoresis, Gel, Two-Dimensional; Electrophoresis, Polyacrylamide Gel; Female; Humans; Immunoblotting; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Kinetics; Male; Middle Aged; Okadaic Acid; Phosphoproteins; Phosphorylation; Serine; Signal Transduction; Sirolimus; Time Factors; Tyrosine

Restenosis rate is lower after sirolimus-eluting stent (SES) implantation than after bare metal stent (BS) implantation. We evaluated the impact of SES implantation on immediate and 12-month outcome in diabetic patients with multivessel coronary artery disease (MVD).. From April 2002 to September 2003, 100 consecutive diabetic patients with MVD without previous myocardial revascularization underwent successful elective percutaneous coronary intervention (PCI) with SES on native coronary arteries at our institutions. A group (n = 122) of consecutive diabetic patients with MVD treated with BS implantation (BS group) for de novo lesions was selected from our database and matched with the SES group. Major adverse cardiac events (MACEs) during hospital stay and at follow-up included nonfatal myocardial infarction, death, bypass surgery, and re-PCI.. At 12 +/- 4 months, MACEs occurred in 25% of patients in the SES group and in 44% of those in the BS group (P = .003, OR .72, 95% CI 0.57-0.91). Need for repeat intervention (re-PCI or bypass surgery) occurred in 17% of patients in the SES group and in 41% of those in the BS group (P < .001, OR .67, 95% CI 0.52-0.86). No significant difference in the rate of death and myocardial infarction was observed. In the SES group, the independent predictors of MACEs at follow-up were premature clopidogrel discontinuation (hazard ratio 20.62, 95% CI 1.60-264.97, P = .020) and chronic renal insufficiency (hazard ratio 4.73, 95% CI 1.99-11.25, P = .0004).. As compared with BS implantation, SES implantation favorably influences outcome in diabetic patients with MVD, mainly by reducing the need for new revascularization.

Topics: Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Carriers; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Postoperative Complications; Sirolimus; Stents; Time Factors

Patients with diabetes mellitus are at increased risk for repeat interventions and mortality after coronary angioplasty and stenting. The efficacy of sirolimus-eluting stents (SESs) to improve the outcomes of these patients is a focus of interest. In the first 1,407 patients treated with SESs at our institution, 492 were diabetic (insulin dependent diabetes mellitus [IDDM], n = 160 and non-insulin-dependent DM [NIDDM], n = 332). The in-hospital and 1- and 6-month clinical outcomes were compared with those of 915 patients without DM (non-DM). The baseline characteristics were similar, except for more women, obesity, previous myocardial infarction, coronary artery bypass grafting, and renal insufficiency in the DM group (p <0.001). Compared with non-DM patients, DM patients had higher in-hospital (p <0.05) and 1-month mortality (p = 0.02). IDDM patients had more in-hospital renal failure (p = 0.04) and Q-wave myocardial infarctions (1.6% vs 0%, p = 0.04) compared with NIDDM patients, and higher mortality (3.1% vs 0.8%, p = 0.04) and subacute stent thromboses (2.3% vs 0.5%, p = 0.07) than non-DM patients at 30 days. At 6 months, DM patients had a higher incidence of Q-wave myocardial infarction, target lesion revascularization-major adverse cardiac events, and composite of death and Q-wave myocardial infarction than non-DM patients (6.0% vs 2.7%, p = 0.01). Late outcomes between the IDDM and NIDDM groups were similar. Multivariate analysis showed diabetes and acute renal failure as independent predictors of target lesion revascularization-major adverse cardiac events. In conclusion, our data showed that, despite a reduction in repeat revascularization, coronary intervention with SESs in diabetic patients is limited by higher mortality at 1 month and a higher incidence of Q-wave myocardial infarction and target lesion revascularization-major adverse cardiac events at 6 months compared with non-DM patients. Careful surveillance is required in IDDM patients undergoing SES implantation.

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Bypass; Coronary Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Hospital Mortality; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Revascularization; Sirolimus; Stents; Treatment Outcome

The effect of diabetes mellitus (DM) on angiographic restenosis and clinical outcomes after implantation of drug-eluting stents (DESs) has not been investigated in real-world practice. This study consisted of 226 patients who had DM and 560 patients who did not who underwent DES implantation between February 2003 and December 2003. We retrospectively compared the incidence of 6-month angiographic restenosis and 9-month major adverse cardiac events (MACEs), defined as cardiac death, myocardial infarction, and target lesion revascularization, between patients with and without DM. The 6-month angiographic restenotic rate (10.1% vs 8.2%, p = 0.41) and late loss (0.41 +/- 0.63 vs 0.36 +/- 0.65, p = 0.31) were similar between patients with and without DM. In addition, incidences of MACEs (4.9% vs 4.8%, p = 1.00) and target lesion revascularization (4.4% vs 4.1%, p = 0.84) were similar. Patients who had insulin-dependent DM manifested higher prevalences of restenosis (25.0% vs 8.5%, p = 0.04) and MACEs (17.2% vs 3.1%, p = 0.01) compared with patients who had non-insulin-dependent DM. In conclusion, in this study of real-world patients who underwent DES implantation, patients who had DM had restenotic rates and clinical outcomes that were similar to those in patients who did not have DM.

Topics: Aged; Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Korea; Male; Middle Aged; Multivariate Analysis; Paclitaxel; Retrospective Studies; Sirolimus; Stents; Treatment Outcome

We have shown previously that hyperinsulinemia inhibits interferon-alpha-dependent activation of phosphatidylinositol 3-kinase (PI3-kinase) through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of insulin receptor substrate (IRS)-1. Here we report that chronic insulin and high glucose synergistically inhibit interleukin (IL)-4-dependent activation of PI3-kinase in macrophages via the mTOR pathway. Resident peritoneal macrophages (PerMPhis) from diabetic (db/db) mice showed a 44% reduction in IRS-2-associated PI3-kinase activity stimulated by IL-4 compared with PerMPhis from heterozygote (db/+) control mice. IRS-2 from db/db mouse PerMPhis also showed a 78% increase in Ser/Thr-Pro motif phosphorylation without a difference in IRS-2 mass. To investigate the mechanism of this PI3-kinase inhibition, 12-O-tetradecanoylphorbol-13-acetate-matured U937 cells were treated chronically with insulin (1 nm, 18 h) and high glucose (4.5 g/liter, 48 h). In these cells, IL-4-stimulated IRS-2-associated PI3-kinase activity was reduced by 37.5%. Importantly, chronic insulin or high glucose alone did not impact IL-4-activated IRS-2-associated PI3-kinase. Chronic insulin + high glucose did reduce IL-4-dependent IRS-2 tyrosine phosphorylation and p85 association by 54 and 37%, respectively, but did not effect IL-4-activated JAK/STAT signaling. When IRS-2 Ser/Thr-Pro motif phosphorylation was examined, chronic insulin + high glucose resulted in a 92% increase in IRS-2 Ser/Thr-Pro motif phosphorylation without a change in IRS-2 mass. Pretreatment of matured U937 cells with rapamycin blocked chronic insulin + high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. Taken together these results indicate that IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway.

Topics: Amino Acid Motifs; Animals; Blood Glucose; Blotting, Western; Cell Line; Diabetes Mellitus, Type 2; Glucose; Heterozygote; Humans; Insulin; Insulin Receptor Substrate Proteins; Interleukin-4; Intracellular Signaling Peptides and Proteins; Macrophages; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Serine; Signal Transduction; Sirolimus; Tetradecanoylphorbol Acetate; Time Factors; Tyrosine; U937 Cells

Topics: Clinical Protocols; Combined Modality Therapy; Coronary Restenosis; Coronary Stenosis; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Delivery Systems; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Randomized Controlled Trials as Topic; Registries; Risk Factors; Sirolimus; Stents

Topics: Animals; B-Lymphocytes; Carrier Proteins; Diabetes Mellitus, Type 2; Disaccharides; Energy-Generating Resources; Glucose; Humans; Hydrogen; Immune Tolerance; Immunophilins; Insulin; Nanotechnology; Phosphotransferases (Alcohol Group Acceptor); Plastics; Polysaccharides; Sirolimus; Tacrolimus Binding Protein 1A; TOR Serine-Threonine Kinases