benzofurans and Diabetes-Mellitus--Type-2

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; Cytokines; Databases, Genetic; Death; Dendritic Cells; Density Functional Theory; Depsides; Diabetes Mellitus, Type 2; Diamond; Diarylheptanoids; Dibenzofurans; Dibenzofurans, Polychlorinated; Diclofenac; Diet; Dietary Carbohydrates; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Dioxins; Diphenylamine; Disease Outbreaks; Disease Susceptibility; Disulfides; Dithiothreitol; Dizocilpine Maleate; DNA Methylation; DNA-Binding Proteins; DNA, Bacterial; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Doublecortin Protein; Drosophila melanogaster; Droughts; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; Drug Resistance; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Dust; Dynactin Complex; Dysferlin; Echo-Planar Imaging; Echocardiography; Edaravone; Egypt; Elasticity; Electrodes; Electrolytes; Emodin; Emtricitabine; Endometriosis; Endothelium, Vascular; Endotoxins; Energy Metabolism; Energy Transfer; 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G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, because of their diversity, cell-specific expression, and druggable sites accessible at the cell surface. Preclinical and clinical studies suggest that targeting GPCRs activated by fatty acid-derived lipids may have potential to improve glucose homeostasis and reduce complications in patients with type 2 diabetes (T2D). Despite the discontinued development of fasiglifam (TAK-875), the first FFA1 agonist to reach late-stage clinical trials, lipid-sensing receptors remain a viable target, albeit with a need for further characterization of their binding mode, intracellular signaling, and toxicity. Herein, we analyze general discovery trends, various signaling pathways, as well as possible challenges following activation of GPCRs that have been validated clinically to control blood glucose levels.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Fatty Acids; Humans; Receptors, G-Protein-Coupled; Sulfones

Of the 415 million people suffering from diabetes worldwide, 90% have type 2 diabetes. Type 2 diabetes is characterized by hyperglycemia and occurs in obese individuals as a result of insulin resistance and inadequate insulin levels. Accordingly, diabetes drugs are tailored to enhance glucose disposal or target the pancreatic islet β cell to increase insulin secretion. The majority of the present-day insulin secretagogues, however, increase the risk of iatrogenic hypoglycemia, and hence alternatives are actively sought. The long-chain fatty acid, G protein-coupled receptor FFA1/Gpr40, is expressed in β cells, and its activation potentiates insulin secretion in a glucose-dependent manner. Preclinical data indicate that FFA1 agonism is an effective treatment to restore glucose homeostasis in rodent models of diabetes. This initial success prompted clinical trials in type 2 diabetes patients, the results of which were promising; however, the field suffered a significant setback when the lead compound TAK-875/fasiglifam was withdrawn from clinical development due to liver safety concerns. Nevertheless, recent developments have brought to light a surprising complexity of FFA1 agonist action, signaling diversity, and biological outcomes, raising hopes that with a greater understanding of the mechanisms at play the second round will be more successful.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Metabolic Diseases; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

Apart from functioning as an energy source and important structural components of biological membranes, Free Fatty acids (FFAs) play a key role in the regulation of metabolic homeostasis. FFAs activate specific G-protein coupled receptors (GPCRs) in pancreatic β-cells, immune cells adipose, and intestine. GPR40 (also known as FFA receptor 1) is primarily expressed in pancreatic .-cells and is activated by medium-chain and long-chain FFAs. GPR40 has been shown to augment glucose dependent insulin secretion (GDIS) from pancreatic .-cells and is widely studied drug discovery target for the treatment of type 2 diabetes mellitus (T2DM) and other metabolic diseases. Several synthetic agonists of GPR40 augment insulin secretion from pancreatic β- cells and consequently improve glucose tolerance and restore metabolic homeostasis in various rodent models of T2DM. GPR40 agonists TAK-875 and AMG 837 have reached clinical trials and TAK 875 was shown to improve glycemic control in Type 2 diabetic patients. However, phase III clinical trials involving TAK-875 were recently terminated due to signs of liver toxicity in patients. Despite this setback, therapies based on GPR40 agonism provide an attractive alternative in the discovery of new anti-diabetic drugs. This review summarizes our current understanding of the physiological functions of GPR40, benefits and future prospects of GPR40 agonists to treat patients with T2DM.

Topics: Animals; Benzofurans; Biphenyl Compounds; Diabetes Mellitus, Type 2; Drug Design; Fatty Acids, Nonesterified; Humans; Hypoglycemic Agents; Insulin; Receptors, G-Protein-Coupled; Sulfones

GPR40 belongs to the GPCR family and the activation of GPR40 has been shown to induce glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells as well as incretin secretion from intestinal endocrine cells. Therefore, GPR40 has emerged as a viable and promising therapeutic target for type 2 diabetes mellitus (T2DM) without the risk of hypoglycemia. However, the termination of TAK-875 in phase III clinical trials for the hepatotoxicity issue threw doubt over the long-term safety of targeting GPR40. Herein, we summarized the newly disclosed biological characteristics and the druglikeness-based structural evolution of GPR40 agonists to advance the development of GPR40-based anti-diabetic drugs.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Drug Discovery; Humans; Hypoglycemic Agents; Models, Molecular; Molecular Targeted Therapy; Receptors, G-Protein-Coupled; Sulfones

The free fatty acid receptor GPR40 has been proposed as a potential target for type 2 diabetes (T2D) pharmacotherapy. This idea has been validated in both preclinical and clinical studies, in which activation of GPR40 was shown to improve glycaemic control by stimulating glucose-dependent insulin secretion; however, the recent termination of phase III clinical trials using the GPR40 agonist TAK-875 (fasiglifam) has raised important questions regarding the long-term safety and viability of targeting GPR40 and, more specifically, about our understanding of this receptor's basic biology. In the present review, we provide a summary of established and novel concepts related to GPR40's pharmacobiology and discuss the current status and future outlook for GPR40-based drug development for the treatment of T2D.

Topics: Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Receptors, G-Protein-Coupled; Safety-Based Drug Withdrawals; Sulfones

The stimulation of insulin secretion by glucose can be modulated by multiple nutritive, hormonal, and pharmacological inputs. Fatty acids potentiate insulin secretion through the generation of intracellular signaling molecules and through the activation of cell surface receptors. The G-protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (we will use GPR40 in this review), has emerged as an important component in the fatty acid augmentation of insulin secretion. By signaling predominantly through Gαq/11, GPR40 increases intracellular calcium and activates phospholipases to generate diacylglycerols resulting in increased insulin secretion. Synthetic small-molecule agonists of GPR40 enhance insulin secretion in a glucose-dependent manner in vitro and in vivo with a mechanism similar to that found with fatty acids. GPR40 agonists have shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes. Recent phase I and phase II clinical trials in humans have shown that the GPR40 agonist TAK-875 reduces fasting and postprandial blood glucose and lowers HbA1c with efficacy equal to that of the sulfonylurea glimepiride without inducing hypoglycemia or evidence of tachyphylaxis. These data suggest that targeting the GPR40 receptor can be a viable therapeutic option for the treatment of type 2 diabetes.

Topics: Benzofurans; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Fatty Acids; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Molecular Targeted Therapy; Receptors, G-Protein-Coupled; Sulfones

Fasiglifam , a novel G protein-coupled receptor 40 (GPR40) agonist, has demonstrated glucose-lowering effects in type 2 diabetes mellitus (T2DM) through stimulation of glucose-dependent insulin secretion.. This review is based on a PubMed search for all articles on fasiglifam and TAK-875. The pharmacology of fasiglifam is reviewed, focusing on studies in human volunteers and patients with T2DM. All published clinical trials with fasiglifam in T2DM are summarized, including two 12-week dose-ranging studies (one from Japan and the other from Central and North America), both of which employed glimepiride as an active comparator.. Fasiglifam, a novel glucose-dependent insulin secretagogue, is the first GPR40 agonist to enter Phase III clinical evaluation. It has been shown to produce statistically significant and clinically relevant improvements in glycemic control in patients with early-stage T2DM. Furthermore, its tolerability and safety profile was comparable to placebo and no dose-related adverse effects were observed. Importantly, fasiglifam was comparable to placebo with regards to the incidence of hypoglycemia and it produced significantly fewer episodes compared with glimepiride. Fasiglifam is an interesting and novel oral anti-diabetic agent which may offer new avenues for treating T2DM, but clearly more thorough clinical evaluation is still needed.

Topics: Administration, Oral; Benzofurans; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glycated Hemoglobin; Humans; Molecular Structure; Receptors, G-Protein-Coupled; Sulfones

Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.

Topics: Acetophenones; Amino Acid Sequence; Animals; Benzoates; Benzofurans; Biphenyl Compounds; Blood Glucose; Catalytic Domain; Catechols; Chromones; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Fluorides; Humans; Insulin; Insulin Resistance; Insulin Secretion; Janus Kinase 2; Models, Molecular; Naphthoquinones; Peptidomimetics; Phosphates; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Pyridazines; Receptor, Insulin; Signal Transduction; STAT3 Transcription Factor; Thiazoles; Thiazolidinediones; Thiophenes; Vanadium Compounds

G-protein-coupled receptor 40 (GPR40), known as free fatty acid receptor 1, is mainly expressed in pancreatic β-cells and activated by medium- and long-chain fatty acids. Increasing evidence indicates that the activation of GPR40 in cells causes insulin secretion, and GPR40 has become an attractive therapeutic target for type 2 diabetes. Recently, certain novel GPR40 agonists have been identified that regulate glucose-stimulated insulin secretion, leading to the development of new drugs for the treatment of type 2 diabetes. In this review, we focus on progress in the physiological role of GPR40 and potential drugs targeting GPR40 over the past decade.

Topics: Animals; Benzofurans; Berberine; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Ligands; Molecular Targeted Therapy; Receptors, G-Protein-Coupled; Sulfones

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; Cytokines; Databases, Genetic; Death; Dendritic Cells; Density Functional Theory; Depsides; Diabetes Mellitus, Type 2; Diamond; Diarylheptanoids; Dibenzofurans; Dibenzofurans, Polychlorinated; Diclofenac; Diet; Dietary Carbohydrates; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Dioxins; Diphenylamine; Disease Outbreaks; Disease Susceptibility; Disulfides; Dithiothreitol; Dizocilpine Maleate; DNA Methylation; DNA-Binding Proteins; DNA, Bacterial; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Doublecortin Protein; Drosophila melanogaster; Droughts; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; Drug Resistance; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Dust; Dynactin Complex; Dysferlin; Echo-Planar Imaging; Echocardiography; Edaravone; Egypt; Elasticity; Electrodes; Electrolytes; Emodin; Emtricitabine; Endometriosis; Endothelium, Vascular; Endotoxins; Energy Metabolism; Energy Transfer; Enterobacteriaceae; Enterococcus faecalis; Enterotoxigenic Escherichia coli; Environmental Monitoring; Enzyme Inhibitors; Epidemiologic Factors; Epigenesis, Genetic; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Esophageal Neoplasms; Esophagectomy; Esophagogastric Junction; Esterases; Esterification; Ethanol; Ethiopia; Ethnicity; Eucalyptus; Evidence-Based Practice; Exercise; Exercise Tolerance; Extracorporeal Membrane Oxygenation; Family; Fatty Acids; Feedback; Female; Ferric Compounds; Fibrin Fibrinogen Degradation Products; Filtration; Fish Diseases; Flavonoids; Flavonols; Fluorodeoxyglucose F18; Follow-Up Studies; Food Microbiology; Food Preservation; Forests; Fossils; Free Radical Scavengers; Freund's Adjuvant; Fruit; Fungi; Gallium; Gender Identity; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Genes, Bacterial; Genes, Plant; Genetic Predisposition to Disease; Genitalia; Genotype; Glomerulonephritis, IGA; Glottis; Glucocorticoids; Glucose; Glucuronides; Glutathione Transferase; Glycogen Synthase Kinase 3 beta; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Grassland; Guinea Pigs; Half-Life; Head Kidney; Heart Atria; Heart Rate; Heart Septum; HEK293 Cells; Hematopoietic Stem Cells; Hemodynamics; Hep G2 Cells; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Hesperidin; High-Frequency Ventilation; High-Temperature Requirement A Serine Peptidase 1; Hippocampus; Hirudins; History, 20th Century; History, 21st Century; HIV Infections; Homeostasis; Hominidae; Housing, Animal; Humans; Hydrocarbons, Brominated; Hydrogen Bonding; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxybutyrates; Hydroxyl Radical; Hypertension; Hypothyroidism; Image Interpretation, Computer-Assisted; Immunoconjugates; Immunogenic Cell Death; Indoles; Infant, Newborn; Infant, Premature; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Infrared Rays; Inhibitory Concentration 50; Injections, Intravenous; Interferon-gamma; Interleukin-23; Interleukin-4; Interleukin-6; Intermediate Filaments; Intermittent Claudication; Intestine, Small; Iridoid Glucosides; Iridoids; Iron; Isomerism; Isotope Labeling; Isoxazoles; Itraconazole; Kelch-Like ECH-Associated Protein 1; Ketoprofen; Kidney Failure, Chronic; Kinetics; Klebsiella pneumoniae; Lactams, Macrocyclic; Lactobacillus; Lactulose; Lakes; Lamivudine; Laparoscopy; Laparotomy; Laryngoscopy; Leucine; Limit of Detection; Linear Models; Lipid A; Lipopolysaccharides; Listeria monocytogenes; Liver; Liver Cirrhosis; Logistic Models; Longitudinal Studies; Losartan; Low Back Pain; Lung; Lupinus; Lupus Erythematosus, Systemic; Machine Learning; Macular Degeneration; Madin Darby Canine Kidney Cells; Magnetic Phenomena; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetics; Malaria, Falciparum; Male; Mannans; MAP Kinase Signaling System; Mass Spectrometry; Melatonin; Membrane Glycoproteins; Membrane Proteins; Meniscectomy; Menisci, Tibial; Mephenytoin; Mesenchymal Stem Cells; Metal Nanoparticles; Metal-Organic Frameworks; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Obese; Mice, Transgenic; Microbial Sensitivity Tests; Microcirculation; MicroRNAs; Microscopy, Video; Microtubules; Microvascular Density; Microwaves; Middle Aged; Minimally Invasive Surgical Procedures; Models, Animal; Models, Biological; Models, Molecular; Models, Theoretical; Molecular Docking Simulation; Molecular Structure; Molecular Weight; Morus; Mouth Floor; Multicenter Studies as Topic; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Muscle, Skeletal; Myocardial Ischemia; Myocardium; NAD; NADP; Nanocomposites; Nanoparticles; Naphthols; Nasal Lavage Fluid; Nasal Mucosa; Neisseria meningitidis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms, Experimental; Neural Stem Cells; Neuroblastoma; Neurofilament Proteins; Neurogenesis; Neurons; New York; NF-E2-Related Factor 2; NF-kappa B; Nicotine; Nitriles; Nitrogen; Nitrogen Fixation; North America; Observer Variation; Occupational Exposure; Ochrobactrum; Oils, Volatile; Olea; Oligosaccharides; Omeprazole; Open Field Test; Optimism; Oregon; Oryzias; Osmolar Concentration; Osteoarthritis; Osteoblasts; Osteogenesis; Ovarian Neoplasms; Ovariectomy; Oxadiazoles; Oxidation-Reduction; Oxidative Stress; Oxygen; Ozone; p38 Mitogen-Activated Protein Kinases; Pakistan; Pandemics; Particle Size; Particulate Matter; Patient-Centered Care; Pelargonium; Peptides; Perception; Peripheral Arterial Disease; Peroxides; Pets; Pharmaceutical Preparations; Pharmacogenetics; Phenobarbital; Phenols; Phenotype; Phosphates; Phosphatidylethanolamines; Phosphines; Phospholipids; Phosphorus; Phosphorylation; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Phylogeny; Phytoestrogens; Pilot Projects; Plant Components, Aerial; Plant Extracts; Plant Immunity; Plant Leaves; Plant Oils; Plants, Medicinal; Plasmodium berghei; Plasmodium falciparum; Platelet Activation; Platelet Function Tests; Pneumonia, Viral; Poaceae; Pogostemon; Poloxamer; Poly I; Poly(ADP-ribose) Polymerase Inhibitors; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Polyethylene Glycols; Polylysine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population Dynamics; Portasystemic Shunt, Transjugular Intrahepatic; Positron Emission Tomography Computed Tomography; Postoperative Complications; Postprandial Period; Potassium Cyanide; Predictive Value of Tests; Prefrontal Cortex; Pregnancy; Prepulse Inhibition; Prevalence; Procalcitonin; Prodrugs; Prognosis; Progression-Free Survival; Proline; Proof of Concept Study; Prospective Studies; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Protein Multimerization; Protein Sorting Signals; Protein Structure, Secondary; Proton Pump Inhibitors; Protozoan Proteins; Psychometrics; Pulse Wave Analysis; Pyridines; Pyrrolidines; Quality of Life; Quantum Dots; Quinoxalines; Quorum Sensing; Radiopharmaceuticals; Rain; Random Allocation; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Rats, Wistar; RAW 264.7 Cells; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, PAR-1; Receptors, CXCR4; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Interleukin-1; Receptors, Interleukin-17; Receptors, Notch; Recombinant Fusion Proteins; Recombinant Proteins; Reducing Agents; Reflex, Startle; Regional Blood Flow; Regression Analysis; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Tract Diseases; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Risk Assessment; Risk Factors; Rituximab; RNA, Messenger; RNA, Ribosomal, 16S; ROC Curve; Rosmarinic Acid; Running; Ruthenium; Rutin; Sarcolemma; Sarcoma; Sarcopenia; Sarcoplasmic Reticulum; SARS-CoV-2; Scavenger Receptors, Class A; Schools; Seasons; Seeds; Sequence Analysis, DNA; Severity of Illness Index; Sex Factors; Shock, Cardiogenic; Short Chain Dehydrogenase-Reductases; Signal Transduction; Silver; Singlet Oxygen; Sinusitis; Skin; Skin Absorption; Small Molecule Libraries; Smoke; Socioeconomic Factors; Soil; Soil Microbiology; Solid Phase Extraction; Solubility; Solvents; Spain; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Speech; Speech Perception; Spindle Poles; Spleen; Sporothrix; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Stomach Neoplasms; Stress, Physiological; Stroke Volume; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Rate; T-Lymphocytes, Cytotoxic; Tandem Mass Spectrometry; Temperature; Tenofovir; Terpenes; Tetracycline; Tetrapleura; Textiles; Thermodynamics; Thiobarbituric Acid Reactive Substances; Thrombin; Thyroid Hormones; Thyroid Neoplasms; Tibial Meniscus Injuries; Time Factors; Tissue Distribution; Titanium; Toluidines; Tomography, X-Ray Computed; Tooth; Tramadol; Transcription Factor AP-1; Transcription, Genetic; Transfection; Transgender Persons; Translations; Treatment Outcome; Triglycerides; Ubiquinone; Ubiquitin-Specific Proteases; United Kingdom; United States; Up-Regulation; Vascular Stiffness; Veins; Ventricular Remodeling; Viral Load; Virulence Factors; Virus Replication; Vitis; Voice; Voice Quality; Wastewater; Water; Water Pollutants, Chemical; Water-Electrolyte Balance; Weather; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Young Adult; Zoogloea

Gastroparesis, defined by delayed gastric emptying in the absence of mechanical outlet obstruction, is a frequent neuropathic complication of diabetes mellitus, and effective treatments are lacking. Prucalopride is a pan-gut prokinetic with selective agonist effects on serotonin 5-HT4 receptors in the gut. This study aimed to assess the effect of prucalopride 4 mg daily on Gastroparesis Cardinal Symptom Index (GCSI), meal-related symptom score (MRSS), and gastric emptying rate in diabetic or connective tissue disease (CTD)-related gastroparesis patients.. This was a double-blind crossover trial of four-week treatment periods with prucalopride or placebo divided by two weeks of washout. GSCI, MRSS, gastric emptying scintigraphy, PAGI-SYM, and PAGI-QoL were assessed at baseline and the end of each treatment period. Daily bowel movement (BM) frequency and gastrointestinal symptoms were recorded in each period.. Fifteen gastroparesis patients (13 diabetic, 2 CTD) were enrolled. GCSI scores were lower than baseline but not different between treatment arms. MRSS scores over time or cumulative score were not significantly different between groups. Gastric emptying was more rapid in the prucalopride treatment period, with mean four-hour meal retention of 22 ± 6% in PRU period vs 40 ± 9% in the placebo period (P = 0.05). Weekly BM frequency was significantly higher in prucalopride than placebo periods (10.5 ± 1.8 vs 7.5 ± 0.8, P < 0.0001). Perception of weight loss was higher in patients on prucalopride. Analysis of diabetic gastroparesis (n = 13) population did not change the conclusions.. Prucalopride at 4 mg accelerates gastric emptying and bowel movement frequency but does not appear to ameliorate gastroparesis or meal-related symptoms in this study.

Topics: Adult; Benzofurans; Cross-Over Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Gastroparesis; Humans; Male; Middle Aged; Mitral Valve Prolapse; Myopia; Pilot Projects; Quality of Life; Radionuclide Imaging; Scleroderma, Systemic; Serotonin 5-HT4 Receptor Agonists; Skin Diseases; Treatment Outcome

Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns.. The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug.. The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN), 5 × ULN, and 10 × ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3 × ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50 mg daily. The cumulative incidence of elevations in serum ALT > 3 × ULN was higher in the first 6 months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT > 3 × ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases.. Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.

Topics: Adult; Aged; Alanine Transaminase; Benzofurans; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Liver; Male; Middle Aged; Sitagliptin Phosphate; Sulfones; Sulfonylurea Compounds

To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes.. A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina.. The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ≥3-5 × upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ≥3 × ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%,. Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.

Topics: Aged; Benzofurans; Cardiovascular Diseases; Cardiovascular System; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Sulfones; Treatment Outcome

To investigate the effect of fasiglifam on glycaemic control in people with type 2 diabetes mellitus (T2DM).. In total, 421 people with T2DM and glycated haemoglobin (HbA1c) ≥7.0% and ≤10.5% who had received only diet and exercise treatment for ≥12 weeks prior to screening were randomized to receive fasiglifam 25 or 50 mg or placebo. The primary efficacy endpoint was change from baseline in HbA1c at week 24.. The mean participant age was 53.5 years, mean baseline body mass index 32.3 kg/m. The data indicate that fasiglifam effectively reduced HbA1c from baseline for 24 weeks in participants with T2DM. The incidence of TEAEs was higher in the fasiglifam groups; however, the incidence of serious AEs was low overall and similar between groups. ALT elevations were observed only in the fasiglifam groups, which contributed to the decision to terminate the fasiglifam programme after completion of the present study.

Topics: Benzofurans; Body Mass Index; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Liver; Lost to Follow-Up; Male; Middle Aged; Obesity; Patient Dropouts; Receptors, G-Protein-Coupled; Sulfones

To evaluate the efficacy and safety of fasiglifam, an orally active G-protein-coupled receptor 40 agonist, in combination with the dipeptidyl peptidase-4 inhibitor sitagliptin, in patients with type 2 diabetes inadequately controlled with diet/exercise (± metformin).. In this randomized, double-blind, phase II study, 368 patients received once-daily placebo, sitagliptin 100 mg, fasiglifam 25 or 50 mg, or the combination of sitagliptin 100 mg plus fasiglifam 25 or 50 mg. The primary endpoint was change from baseline glycated haemoglobin (HbA1c) at 12 weeks; a key secondary endpoint was change in fasting plasma glucose (FPG).. The fasiglifam 25 and 50 mg combination regimens produced significantly greater HbA1c reductions than sitagliptin (treatment differences of -0.45% and -0.61%; P < .01, respectively) or respective doses of fasiglifam monotherapy (-0.43% and -0.48%; P < .01) and significantly greater FPG reductions than sitagliptin (-1.1 mmol/L for both combination regimens; P < .01). Improved glycaemic control occurred by week 1 for FPG and week 4 for HbA1c in all groups. Hypoglycaemia rates were low (≤3.3%) and similar across treatments. Liver enzymes >3 × upper limit of normal occurred in four patients (fasiglifam 25 mg, n = 1; fasiglifam 50 mg, n = 2; 1 fasiglifam/sitagliptin 50/100 mg, n = 1).. Combination of fasiglifam and sitagliptin provided significant additional effects on glycaemic control, with hypoglycaemia rates similar to placebo with or without metformin. This study provides supportive clinical evidence for the complementary mechanism of actions of this GPR40 agonist and DPP-4 inhibitor.

Topics: Benzofurans; Combined Modality Therapy; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Hemoglobins, Abnormal; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Male; Metformin; Middle Aged; Receptors, G-Protein-Coupled; Sitagliptin Phosphate; Sulfones; United States

This multicentre, open-label, phase III study investigated the safety and efficacy of the G-protein-coupled receptor 40 agonist fasiglifam. Japanese patients with type 2 diabetes and inadequate glycaemic control despite diet and/or exercise (n = 282), or despite diet and/or exercise plus one oral antidiabetic agent [sulphonylurea (n = 262), rapid-acting insulin secretagogue (n = 124), α-glucosidase inhibitor (n = 141), biguanide (n = 136), thiazolidinedione (n = 139) or dipeptidyl peptidase-4 inhibitor (n = 138)] were randomized to treatment with fasiglifam 25 or 50 mg once daily for 52 weeks. The primary endpoints were safety variables. The overall incidence of treatment-emergent adverse events (TEAEs) was 75.4-85.1% in the 25 mg group and 78.9-89.9% in the 50 mg group; most TEAEs were mild. Hypoglycaemia was negligible with fasiglifam monotherapy and most common with sulphonylurea combination therapy (12.4 and 9.1% for 25 and 50 mg groups, respectively). Abnormal liver-related laboratory values were uncommon. Glycated haemoglobin levels decreased from week 2 in all groups and were maintained to week 52. Although fasiglifam as monotherapy or in combination regimens was well tolerated during long-term treatment, global concerns about liver safety led to termination of its development after study completion.

Topics: Benzofurans; Biguanides; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Japan; Liver; Male; Middle Aged; Receptors, G-Protein-Coupled; Sulfones; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Glucokinase enhances glucose conversion to glucose-6-phosphate, causing glucose-stimulated insulin secretion from pancreatic β cells and increased hepatic glucose uptake. PF-04937319 is a partial glucokinase activator designed to maintain efficacy with reduced hypoglycemia risk. In this randomized, double-blind, double-dummy, 3-period crossover phase 1b study, patients aged 18-70 years with type 2 diabetes mellitus and on metformin received once-daily PF-04937319 (300 mg), split-dose PF-04937319 (150+100 mg; breakfast+lunch), or sitagliptin (100 mg once daily). The primary end point was day 14 weighted mean daily glucose (WMDG) change from period-specific baseline. Secondary end points included change from baseline in fasting plasma glucose, premeal C-peptide and insulin, and safety, including hypoglycemia frequency. Mean decrease from baseline in observed WMDG (mg/dL) was greater for PF-04937319 (split-dose, -31.24; once daily, -31.33) versus sitagliptin (-19.24). Using the integrated glucose red-cell HbA

Topics: Adult; Aged; Benzofurans; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Enzyme Activators; Female; Glucokinase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Pyrimidines; Sitagliptin Phosphate

The effects of 12 weeks of supplementation with a dieckol-rich extract (AG-dieckol) from brown algae, Ecklonia cava, on glycemic parameters, serum biochemistry, and hematology were investigated in this study. Eighty pre-diabetic male and female adults were enrolled in a randomized, double-blind, placebo-controlled trial with parallel-group design. Subjects were randomly allocated into two groups designated as placebo and AG-dieckol (1500 mg per day). Compared with the placebo group, the AG-dieckol group showed a significant decrease in postprandial glucose levels after 12 weeks. The AG-dieckol group also showed a significant decrease in insulin and C-peptide levels after 12 weeks, but there was no significant difference between the AG-dieckol and placebo groups. There were no significant adverse events related to the consumption of AG-dieckol, and biochemical and hematological parameters were maintained within the normal range during the intervention period. In conclusion, these results demonstrate that AG-dieckol supplementation significantly contributes to lowering postprandial hyperglycemia and in reducing insulin resistance. Furthermore, we believe that based on these results the consumption of phlorotannin-rich foods such as marine algae may be useful for the treatment of diabetes.

Topics: Benzofurans; Biological Products; C-Peptide; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Pacific Ocean; Phaeophyceae; Prediabetic State; Republic of Korea; Seaweed

To assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.. This phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24.. At week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, -0.57% with fasiglifam 25 mg and -0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group.. Fasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed.

Topics: Aged; Asian People; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Exercise; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Japan; Male; Middle Aged; Receptors, G-Protein-Coupled; Sulfones

To assess the efficacy and safety of a range of doses of a systemic, partial, glucokinase activator, PF-04937319, as add-on therapy to metformin, in patients with type 2 diabetes mellitus (T2DM).. Patients were randomized to once-daily PF-04937319 doses of 10, 50, 100 mg, or matching placebo (Study B1621002); or PF-04937319 doses of 3, 20, 50, 100 mg, or matching placebo (Study B1621007). Titrated glimepiride (Study B1621002) or sitagliptin (Study B1621007) were included in a double-dummy manner. The primary measure was change from baseline in glycated haemoglobin (HbA1c) at week 12. Key secondary measures included other glycaemic variables and safety and tolerability.. In the 639 patients randomized, the minimally efficacious PF-04937319 dose was identified as 50 mg once daily. At the highest PF-04937319 dose tested (100 mg), on average, a clinically significant reduction in HbA1c [-4.94 or -5.11 mmol/mol (-0.45 or -0.47%), placebo-adjusted], which was similar to that achieved with sitagliptin [-4.69 mmol/mol (-0.43%)] but lower than that achieved with titrated glimepiride [-9.07 mmol/mol (-0.83%)], was observed. At this dose, the effect on fasting plasma glucose was not consistent between the two studies (Study B1621002 vs Study B1621007: placebo-adjusted mean change of -0.83 vs +0.50 mmol/l). PF-04937319 was well tolerated at doses up to 100 mg. Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100 mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride).. In patients on metformin monotherapy, the addition of a 100-mg dose of PF-04937319 improved glycaemic control and was well tolerated.

Topics: Aged; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glucokinase; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pyrimidines; Sitagliptin Phosphate; Sulfonylurea Compounds

Assessment of the efficacy and safety of TAK-875 (a novel GPR40 agonist) in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise.. This was a phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week dose-ranging evaluation of TAK-875 (6.25-200 mg once daily) with the primary end point of change in A1C at week 12. A nonblinded group received 1 mg glimepiride once daily as an active control.. A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; -0.54, -0.67, -0.88, -1.27, -1.29, and -1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and -1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving ≥50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group.. TAK-875 produced clinically and statistically significant improvements in glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise, and it was well tolerated with a lower propensity to cause hypoglycemia.

Topics: Aged; Asian People; Benzofurans; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Receptors, G-Protein-Coupled; Sulfones; Treatment Outcome

Free fatty acids act as signalling molecules for modulating insulin secretion, and their insulinotropic effects are glucose-dependent and mediated through G protein-coupled receptor 40 (GPR40). This mechanism is a potential target for new treatments for managing diabetes. In this study, we present the first clinical data for TAK-875, a novel highly selective, orally bioavailable GPR40 agonist, in Japanese patients with type 2 diabetes insufficiently controlled by diet or exercise therapy.. This was an exploratory phase II, multicentre, randomized, double-blind, parallel group study comparing the efficacy and tolerability of TAK-875 100 and 400 mg, and placebo, all administered once daily for 2 weeks.. After 2 weeks of treatment, TAK-875 produced marked glucose lowering effects in a 75 g oral glucose tolerance test (OGTT) as evidenced by mean ± SE intergroup differences in plasma glucose AUC(0-3 h) of -12.98 ± 1.48 (p < 0.0001) and -8.12 ± 1.49 mmol·h/l (p < 0.0001), for TAK-875 400 mg vs. placebo and TAK-875 100 mg vs. placebo, respectively, and 2 h plasma glucose [-4.95 ± 0.71 (p < 0.0001) and -3.21 ± 0.71 mmol/l (p < 0.0001), respectively]. This was accompanied by a significant increase in insulin AUC(0-3 h) [34.68 ± 12.16 (p < 0.01) and 31.49 ± 12.20 (p < 0 · 05) µIU·h/ml, respectively]. Improvement in glycaemic profile was mirrored by a significant change in fasting plasma glucose [-2.37 ± 0·27 (p < 0.0001) and -1.88 ± 0.27 mmol/l (p < 0.0001), respectively]. No cases of hypoglycaemia were observed despite the significant reduction in plasma glucose.. These exploratory findings provide evidence of the glucose-dependent insulinotropic potential of the GPR40 agonist TAK-875, and the promising clinical changes support future longer term clinical investigation.

Topics: Adult; Aged; Analysis of Variance; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Japan; Male; Middle Aged; Receptors, G-Protein-Coupled; Sulfones; Treatment Outcome

Activation of free fatty acid receptor 1 (FFAR1; also known as G-protein-coupled receptor 40) by fatty acids stimulated glucose-dependent β-cell insulin secretion in preclinical models. We aimed to assess whether selective pharmacological activation of this receptor by TAK-875 in patients with type 2 diabetes mellitus improved glycaemic control without hypoglycaemia risk.. We undertook a phase 2, randomised, double-blind, and placebo-controlled and active-comparator-controlled trial in outpatients with type 2 diabetes who had not responded to diet or metformin treatment. Patients were randomly assigned equally to receive placebo, TAK-875 (6·25, 25, 50, 100, or 200 mg), or glimepiride (4 mg) once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary outcome was change in haemoglobin A(1c) (HbA(1c)) from baseline. Analysis included all patients randomly assigned to treatment groups who received at least one dose of double-blind study drug. The trial is registered at ClinicalTrials.gov, NCT01007097.. 426 patients were randomly assigned to TAK-875 (n=303), placebo (n=61), and glimepiride (n=62). At week 12, significant least-squares mean reductions in HbA(1c) from baseline occurred in all TAK-875 (ranging from -1·12% [SE 0·113] with 50 mg to -0·65% [0·114] with 6·25 mg) and glimepiride (-1·05% [SE 0·111]) groups versus placebo (-0·13% [SE 0·115]; p value range 0·001 to <0·0001). Treatment-emergent hypoglycaemic events were similar in the TAK-875 and placebo groups (2% [n=7, all TAK-875 groups] vs 3% [n=2]); significantly higher rates were reported in the glimepiride group (19% [n=12]; p value range 0·010-0·002 vs all TAK-875 groups). Incidence of treatment-emergent adverse events was similar in the TAK-875 overall (49%; n=147, all TAK-875 groups) and placebo groups (48%, n=29) and was lower than in the glimepiride group (61%, n=38).. TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes.. Takeda Global Research and Development.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Male; Maximum Tolerated Dose; Middle Aged; Risk Assessment; Sulfones; Sulfonylurea Compounds; Treatment Outcome

G-protein-coupled receptor 40 (GPR40), highly expressed in pancreatic β-cells, mediates free fatty acid (FFA)-induced insulin secretion. This phase I, double-blind, randomized study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel, glucose-lowering GPR40 agonist, TAK-875 (q.d., orally × 14 days), in type 2 diabetics (placebo, n = 14; at 25, 50, 100, 200, or 400 mg, n = 45). Approximately dose-proportional increases in AUC(0-24) and C(max) occurred. TAK-875 showed good tolerability with no dose-limiting side effects. Two subjects (on TAK-875) had mild hypoglycemia, probably related to prolonged fasting after oral glucose tolerance tests (OGTTs). TAK-875 showed reductions from baseline in fasting (2 to -93 mg/dl) and post-OGTT glucose (26 to -172 mg/dl), with an apparent dose-dependent increase in post-OGTT C-peptide over 14 days. Consistent with preclinical data, TAK-875 apparently acts as a glucose-dependent insulinotropic agent with low hypoglycemic risk. Its PK is suitable for once-daily oral administration.

Topics: Administration, Oral; Benzofurans; Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Fatty Acids, Nonesterified; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Receptors, G-Protein-Coupled; Sulfones; Treatment Outcome

To determine whether raxofelast, a new water soluble antioxidant decreases oxidative stress and improves endothelial function in men with Type II (non-insulin dependent) diabetes mellitus.. We treated ten normotensive, normocholesterolaemic men with Type II diabetes and as controls ten healthy men matched with them for age with raxofelast (600 mg twice daily) for 1 week. Plasma 8-epi-PGF(2a), a non-enzymic oxidation product of arachidonic acid was measured by gas chromatography/mass spectrometry as an index of oxidative stress. Forearm vasodilator responses to brachial artery infusion of acetylcholine (7.5, 15 and 30 microg min(-1)) and of the nitric oxide donor nitroprusside (1, 3 and 10 microg min(-1)) were measured by strain gauge plethysmography.. Plasma concentrations of 8-epi-PGF(2a), were greater in diabetic than in control men (0.99 +/- 0.20 vs 0.18 +/- 0.01 nmol 1(-1), means +/- SEM, p < 0.001) and fell after raxofelast (from 0.99 +/- 0.20 to 0.47 +/- 0.07 nmol 1(-1), p < 0.05) in diabetic men but not in control men. Blood flow responses to acetylcholine were lower (p < 0.05) in diabetic than in control men (7.4 +/- 1.0 vs 12.9 +/- 2.3 ml min(-1) x 100 ml(-1) for the highest dose). In diabetic men, but not in control men, raxofelast increased (p < 0.05) blood flow responses to acetylcholine (from 7.4 +/- 1.0 m x min(-1) x 100 ml(-1) to 11.3 +/- 2.3 ml x min(-1) x 100 ml(-1) at highest dose). Blood flow responses to nitroprusside were similar in control and diabetic men and in both groups were similar before and after raxofelast.. Oral treatment with raxofelast for 1 week reduces oxidative stress and improves endothelial function in men with Type II diabetes.

Topics: Acetylcholine; Administration, Oral; Antioxidants; Benzofurans; Biomarkers; Brachial Artery; Diabetes Mellitus, Type 2; Dinoprost; Endothelium, Vascular; Female; Forearm; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Nitric Oxide Donors; Nitroprusside; Oxidative Stress; Reference Values; Vasodilation; Vitamin E

Riligustilide (RG), one of the dimeric phthalides of Angelica sinensis and Ligusticum chuanxiong, was confirmed effective against many diseases. However, its effects on type 2 diabetes mellitus (T2DM) and the underlying molecular mechanisms have not been clearly elucidated yet. The current study was designed to investigate the hypoglycemic potential by which RG affects the pathogenesis of T2DM. Comprehensive insights into the effects and underlying molecular mechanisms of RG on attenuating aberrant metabolism of glucose were determined in high-fat diet-induced T2DM mice and insulin-resistant (IR) HepG2 cells. In high-fat diet-induced C57BL/6J mice, RG administration significantly reduced hyperglycemia, decreased hyperinsulinemia, and ameliorated glucose intolerance. Mechanistically, RG activated PPARγ and insulin signaling pathway to improve insulin sensitivity, and increase glucose uptake as well as glycogenesis. In addition, RG also upregulated AMPK-TORC2-FoxO1 axis to attenuate gluconeogenesis in vivo and in vitro. According to the findings, RG may be a promising candidate for the treatment of T2DM.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Gluconeogenesis; Insulin Resistance; Mice; Mice, Inbred C57BL

Epidemiological studies have inconsistently shown an association between dioxin and risk of type 2 diabetes mellitus (T2DM) and cancer. This study aims to examine the effects of blood concentration of dioxin-like polychlorinated biphenyls (DL-PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) on T2DM and thyroid cancer.. We conducted a nested case-control study within the Korean cancer prevention study-II (KCPS-II) consisting of 15 thyroid cancer cases, 30 T2DM cases, and 55 controls. A total of 500 samples were used in 100 pooling samples. An average value of a pooled sample was calculated weighted by the blood volume of each sample.. The study population included 100 participants from the KCPS-II (median (IQR) baseline age, 54.06 [21.04] years; 48 women). The toxic equivalents of PCDD/DFs showed a significant positive association with T2DM and thyroid cancer, after adjustments for potential confounders (T2DM ORs  =  1.23; 95% CI  =  1.05-1.43; thyroid cancer ORs  =  1.34; 95% CI  =  1.12-1.61).. In this study, both T2DM and thyroid cancer were associated with the blood concentrations of PCDD/DFs. The association between PCDD/DFs and T2D was found among women but not among men. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the association between dioxins concentrations and diseases.

Topics: Benzofurans; Case-Control Studies; Diabetes Mellitus, Type 2; Dioxins; Female; Humans; Male; Middle Aged; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Thyroid Neoplasms

GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.

Topics: Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Male; Mice; Rats; Sulfones

In this study, we have investigated a series of hydroxylated 2-phenylbenzofurans compounds for their inhibitory activity against α-amylase and α-glucosidase activity. Inhibitors of carbohydrate degrading enzymes seem to have an important role as antidiabetic drugs. Diabetes mellitus is a wide-spread metabolic disease characterized by elevated levels of blood glucose. The most common is type 2 diabetes, which can lead to severe complications. Since the aggregates of islet amyloid polypeptide (IAPP) are common in diabetic patients, the effect of compounds to inhibit amyloid fibril formation was also determined. All the compounds assayed showed to be more active against α-glucosidase. Compound 16 showed the lowest IC

Topics: alpha-Amylases; alpha-Glucosidases; Amyloid; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Hydroxylation; Hypoglycemic Agents; Islet Amyloid Polypeptide; Molecular Docking Simulation; Prospective Studies

Topics: Animals; Apoptosis; Benzofurans; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Dendrites; Diabetes Mellitus, Type 2; Hippocampus; Male; Mice, Inbred C57BL; Morris Water Maze Test; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Synapses

Topics: Animals; Benzofurans; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Methylamines; Molecular Docking Simulation; Phenols; Propionates; Protein Binding; Protein Conformation; Receptors, G-Protein-Coupled; Sulfones

Accumulating evidence have shown a strong pathological correlation between cardiovascular disease (CVD) and Type II diabetes (T2D), both of which share many common risk factors (e.g., hyperglycemia, hypertension, hypercoagulability, and dyslipidemia) and mutually contribute to each other. Driven by such strong CVD-T2D correlation and marginal benefits from drug development for T2D, here we proposed to repurpose a CVD drug of cloridarol as human islet amyloid peptide (hIAPP) inhibitor against its abnormal misfolding and aggregation, which is considered as a common and critical pathological event in T2D. To this end, we investigated the inhibition activity of cloridarol on the aggregation and toxicity of hIAPP

Topics: Amyloidogenic Proteins; Benzofurans; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Repositioning; Humans; Islet Amyloid Polypeptide; Pharmaceutical Preparations

Topics: Animals; Benzofurans; Blood Glucose; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rats, Zucker; Receptors, G-Protein-Coupled; Sulfones

As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions in a personal glucose meter (PGM). α-glucosidase catalyzes the hydrolysis of maltose to produce glucose, which triggers the reduction of ferricyanide (K

Topics: Acarbose; alpha-Glucosidases; Benzaldehydes; Benzofurans; Binding Sites; Biosensing Techniques; Blood Glucose; Catechols; Depsides; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Hydrolysis; Kinetics; Maltose; Molecular Docking Simulation; Monitoring, Ambulatory; Plant Extracts; Plants, Medicinal; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Small Molecule Libraries; Thermodynamics; Wearable Electronic Devices

Impaired insulin sensitivity of insulin-sensitive tissues plays a major role in the pathogenesis of type 2 diabetes, salvianolic acid B (SalB), a natural antioxidant usually treated various cardiovascular diseases was also reported potential utility on diabetes and dyslipidemia. Based on these, we aimed to explored whether the antioxidant effect of SalB play a pivotal role in the molecular mechanisms leading to insulin resistance. We found that SalB improved glucose tolerance and insulin sensitivity, decreased serum ALT, AST and ALP levels of ob/ob mice. Also, transcription of Bip and CHOP, phosphorylation of PERK and IRE1 for endoplasmic reticulum stress (ER) and phosphorylation of IRS-1 for insulin sensitivity in the liver of ob/ob mice were relieved by SalB. Further, SalB decreased phosphorylation of PERK, IRE1 and IRS1 and transcription of Bip and CHOP stimulated by palmitate of hepatic cells HL7702, but did not reversed phosphorylation of JNK and IRS1 and transcription of Bip and CHOP when ER stress was stimulated by tunicamycin. These data shows that SalB improved insulin resistance of ob/ob mice through suppression of hepatic ER stress.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Hepatocytes; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Membrane Proteins; Mice; Palmitates; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factor CHOP; Tunicamycin

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t

Topics: Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Phenylpropionates; Pyridines; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Sulfones

Topics: Allosteric Regulation; Benzofurans; Catalytic Domain; Diabetes Mellitus, Type 2; Enzyme Assays; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Insulin; Kinetics; Molecular Docking Simulation; Morus; Plant Bark; Plant Extracts; Plant Roots; Prenylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Numerous epidemiological studies have shown that diabetes mellitus (DM) is associated with dementia and cognition decline. However, there is currently no effective treatment for diabetes-induced cognitive dysfunction. The neuroprotective effect of L-3-n-butylphthalide (L-NBP) has been demonstrated in vascular dementia animal models. The purpose of this study was to determine whether L-NBP can ameliorate cognitive deficits in db/db mice, a model of obesity and type 2 diabetes. The mice were administered with vehicle or L-NBP (120 mg/kg) by gavage daily for 6 weeks. Then, Morris water maze tasks were performed, and hippocampal LTP was recorded in vivo. Next, the synaptic structure of the CA1 hippocampus region was investigated via electron microscopy. Finally, the expression levels of MDA, SOD, 8-OHdG, and NADPH oxidase subunits gp91 and p67, as well as the expression of NF-κB p65, TNF-α, IL-1β and caspase-3 were measured by Western blot, RT-PCR and ELISA. Treatment with L-NBP significantly attenuated the learning and memory deficits in db/db mice. Concomitantly, L-NBP also increased hippocampus synaptic plasticity, characterized by an enhanced in vivo LTP, and suppressed oxidative stress, as indicated by increased SOD activity and decreased MDA, 8-OHdG, and NADPH oxidase subunits p67 and gp91. L-NBP also significantly decreased NF-κB p65, TNF-α, IL-1βand caspase-3 levels in the hippocampus. L-NBP significantly ameliorated cognitive decline in type 2 diabetic mice, and this effect was accompanied by an improvement in hippocampal plasticity and an amelioration of oxidative stress, inflammation and apoptosis cascades. Thus, L-NBP may be a promising therapeutic agent against DM-mediated cognitive dysfunction.

Topics: Animals; Benzofurans; Caspase 3; Cognition; Cognitive Dysfunction; Cytokines; Diabetes Mellitus, Type 2; Disease Models, Animal; Hippocampus; Maze Learning; Mice; Neuroprotective Agents; Oxidative Stress

Hemophilia A is an X-linked genetic hemorrhagic disorder characterized by a factor VIII deficiency. The availability of secured substitution products has led to a dramatic improvement of life expectancy in hemophiliac patients. Nowadays, adult hemophiliac patients may develop Chronic Kidney Disease (CKD) resulting from age-related comorbidities (hypertension, obesity, diabetes). In addition, the high prevalence of viral infections in this population exposes patients to an increased risk of CKD. The risk of hemorrhage in hemophiliac patients is a challenge for their clinical management, both for diagnostic procedures (kidney biopsy in particular) and for renal replacement therapy (dialysis or renal transplantation) when it is needed. This work provides an update of the literature data concerning the management of hemophiliac patients in nephrology, illustrated by the cases of two patients.

Topics: Acute Kidney Injury; Antiviral Agents; Arteriovenous Shunt, Surgical; Benzofurans; Catheters, Indwelling; Diabetes Mellitus, Type 2; Drug Combinations; Hemophilia A; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Nephrotic Syndrome; Quinoxalines; Renal Dialysis; Virus Replication

Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided.. This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program.. Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy's Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29-4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03-14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18-17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients.. In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.

Topics: Benzofurans; Chemical and Drug Induced Liver Injury; Clinical Trials Data Monitoring Committees; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Liver Function Tests; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Sulfones

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gα

Topics: Allosteric Site; Animals; Benzofurans; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Drug Synergism; gamma-Linolenic Acid; HEK293 Cells; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Molecular Docking Simulation; Mutagenesis, Site-Directed; Receptors, G-Protein-Coupled; Recombinant Proteins; Sulfones

Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.

Topics: Aging; AMP-Activated Protein Kinases; Animals; Benzofurans; Diabetes Mellitus, Type 2; DNA-Activated Protein Kinase; Energy Metabolism; Macaca mulatta; Mice, SCID; Mitochondria, Muscle; Muscle, Skeletal; Physical Conditioning, Animal; Quinolines; Rats

Topics: Administration, Oral; Animals; Benzofurans; Blood Glucose; Cell Line; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Male; Mice, Inbred ICR; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Sulfones; Thiophenes

The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes.

Topics: Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Hypoglycemic Agents; Mice; Propionates; Receptors, G-Protein-Coupled

Salvia miltiorrhiza Bge. (Labiatae) has been widely used for treating diabetes for centuries. Salvianolic acid B (SalB) is the main bioactive component in Salvia miltiorrhiza; however, its antidiabetic activity and possible mechanism are not yet clear.. To investigate the effects of SalB on glycometabolism, lipid metabolism, insulin resistance, oxidative stress, and glycogen synthesis in type 2 diabetic rat model.. High-fat diet (HFD) and streptozotocin-induced diabetic rats were randomly divided into model group, SalB subgroups (50, 100, and 200 mg/kg), and rosiglitazone group.. Compared with the model group, SalB (100 and 200 mg/kg) significantly decreased blood glucose (by 23.8 and 21.7%; p < 0.05 and p < 0.01) and insulin (by 31.3 and 26.6%; p < 0.05), and increased insulin sensitivity index (by 10.9 and 9.3%; p < 0.05). They also significantly decreased total cholesterol (by 24.9 and 27.9%; p < 0.01), low-density lipoprotein cholesterol (by 56.2 and 64.6%; p < 0.01), non-esterified fatty acids (by 32.1 and 37.9%; p < 0.01), hepatic glycogen (by 41.3 and 60.5%; p < 0.01), and muscle glycogen (by 33.2 and 38.6%; p < 0.05), and increased high-density lipoprotein cholesterol (by 50.0 and 61.4%; p < 0.05 and p < 0.01), which were originally altered by HFD and streptozotocin. In addition, SalB (200 mg/kg) markedly decreased triglyceride and malondialdehyde (by 31.5 and 29.0%; p < 0.05 and p < 0.01), and increased superoxide dismutase (by 56.6%; p < 0.01), which were originally altered by HFD and streptozotocin.. The results indicate that SalB can inhibit symptoms of diabetes mellitus in rats and these effects may partially be correlated with its insulin sensitivity, glycogen synthesis and antioxidant activities.

Topics: Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Diet, High-Fat; Drugs, Chinese Herbal; Male; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Streptozocin

The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy.

Topics: Animals; Azepines; Benzofurans; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Heart; Male; Mice; Myocardium; Organ Size; Phosphorylation; Protein Kinase C; Protein Kinase Inhibitors; Transcriptome; Ventricular Dysfunction; Ventricular Function, Left

With growing needs for new antidiabetic drugs which are safe and effective alone or in combination with existing drugs, G-protein coupled receptor 40 (GPR40) has drawn a considerable attention as a potential therapeutic target for type 2 diabetes. As GPR40 agonist may offer advantages to commonly used agents, by acting ambient glucose dependent manner which mechanistically leads to reduced risk of developing hypoglycemia. Since deorphanization in 2003, development of small molecule GPR40 agonists has been spurred by several research groups. There are a number of lead molecules targeting GPR40, and among these molecules TAK-875 (full agonist) and AMG 837 (partial agonist) advanced into clinical stage.

Topics: Benzofurans; Biphenyl Compounds; Diabetes Mellitus, Type 2; Drug Discovery; Drugs, Investigational; Humans; Hypoglycemic Agents; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

Human Hexokinase IV, or glucokinase (GK), is a regulator of glucose concentrations in the body. It plays a key role in pancreatic insulin secretion as well as glucose biotransformation in the liver, making it a potentially viable target for treatment of Type 2 diabetes. Allosteric activators of GK have been shown to decrease blood glucose concentrations in both animals and humans. Here, the development of a mathematical model is presented that describes glucose modulation in an ob/ob mouse model via administration of a potent GK activator, with the goal of projecting a human efficacious dose and plasma exposure. The model accounts for the allosteric interaction between GK, the activator, and glucose using a modified Hill function. Based on model simulations using data from the ob/ob mouse and in vitro studies, human projections of glucose response to the GK activator are presented, along with dose and regimen predictions to maintain clinically significant decreases in blood glucose in a Type 2 diabetic patient. This effort serves as a basis to build a detailed mechanistic understanding of GK and its role as a therapeutic target for Type 2 diabetes, and it highlights the benefits of using such an approach in a drug discovery setting.

Topics: Animals; Azetidines; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Enzyme Activators; Glucokinase; Humans; Hypoglycemic Agents; Male; Mice; Mice, Obese; Models, Biological

Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus. Data from clinical studies indicate that TAK-875, which is an ago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients. Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 Å resolution. The co-complex structure reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. The atomic details of the extensive charge network in the ligand binding pocket reveal additional interactions not identified in previous studies and contribute to a clear understanding of TAK-875 binding to the receptor. The hGPR40-TAK-875 structure also provides insights into the plausible binding of multiple ligands to the receptor, which has been observed in radioligand binding and Ca(2+) influx assay studies. Comparison of the transmembrane helix architecture with other G-protein-coupled receptors suggests that the crystallized TAK-875-bound hGPR40 complex is in an inactive-like state.

Topics: Allosteric Regulation; Benzofurans; Binding Sites; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Drug Partial Agonism; Humans; Ligands; Lipid Bilayers; Models, Molecular; Receptors, G-Protein-Coupled; Structural Homology, Protein; Sulfones; Surface Properties

Topics: Animals; Benzofurans; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Design; Drug Evaluation, Preclinical; Humans; Receptors, G-Protein-Coupled; Sulfones

The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys.

Topics: Administration, Oral; Animals; Benzofurans; Diabetes Mellitus, Type 2; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Humans; Macaca mulatta; Mice; Models, Molecular; Molecular Structure; Rats; Receptors, G-Protein-Coupled; Small Molecule Libraries; Structure-Activity Relationship; Sulfones

TAK-875, a selective GPCR40/free fatty acid receptor 1 agonist, improves glycaemic control by increasing glucose-dependent insulin secretion. Metformin is a first-line drug for treatment of type 2 diabetes that improves peripheral insulin resistance. Based on complementary mechanism of action, combining these agents is expected to enhance glycaemic control. Here, we evaluated the chronic effects of TAK-875 monotherapy and combination therapy with metformin in diabetic rats.. Long-term effects on glycaemic control and β-cell function were evaluated using Zucker diabetic fatty (ZDF) rats, which develop diabetes with hyperlipidaemia and progressive β-cell dysfunction.. Single doses of TAK-875 (3-10 mg·kg(-1) ) and metformin (50-150 mg·kg(-1) ) significantly improved both postprandial and fasting hyperglycaemia, and additive improvements were observed in their combination. Six-week treatment with TAK-875 (10 mg·kg(-1) , b.i.d.) significantly decreased glycosylated Hb (GHb) by 1.7%, and the effect was additively enhanced by combination with metformin (50 mg·kg(-1) , q.d.; GHb: -2.4%). This improvement in glycaemic control in the combination group was accompanied by significant 3.2-fold increase in fasting plasma insulin levels. Pancreatic insulin content was maintained at a level comparable to that in normal rats by combination treatment (vehicle: 26, combination: 67.1; normal lean: 69.1 ng·mg(-1) pancreas) without affecting pancreatic glucagon content. Immunohistochemical analyses revealed normal morphology, enhanced pancreas duodenum homeobox-1 expression and increased PCNA-positive cells in islets of the combination group.. Our results indicate that combination therapy with TAK-875 and metformin could be a valuable strategy for glycaemic control and β-cell preservation in type 2 diabetes.

Topics: Animals; Benzofurans; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Glucagon; Glycated Hemoglobin; Homeodomain Proteins; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Proliferating Cell Nuclear Antigen; Rats; Rats, Zucker; Receptors, G-Protein-Coupled; Sulfones; Time Factors; Trans-Activators

Selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist fasiglifam (TAK-875), an antidiabetic drug under phase 3 development, potentiates insulin secretion in a glucose-dependent manner by activating FFAR1 expressed in pancreatic β cells. Although fasiglifam significantly improved glycemic control in type 2 diabetes patients with a minimum risk of hypoglycemia in a phase 2 study, the precise mechanisms of its potent pharmacological effects are not fully understood. Here we demonstrate that fasiglifam acts as an ago-allosteric modulator with a partial agonistic activity for FFAR1. In both Ca(2+) influx and insulin secretion assays using cell lines and mouse islets, fasiglifam showed positive cooperativity with the FFAR1 ligand γ-linolenic acid (γ-LA). Augmentation of glucose-induced insulin secretion by fasiglifam, γ-LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice. In diabetic rats, the insulinotropic effect of fasiglifam was suppressed by pharmacological reduction of plasma free fatty acid (FFA) levels using a lipolysis inhibitor, suggesting that fasiglifam potentiates insulin release in conjunction with plasma FFAs in vivo. Point mutations of FFAR1 differentially affected Ca(2+) influx activities of fasiglifam and γ-LA, further indicating that these agonists may bind to distinct binding sites. Our results strongly suggest that fasiglifam is an ago-allosteric modulator of FFAR1 that exerts its effects by acting cooperatively with endogenous plasma FFAs in human patients as well as diabetic animals. These findings contribute to our understanding of fasiglifam as an attractive antidiabetic drug with a novel mechanism of action.

Topics: Allosteric Regulation; Animals; Benzofurans; Cell Line; Cricetinae; Diabetes Mellitus, Type 2; Drug Partial Agonism; Fatty Acids, Nonesterified; gamma-Linolenic Acid; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Mice; Mutation; Rats; Receptors, G-Protein-Coupled; Sulfones

The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as one of the causative factors of type 2 diabetes mellitus (T2DM). Salvia miltiorrhiza (Danshen), one of the most commonly used of traditional Chinese medicines, is often used in Compound Recipes for treating diabetes, however with unclear mechanisms. Since salvianolic acid B (SalB) is the most abundant bioactive ingredient of salvia miltiorrhiza water-extract. In this study, we tested whether SalB has any effect on the amyloidogenicity of hIAPP. Our results clearly suggest that SalB can significantly inhibit the formation of hIAPP amyloid and disaggregate hIAPP fibrils. Furthermore, photo-crosslinking based oligomerization studies suggest SalB significantly suppresses the toxic oligomerization of hIAPP monomers. Cytotoxicity protection effects on pancreatic INS-1 cells by SalB were also observed using MTT-based assays, potentially due to the inhibition on the membrane disruption effects and attenuated mitochondria impairment induced by hIAPP. These results provide evidence that SalB may further be studied on the possible pharmacological treatment for T2DM.

Topics: Amino Acid Sequence; Amyloid; Benzofurans; Cell Line; Cell Survival; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Erythrocytes; Hemolysis; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Mitochondria; Molecular Sequence Data; Protein Structure, Secondary; Salvia miltiorrhiza

Selective modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type 2 diabetes mellitus. Besides its blood pressure-lowering properties, the AT1-receptor blocker telmisartan has been shown to be a partial agonist of PPARγ with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure-activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARγ ligands with a benzimidazole (agonists 4-5 and 4-6), benzothiophene (agonists 5-5 and 5-6) or benzofuran (agonists 6-5 and 6-6) moiety either at position 5 or 6 of the benzimidazole core structure. Lipophilicity and EC50 values were improved for all new compounds compared with telmisartan. Regarding PPARγ activation, the compounds were characterized by a differentiation assay using 3T3-L1 cells and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgDEF, pGal5-TK-pGL3 and pRL-CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position 6 to position 5. Selective recruitment of the coactivators TRAP220, SRC-1 and PGC-1α, and release of corepressor NCoR1 determined by time-resolved fluorescence resonance energy transfer (TR-FRET) was detected depending on residues in position 5 or 6.

Topics: 3T3-L1 Cells; Animals; Benzimidazoles; Benzoates; Benzofurans; Chlorocebus aethiops; COS Cells; Diabetes Mellitus, Type 2; Humans; Ligands; Mice; PPAR gamma; Structure-Activity Relationship; Telmisartan; Thiophenes

The inhibition of protein tyrosine phosphatase 1B (PTP1B) is considered a valid strategy to combat insulin resistance and type II diabetes. We show here that a dichloromethane extract of Ratanhiae radix ( RR_EX) dose-dependently inhibits human recombinant PTP1B in vitro and enhances insulin-stimulated glucose uptake in murine myocytes. By determination of the PTP1B inhibiting potential of 11 recently isolated lignan derivatives from RR_EX, the observed activity of the extract could be partly assigned to ratanhiaphenol III. This compound inhibited PTP1B in vitro with an IC (50) of 20.2 µM and dose-dependently increased insulin receptor phosphorylation as well as insulin-stimulated glucose uptake in cultured myotubes. This is the first report to reveal an antidiabetic potential for a constituent of rhatany root, traditionally used against inflammatory disorders, by showing its capability of inhibiting PTP1B.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Krameriaceae; Lignans; Metabolic Syndrome; Mice; Muscle Cells; Muscle Fibers, Skeletal; Phytotherapy; Plant Preparations; Plant Roots; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics: Benzofurans; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Sulfones; Sulfonylurea Compounds

G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic β-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 μM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to β-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin; Insulin Secretion; Male; Rats; Receptors, G-Protein-Coupled; Stereoisomerism; Sulfones

Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg.

Topics: Animals; Benzofurans; Cell Line, Tumor; Chemistry Techniques, Synthetic; Diabetes Mellitus, Type 2; Female; Genes, Reporter; Humans; Hypoglycemic Agents; Models, Molecular; PPAR gamma; Protein Conformation; Rats

Inspired by recent speculation about the potential utility of α(2A)-antagonism in the treatment of type 2 diabetes, the study examined the contribution of α(2)-antagonism vs other mechanisms to the antihyperglycaemic activity of the imidazoline (±)-efaroxan.. Effects of the racemate and its pure enantiomers on isolated pancreatic islets and beta cells in vitro, as well as on hyperglycaemia in vivo, were investigated in a comparative manner in mice.. In isolated perifused islets, the two enantiomers of efaroxan were equally potent in counteracting inhibition of insulin release by the ATP-dependent K(+) (K(ATP)) channel-opener diazoxide but (+)-efaroxan, the presumptive carrier of α(2)-antagonistic activity, was by far superior in counteracting inhibition of insulin release by the α(2)-agonist UK14,304. In vivo, (+)-efaroxan improved oral glucose tolerance at 100-fold lower doses than (-)-efaroxan and, in parallel with observations made in vitro, was more effective in counteracting UK14,304-induced than diazoxide-induced hyperglycaemia. The antihyperglycaemic activity of much higher doses of (-)-efaroxan was associated with an opposing pattern (i.e. with stronger counteraction of diazoxide-induced than UK14,304-induced hyperglycaemia), which implicates a different mechanism of action.. The antihyperglycaemic potency of (±)-efaroxan in mice is almost entirely due to α(2)-antagonism, but high doses can also lower blood glucose via another mechanism. Our findings call for reappraisal of the possible clinical utility of α(2A)-antagonistic compounds in recently identified subpopulations of patients in which a congenitally higher level of α(2A)-adrenergic activation contributes to the development and pathophysiology of type 2 diabetes.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Brimonidine Tartrate; Calcium; Cells, Cultured; Diabetes Mellitus, Type 2; Diazoxide; Female; Hyperglycemia; Imidazoles; Insulin; Insulin-Secreting Cells; KATP Channels; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Quinoxalines; Yohimbine

The variable pathogenesis and progressive nature of type 2 diabetes emphasise the need for new antidiabetic treatments. The long acting glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors have improved the treatment. Novel approaches include inhibitors of sodium glucose co-transporter 2, which increase renal glucose elimination, G-protein-coupled receptor agonists, which potentiate insulin and incretin hormone secretion. Proof of principle has been shown for glucagon receptor agonists, glucokinase activators and treatment with dual intestinal peptides, which all induce weight loss and improve glucose tolerance.

Topics: Benzofurans; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dopamine Agonists; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin, Long-Acting; Peptides, Cyclic; Receptors, G-Protein-Coupled; Receptors, Glucagon; Sodium-Glucose Transporter 2 Inhibitors; Sulfones; Weight Loss

Lithospermic acid B (LAB) has been reported to protect OLETF rats, an established type 2 diabetic animal model, from the development of diabetes-related vascular complications. We investigated whether magnesium lithospermate B (LAB) has a protective role under cytokine-induced apoptosis in INS-1 cells in vitro and whether it slows the development of diabetes in OLETF rats in vivo. Pretreatment with 50 μM LAB significantly reduced the 1000 U/mL INF-γ and 100 U/mL IL-1β-induced INS-1 cell death. LAB significantly alleviated cytokine-induced phosphorylations of p38 and JNK in accordance with a decrease in cleaved caspase-3 activity in beta-cells. LAB also protected against the cytokine-induced caspase-3 apoptotic pathway via significant activation of Nrf2-HO (heme-oxygenase)-1 and Sirt1 expression. OLETF rats treated with 40 mg/kg/day LAB showed a significant improvement in glucose tolerance compared to untreated OLETF control rats in vivo. Our results suggest that the cytoprotective effects of LAB on pancreatic β-cells are related with both alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2-HO-1 and Sirt1.

Topics: Animals; Apoptosis; Benzofurans; Cells, Cultured; Cytokines; Depsides; Diabetes Mellitus, Type 2; Heme Oxygenase (Decyclizing); Insulin-Secreting Cells; Male; NF-E2-Related Factor 2; Protective Agents; Random Allocation; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Signal Transduction; Sirtuin 1

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.

Topics: Animals; Benzofurans; Blood Glucose; Calcium; Caspase 3; Caspase 7; Cell Survival; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fasting; Glucose; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Postprandial Period; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Receptors, G-Protein-Coupled; Sulfones

OP-lysine, a glycation product of lysine residues of proteins, has been reported to be formed with glyceraldehyde and glycolaldehyde as precursors in the lens, and has been suggested to play a role in senile cataracts. However, there has been no reliable information regarding the content of glyceraldehyde in tissues. This study determined the glyceraldehyde levels in the lenses of normal and diabetic rats.. Glyceraldehyde was derivatized to a fluorescent compound, and the compound was then quantified by high-performance liquid chromatography.. The lens glyceraldehyde levels in normal and diabetic rats were 0.75 +/- 0.06 and 1.26 +/- 0.21 nmol/g wet weight (means +/- standard deviations of 6 animals, p < 0.01), respectively. Isolated rat lenses accumulated a higher level of glyceraldehyde when cultured for 6 days in 25.5 mM glucose than when cultured in 5.5 mM glucose.. Glyceraldehyde was found to be present in the lens and was increased in diabetes mellitus. OP-lysine is thus likely to be a potential risk factor for senile and diabetic cataracts.

Topics: Aldehyde Reductase; Animals; Benzofurans; Blood Glucose; Cataract; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Disease Models, Animal; Glyceraldehyde; Hydantoins; Lens, Crystalline; Lysine; Male; Pyridinium Compounds; Rats; Rats, Wistar

Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal models. In the present study we investigated the effects of LAB on the prevention of diabetic nephropathy in type 2 diabetic Otsuka Long-Evans-Tokushima Fatty (OLETF) rats. LAB (20 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. Treatment of OLETF rats with LAB had little effects on body weight and blood glucose levels. Treatment with LAB resulted in significant reduction in blood pressure. LAB markedly attenuated albuminuria and significantly lowered levels of lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-beta1) expression in renal tissues of OLETF rats. In addition, LAB inhibited the progression of glomerular hypertrophy, mesangial expansion, and expansion of the extracellular matrix in the renal cortex. Collectively, these results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing blood pressure, oxidative stress, and MCP-1 expression. Our results suggest that LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes.

Topics: Administration, Oral; Aldehyde Reductase; Animals; Benzofurans; Blood Glucose; Blood Pressure; Chemokine CCL2; Depsides; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression Regulation; Male; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Salvia miltiorrhiza

A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.

Topics: Acrylates; Animals; Benzofurans; Binding Sites; Cell Line; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Haplorhini; Humans; Hypoglycemic Agents; Ligands; Lipids; Male; Mice; Models, Molecular; Radioligand Assay; Rats; Rats, Zucker; Receptors, Retinoic Acid; Retinoid X Receptors; Stereoisomerism; Structure-Activity Relationship; Transcription Factors; Transfection

The effect of alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, on the plasma glucose and insulin levels was studied in non-diabetic control, type-I (insulin-dependent) and type-II (non-insulin-dependent) diabetic rats. Pretreatment with either yohimbine or efaroxan potentiated glucose-induced insulin release in non-diabetic control rats and produced an improvement of the oral glucose tolerance and potentiated glucose-induced insulin release in type-II but not in type-I diabetic rats. Treatment with either yohimbine or efaroxan reduced the plasma glucose level and increased the plasma insulin level of non-diabetic control and type-II diabetic rats but not of type-I diabetic rats. Effects of efaroxan were more marked. Pretreatment of non-diabetic control and type-II diabetic rats with either yohimbine or efaroxan inhibited clonidine-induced hyperglycaemia and suppressed or reversed clonidine-induced hypoinsulinaemia. Also, pretreatment of these animals with either yohimbine or efaroxan enhanced the hypoglycaemic and insulinotropic effects of glibenclamide. The combination of glibenclamide and efaroxan led to a synergistic increase in insulin secretion, while that of glibenclamide and yohimbine led to an additive increase. The hyperglycaemic effect of diazoxide in non-diabetic control and type-II diabetic rats was inhibited by pretreatment with either yohimbine or efaroxan. The hypoinsulinaemic effect of diazoxide in these animals was antagonized and reversed by pretreatment with yohimbine and efaroxan, respectively. In type-I diabetic rats, there was no change in the plasma glucose and insulin levels induced by the treatment of animals with each of clonidine or diazoxide alone or in combination with either yohimbine or efaroxan. Glibenclamide produced a slight decrease in the plasma glucose level of type-I diabetic rats, at the end of the 120 min period of investigation but there was no change in the plasma insulin level. Pretreatment of these animals with either yohimbine or efaroxan produced no change in glibenclamide effects. Additionally, bath application of efaroxan or glibenclamide inhibited the relaxant effects of different concentrations of diazoxide on the isolated norepinephrine-contracted aortic strips, while the application of yohimbine produced insignificant changes. The combination of glibenclamide and efaroxan led to complete inhibition of the relaxant effects of different concentrations of diazoxide, while that of glibenclamide and

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Aorta, Thoracic; Benzofurans; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hypoglycemic Agents; Imidazoles; In Vitro Techniques; Insulin; Male; Rabbits; Rats; Rats, Wistar; Vasodilation; Yohimbine

The thiazolidinedione moiety of ciglitazone and its analogues can be replaced by an alpha-alkoxy or alpha-thioether carboxylic acid group. The influence of the nature of the R group, the length of the connector to the aromatic backbone of the molecule, and the stereochemistry have been studied. The most potent compounds have glucose-lowering activity at doses as low as 0.01 mg/kg.

Topics: 3T3 Cells; Adipocytes; Animals; Benzofurans; Carboxylic Acids; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Mice; Mice, Mutant Strains; Mice, Obese; Molecular Structure; Oxazoles; Stereoisomerism; Structure-Activity Relationship; Thiazoles; Thiazolidinediones

The effect of a single oral administration of M16209 (1-(3-bromobenzo[b]furan-2-yl-sulfonyl)hydantoin), a novel aldose reductase inhibitor, on serum glucose was investigated. In normal rats, M16209 (100 mg/kg) had a weak hypoglycemic effect but markedly stimulated the disappearance of serum glucose in intravenous glucose tolerance tests. In diabetic rats, M16209 (100 mg/kg) significantly suppressed the hyperglycemia of streptozotocin-induced, mildly diabetic rats and stimulated serum glucose disappearance in neonatally streptozotocin-induced, non-insulin-dependent diabetes mellitus (NIDDM) rats in glucose tolerance tests. Additionally, M16209 augmented insulin secretion in glucose-loaded, normal and NIDDM rats and restored the reduced serum insulin in streptozotocin-induced, mildly diabetic rats. M16209, however, showed no hypoglycemic effect in severely diabetic rats. In contrast, gliclazide, a sulfonylurea, showed a much more potent hypoglycemic effect in normal rats than in mildly diabetic rats. These results suggest that M16209 suppresses hypoglycemia through augmentation of glucose-stimulated insulin secretion. The antihyperglycemic activity of M16209, combined with its potent aldose reductase inhibiting activity, is expected to be beneficial in the treatment of diabetic complications.

Topics: Aldehyde Reductase; Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hydantoins; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Rats; Rats, Wistar; Streptozocin

We investigated the stimulatory effect of M16209 (1-(3-bromobenzo[b]furan-2-yl-sulfonyl)hydantoin), a novel aldose reductase inhibitor, on insulin secretion using isolated, perfused pancreases of rats. In the pancreases from normal rats, M16209 (100 microM) greatly augmented glucose-stimulated insulin secretion, but showed no effect on unstimulated insulin secretion at 2.8 mM glucose. In contrast, gliclazide (10 microM), a sulfonylurea, strongly enhanced both glucose-stimulated and unstimulated insulin secretion. Sorbinil and epalrestat, potent aldose reductase inhibitors, had no stimulatory effect on insulin secretion. M16209 (100 microM) improved appreciably the decreased insulin response to 22.2 mM glucose and enhanced slightly unstimulated insulin secretion in the pancreases of rats with neonatally streptozotocin-induced, non-insulin-dependent diabetes mellitus (NIDDM). Gliclazide (10 microM), however, failed to affect the pancreases of NIDDM rats. Furthermore, M16209 showed no appreciable effect on ATP-sensitive K(+)-channels in pancreatic beta-cells. These results suggest that M16209, unlike sulfonylureas, selectively enhances glucose-stimulated insulin secretion in both normal and NIDDM rats through a direct action on the pancreas. The site of action remains unknown, but the inhibition of aldose reductase or the ATP-sensitive K+ channels is unlikely to be involved.

Topics: Aldehyde Reductase; Animals; Benzofurans; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hydantoins; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Pancreas; Perfusion; Potassium Channels; Rats; Rats, Wistar; Streptozocin