RESUMEN
Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Insulina/agonistas , Secretagogos/efectos adversos , Reclamos Administrativos en el Cuidado de la Salud , Anciano , Anciano de 80 o más Años , Carbamatos/efectos adversos , Bases de Datos Factuales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Interacciones Farmacológicas , Femenino , Glipizida/efectos adversos , Gliburida/efectos adversos , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Medicaid , Metformina/efectos adversos , Persona de Mediana Edad , Nateglinida/efectos adversos , Farmacoepidemiología , Piperidinas/efectos adversos , Compuestos de Sulfonilurea/efectos adversos , Estados UnidosRESUMEN
This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long-Evans rat model. After a one-week intervention, the animals' blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.
Asunto(s)
Antioxidantes/farmacología , Combretum/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Arbutina/química , Arbutina/aislamiento & purificación , Sitios de Unión , Glucemia/efectos de los fármacos , HDL-Colesterol/agonistas , HDL-Colesterol/sangre , LDL-Colesterol/antagonistas & inhibidores , LDL-Colesterol/sangre , Biología Computacional/métodos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Flavonoides/química , Flavonoides/aislamiento & purificación , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Insulina/agonistas , Insulina/metabolismo , Masculino , Modelos Moleculares , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Extractos Vegetales/química , Hojas de la Planta/química , Unión Proteica , Conformación Proteica , Ratas , Ratas Long-Evans , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
The aim of the study was to determine the acute contribution of fuel oxidation in mediating the increase in insulin secretion rate (ISR) in response to fatty acids. Measures of mitochondrial metabolism, as reflected by oxygen consumption rate (OCR) and cytochrome c reduction, calcium signaling, and ISR by rat islets were used to evaluate processes stimulated by acute exposure to palmitic acid (PA). The contribution of mitochondrial oxidation of PA was determined in the presence and absence of a blocker of mitochondrial transport of fatty acids (etomoxir) at different glucose concentrations. Subsequent to increasing glucose from 3 to 20 mM, PA caused small increases in OCR and cytosolic calcium (about 20% of the effect of glucose). In contrast, the effect of PA on ISR was almost 3 times that by glucose, suggesting that the metabolism of PA is not the dominant mechanism mediating PA's effect on ISR. This was further supported by lack of inhibition of PA-stimulated OCR and ISR when blocking entry of PA into mitochondria (with etomoxir), and PA's lack of stimulation of reduced cytochrome c in the presence of high glucose. Consistent with the lack of metabolic stimulation by PA, an inhibitor of calcium release from the endoplasmic reticulum, but not a blocker of L-type calcium channels, abolished the PA-induced elevation of cytosolic calcium. Notably, ISR was unaffected by thapsigargin showing the dissociation of endoplasmic reticulum calcium release and second phase insulin secretion. In conclusion, stimulation of ISR by PA was mediated by mechanisms largely independent of the oxidation of the fuel.
Asunto(s)
Calcio/metabolismo , Retículo Endoplásmico/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Palmitatos/metabolismo , Animales , Retículo Endoplásmico/efectos de los fármacos , Insulina/agonistas , Islotes Pancreáticos/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxidación-Reducción/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Palmitatos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase-type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared [d-HisB24, GlyB31, TyrB32]-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of [d-HisB24, GlyB31, TyrB32]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-HisB24, GlyB31, TyrB32]-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.
Asunto(s)
Insulina/agonistas , Insulina/metabolismo , Receptor de Insulina/metabolismo , Receptores de Somatomedina/metabolismo , Secuencia de Aminoácidos , Cristalografía por Rayos X , Humanos , Factor I del Crecimiento Similar a la Insulina/química , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Cinética , Unión Proteica , Receptor IGF Tipo 1 , Receptor de Insulina/química , Receptor de Insulina/genética , Receptores de Somatomedina/química , Receptores de Somatomedina/genéticaRESUMEN
The effects of the pegylated form of glucagon-like peptide 1 (pegGLP-1) on oligopotent ß cell precursors (CD45-TER119-CD133+CD49flow) in the pancreas were studied in C57Bl/6 mice. Under conditions of streptozotocin-induced type 1 diabetes mellitus, intraperitoneal injection of pegGLP1 increased the content of ß cell precursors and dithizone-stained cells in the pancreas. ß Cell precursors of mice with diabetes demonstrated high self-maintenance potential. In contrast to pegGLP-1, native GLP-1 did not affect ß cell precursors in diabetic animals. Treatment of a culture of ß cell precursors from mice with diabetes induced the yield of dithizone-stained mononuclears. In conditioned mediums of dithizone-positive cells obtained as a result of differentiation of ß cell precursors from mice with diabetes, insulin was detected after administration of pegGLP-1 (10-7 M) and glucose (3 mmol/liter); the level of insulin increased with increasing glucose concentration (to 20 mmol/liter). The in vitro effect of pegGLP-1 did not differ from the effect of GLP-1 (10-7 M).
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Péptido 1 Similar al Glucagón/farmacología , Incretinas/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Insulina/agonistas , Polietilenglicoles/química , Animales , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Péptido 1 Similar al Glucagón/análogos & derivados , Incretinas/química , Inyecciones Intraperitoneales , Insulina/biosíntesis , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Regeneración , EstreptozocinaRESUMEN
IFNα is a cytokine essential to a vast array of immunologic processes. Its induction early in the innate immune response provides a priming mechanism that orchestrates numerous subsequent pathways in innate and adaptive immunity. Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes. In this review, we dissect the role of IFNα in T1D, focusing on the potential pathophysiological mechanisms involved. Evidence from human and mouse studies indicates that IFNα plays a key role in enhancing islet expression of HLA-I in patients with T1D, thereby increasing autoantigen presentation and beta cell activation of autoreactive cytotoxic CD8 T-lymphocytes. The binding of IFNα to its receptor induces the secretion of chemokines, attracting monocytes, T lymphocytes, and NK cells to the infected tissue triggering autoimmunity in susceptible individuals. Furthermore, IFNα impairs insulin production through the induction of endoplasmic reticulum stress as well as by impairing mitochondrial function. Due to its central role in the early phases of beta cell death, targeting IFNα and its pathways in genetically predisposed individuals may represent a potential novel therapeutic strategy in the very early stages of T1D.
Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Diabetes Mellitus Tipo 1/inmunología , Regulación de la Expresión Génica/inmunología , Células Secretoras de Insulina/inmunología , Interferón-alfa/inmunología , Receptor de Interferón alfa y beta/inmunología , Animales , Autoantígenos/inmunología , Autoinmunidad/efectos de los fármacos , Quimiocinas/genética , Quimiocinas/inmunología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Humanos , Insulina/agonistas , Insulina/biosíntesis , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/patología , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/genética , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/inmunología , Terapia Molecular Dirigida/métodos , Receptor de Interferón alfa y beta/antagonistas & inhibidores , Receptor de Interferón alfa y beta/genética , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patologíaRESUMEN
The decrement in plasma glucose concentration with SGLT2 inhibitors (SGLT2i) is blunted by a rise in endogenous glucose production (EGP). We investigated the ability of incretin treatment to offset the EGP increase. Subjects with type 2 diabetes (n = 36) were randomized to 1) canagliflozin (CANA), 2) liraglutide (LIRA), or 3) CANA plus LIRA (CANA/LIRA). EGP was measured with [3-3H]glucose with or without drugs for 360 min. In the pretreatment studies, EGP was comparable and decreased (2.2 ± 0.1 to 1.7 ± 0.2 mg/kg â min) during a 300- to 360-min period (P < 0.01). The decrement in EGP was attenuated with CANA (2.1 ± 0.1 to 1.9 ± 0.1 mg/kg â min) and CANA/LIRA (2.2 ± 0.1 to 2.0 ± 0.1 mg/kg â min), whereas with LIRA it was the same (2.4 ± 0.2 to 1.8 ± 0.2 mg/kg â min) (all P < 0.05 vs. baseline). After CANA, the fasting plasma insulin concentration decreased (18 ± 2 to 12 ± 2 µU/mL, P < 0.05), while it remained unchanged in LIRA (18 ± 2 vs. 16 ± 2 µU/mL) and CANA/LIRA (17 ± 1 vs. 15 ± 2 µU/mL). Mean plasma glucagon did not change during the pretreatment studies from 0 to 360 min, while it increased with CANA (69 ± 3 to 78 ± 2 pg/mL, P < 0.05), decreased with LIRA (93 ± 6 to 80 ± 6 pg/mL, P < 0.05), and did not change in CANA/LIRA. LIRA prevented the insulin decline and blocked the glucagon rise observed with CANA but did not inhibit the increase in EGP. Factors other than insulin and glucagon contribute to the stimulation of EGP after CANA-induced glucosuria.
Asunto(s)
Canagliflozina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Regulación hacia Abajo/efectos de los fármacos , Gluconeogénesis/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Incretinas/uso terapéutico , Liraglutida/uso terapéutico , Adulto , Canagliflozina/efectos adversos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada/efectos adversos , Femenino , Glucagón/agonistas , Glucagón/antagonistas & inhibidores , Glucagón/sangre , Glucagón/metabolismo , Células Secretoras de Glucagón/efectos de los fármacos , Células Secretoras de Glucagón/metabolismo , Humanos , Hiperglucemia/prevención & control , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Incretinas/efectos adversos , Insulina/agonistas , Insulina/sangre , Insulina/química , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Liraglutida/efectos adversos , Masculino , Moduladores del Transporte de Membrana/efectos adversos , Moduladores del Transporte de Membrana/uso terapéutico , Persona de Mediana Edad , Reproducibilidad de los Resultados , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2RESUMEN
Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent.
Asunto(s)
Hipoglucemiantes/farmacología , Insulina/metabolismo , Mioblastos/efectos de los fármacos , Fenoles/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Rhodophyta/química , Animales , Dominio Catalítico , Línea Celular Transformada , Regulación de la Expresión Génica , Glucosa/metabolismo , Glucosa/farmacología , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Enlace de Hidrógeno , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Insulina/agonistas , Resistencia a la Insulina , Ratones , Simulación del Acoplamiento Molecular , Mioblastos/metabolismo , Mioblastos/patología , Ácido Palmítico/antagonistas & inhibidores , Ácido Palmítico/farmacología , Fenoles/química , Fenoles/aislamiento & purificación , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti-diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recent addition to the anti-diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side-effect profile and their low hypoglycaemia risk. The actions of DPP-4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are known substrates, but other incretin-independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP-4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Incretinas/uso terapéutico , Modelos Biológicos , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Polipéptido Inhibidor Gástrico/agonistas , Polipéptido Inhibidor Gástrico/metabolismo , Motilidad Gastrointestinal/efectos de los fármacos , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Incretinas/efectos adversos , Incretinas/farmacología , Insulina/agonistas , Insulina/metabolismo , Secreción de Insulina , Páncreas/efectos de los fármacos , Páncreas/inervación , Páncreas/metabolismo , Proteolisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
Insulin secretagogues including sulfonylureas, glinides and incretin-related drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists are widely used for treatment of type 2 diabetes. In addition, glucokinase activators and G-protein-coupled receptor 40 (GPR40) agonists also have been developed, although the drugs are not clinically usable. These different drugs exert their effects on insulin secretion by different mechanisms. Recent advances in ß-cell signalling studies have not only deepened our understanding of insulin secretion but also revealed novel mechanisms of insulin secretagogues. Clarification of the signalling mechanisms of the insulin secretagogues will contribute to improved drug therapy for diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Drogas en Investigación/uso terapéutico , Hipoglucemiantes/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Insulina/agonistas , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/metabolismo , Drogas en Investigación/efectos adversos , Drogas en Investigación/farmacología , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Incretinas/efectos adversos , Incretinas/farmacología , Incretinas/uso terapéutico , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismoRESUMEN
Diabetes is caused by the lack of release or action of insulin. Some foods and supplements can compensate for this deficiency; thus, they can aid in the prevention or treatment of diabetes. The aim of this study was to investigate the effects of Cyclocarya paliurus extract (CPE) on insulin signaling and its capacity to correct hyperglycemia in the absence of insulin. To investigate the hypoglycemic effects of CPE, C2C12 cells were exposed to CPE (50 and 100 µg/mL). CPE promoted 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2NBDG) uptake into the cells via translocation of glucose transporter 4 (Glut4) to the plasma membrane. In addition, CPE enhanced tyrosine phosphorylation of insulin receptor substrate and activated phosphatidylinositol 3-kinase and protein kinase B (Akt) via sirtuin1 in C2C12 cells. Moreover, we found that oral administration of CPE (1 g/kg) to streptozotocin-induced hyperglycemic mice produced a progressive decrease in plasma glucose levels at 1 h after single dosing. At that point, CPE significantly increased the expression of skeletal muscle membrane Glut4 and enhanced the phosphorylation of Akt. These results suggest that CPE exerts antidiabetic effects similar to those of insulin, and may be an oral therapeutic alternative for the management of diabetes.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Fagaceae/química , Hipoglucemiantes/farmacología , Insulina/agonistas , Transducción de Señal/efectos de los fármacos , Sirtuina 1/genética , 4-Cloro-7-nitrobenzofurazano/análogos & derivados , 4-Cloro-7-nitrobenzofurazano/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular , Desoxiglucosa/análogos & derivados , Desoxiglucosa/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Medicamentos Herbarios Chinos/aislamiento & purificación , Regulación de la Expresión Génica , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Hipoglucemiantes/aislamiento & purificación , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Fosforilación/efectos de los fármacos , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirtuina 1/metabolismoRESUMEN
STUDY QUESTION: Are bisphenol A (BPA) and BPA analogs (BPA-A) safe for male human reproductive function? SUMMARY ANSWER: The endocrine function of human testes explants [assessed by measuring testosterone and insulin-like factor 3 (INSL3)] was impacted by exposure of the human adult testis explants to BPA/BPA-A. WHAT IS KNOWN ALREADY: The few epidemiologic studies performed suggest that bisphenols have potential endocrine disruptive properties, but they did not identify clear and direct patterns of endocrine disruption. STUDY DESIGN, SIZE, DURATION: Adult human testis explants in culture were exposed to BPA and the analogs bisphenol F (BPF), bisphenol S (BPS), bisphenol E (BPE), bisphenol B (BPB) and bisphenol A diglycidyl ether (BADGE) at 10-9-10-5 M for 24 or 48 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human adult testes were obtained from prostate cancer patients who had no hormone therapy, or from multiorgan donors. After ex vivo exposure to the investigated bisphenols, the measured outcomes were related to histopathology (gross morphology and germ cell viability determined by anti-caspase three immunohistochemistry), and the levels of testosterone, INSL3 and inhibin B were measured using immunoassays. The levels of mRNA encoding key enzymes of bisphenol biotransformation were investigated by quantitative PCR: UGT2B15 UDP (glucuronosyltransferase two family, polypeptide B15), GUSB (glucuronidase beta), SULT1A1 and 3 (sulfotransferase family 1 A member 1 and 3) and STS (steroid sulfatase). MAIN RESULTS AND THE ROLE OF CHANCE: A significant dose-dependent inhibition was found between testosterone levels measured in the culture medium and concentrations of BPA (P = 0.00778 at 24 h and P = 0.0291 at 48 h), BPE (P = 0.039) and BPF (P = 0.00663). The observed BPA and BPA-A-induced inhibition of testosterone production varied according to duration of exposure and BPA/BPA-A concentrations. BPA (10-9 M; P < 0.05), BPB (10-9 M; P < 0.05), BPS (10-9 and 10-8 M; P < 0.05) and BADGE (10-5 M; P < 0.05) increased Leydig cell INSL3 production. By contrast, BPE dose dependently inhibited INSL3 (P = 0.0372). Conversely, Sertoli cell function (inhibin B) and germ cell viability were not significantly affected by either bisphenols. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Environmental compounds cannot be deliberately administered to men, justifying the use of an ex vivo approach. A relatively low number of testes samples were available for analysis (n = 3, except for testosterone secretion with n = 5). The active concentrations of BPA and BPA-A used in the study were higher than those found in human biological fluids. WIDER IMPLICATIONS OF THE FINDINGS: Under our experimental conditions, direct exposure to BPA or BPA-A can result in endocrine disturbance in the adult human testis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Inserm (Institut National de la Santé et de la Recherche Médicale), EHESP-School of Public Health, University of Rennes1, by grants from the Agence Nationale de la Recherche (ANR; grant#ANR-13-CESA-0012-03 NEWPLAST) and Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES; grant#EST-2010/2/046 (BPATESTIS)). All authors declare they have no current or potential competing financial interests.
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Compuestos de Bencidrilo/toxicidad , Disruptores Endocrinos/toxicidad , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Insulina/agonistas , Antiandrógenos no Esteroides/toxicidad , Fenoles/toxicidad , Proteínas/agonistas , Testículo/efectos de los fármacos , Testosterona/antagonistas & inhibidores , Adulto , Apoptosis/efectos de los fármacos , Arilsulfotransferasa/genética , Arilsulfotransferasa/metabolismo , Compuestos de Bencidrilo/química , Disruptores Endocrinos/química , Compuestos Epoxi/toxicidad , Glucuronidasa/genética , Glucuronidasa/metabolismo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Insulina/metabolismo , Células Intersticiales del Testículo/citología , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Masculino , Antiandrógenos no Esteroides/química , Fenoles/química , Proteínas/antagonistas & inhibidores , Proteínas/metabolismo , Reproducibilidad de los Resultados , Células de Sertoli/citología , Células de Sertoli/efectos de los fármacos , Células de Sertoli/metabolismo , Esteril-Sulfatasa/genética , Esteril-Sulfatasa/metabolismo , Sulfonas/toxicidad , Testículo/citología , Testículo/metabolismo , Testosterona/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
Protein hydrolysates (PH) are rich sources of proteins that supply the need of exercising muscles. PHs are enriched in di- and tripeptides and are better than free amino acids or intact proteins when muscle anabolic effect is considered. Digestion, absorption and muscle uptake of amino acids are faster and more efficient when PH is ingested in comparison to the respective intact protein. PHs not only enhance endurance in high intensity exercise regimen, but also help in faster post-exercise recovery of muscle by promoting glycogen synthesis, although the latter effect requires more convincing evidence. PHs have been shown to exhibit insulinotrophic effect as it enhances the secretion of insulin and the hormone, in turn, exerts muscle anabolic effect.
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Proteínas en la Dieta/administración & dosificación , Resistencia Física/efectos de los fármacos , Hidrolisados de Proteína/administración & dosificación , Ciencias de la Nutrición y del Deporte , Aminoácidos/metabolismo , Transporte Biológico , Proteínas en la Dieta/metabolismo , Ejercicio Físico , Glucógeno/biosíntesis , Humanos , Insulina/agonistas , Insulina/metabolismo , Secreción de Insulina , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Resistencia Física/fisiología , Hidrolisados de Proteína/metabolismo , Deportes/fisiologíaRESUMEN
AIMS: 55P0251 is a novel compound with blood glucose lowering activity in mice, which has been developed from a molecular backbone structure found in herbal remedies. We here report its basic pharmacological attributes and initial progress in unmasking the mode of action. MATERIALS AND METHODS: Pharmacokinetic properties of 55P0251 were portrayed in several species. First efforts to elucidate the glucose lowering mechanism in rodents included numerous experimental protocols dealing with glucose tolerance, insulin secretion from isolated pancreatic islets and comparison to established drugs. RESULTS: A single oral dose of 55P0251 improved glucose tolerance in mice with an ED50 between 1.5 and 2 mg/kg (reductions in areas under the curve, 1 mg/kg, -18%; 5 mg/kg, -30%; 27 mg/kg, -47%). Pharmacokinetic studies revealed attractive attributes, including a plasma half-life of approximately 3 hours and a bioavailability of approximately 58% in rats. 55P0251 amplified glucose stimulated insulin release from isolated mouse islets and improved glucose tolerance via increased insulin secretion in rats (increase in area under the insulin curve, +184%). Unlike sulfonylureas and glinides, 55P0251 hardly stimulated insulin release under basal conditions and did not induce hypoglycaemia in vivo, but it amplified the secretory response to glucose and other insulinotropic stimuli (KCl, glucagon-like peptide-1). Comparison to established anti-diabetic agents and examination of interaction with molecular targets (KATP channel, dipeptidyl peptidase-4, glucagon-like peptide-1 receptor) excluded molecular mechanisms addressed by presently marketed drugs. CONCLUSIONS: 55P0251 is a novel compound that potently counteracts hyperglycaemia in rodents via amplification of glucose-stimulated insulin release.
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Alcaloides/uso terapéutico , Drogas en Investigación/uso terapéutico , Intolerancia a la Glucosa/tratamiento farmacológico , Hiperglucemia/prevención & control , Incretinas/uso terapéutico , Administración Oral , Alcaloides/administración & dosificación , Alcaloides/farmacocinética , Alcaloides/farmacología , Animales , Disponibilidad Biológica , Glucemia/análisis , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Drogas en Investigación/administración & dosificación , Drogas en Investigación/farmacocinética , Drogas en Investigación/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/metabolismo , Semivida , Hipoglucemiantes/farmacología , Incretinas/administración & dosificación , Incretinas/farmacocinética , Incretinas/farmacología , Insulina/agonistas , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Canales KATP/antagonistas & inhibidores , Canales KATP/metabolismo , Masculino , Tasa de Depuración Metabólica , Ratones Endogámicos C57BL , Ratas Sprague-DawleyRESUMEN
Omega-3 fatty acids have multiple effects in peripheral tissues and pancreatic beta cell function. Dietary depletion of omega-3 fatty acids is associated with pancreatic islet dysfunction and insulin resistance in rats. Herein, the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on pancreatic beta cell redox state and function were investigated. INS-1E insulin-secreting cells were incubated with EPA and DHA in combination with palmitic acid, and productions of reactive oxygen species (ROS), nitric oxide (NO) and insulin were measured. The involvement of the NADPH oxidase complex in ROS production and expression of the antioxidant enzymes was also investigated. After incubation for 1 or 48 h, productions of superoxide (by hydroethidine method), nitric oxide (by 4,5-diaminofluorescein diacetate-DAF-2DA assay), insulin (by radioimmunoassay), and expressions (by western blot analysis) of glutathione peroxidase (GPx-1) and gp91PHOX were measured. EPA and DHA reduced superoxide production after 1-h incubation. After 48 h, palmitic acid reduced superoxide production that was normalized by EPA treatment. Palmitic acid increased NO production that was reverted by EPA and DHA. Palmitic acid increased insulin secretion after 48 h, whereas both omega-3 fatty acids increased intracellular insulin content. EPA and DHA enhanced GPx-1 expression as well as gp91PHOX glycosylated form. In conclusion, EPA and DHA increased intracellular insulin content and antioxidant enzymatic defense capacity and decreased pro-oxidant generating activities that are associated with maintenance of pancreatic beta cell redox state in response to palmitic acid.
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Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Insulina/biosíntesis , Óxido Nítrico/metabolismo , Superóxidos/metabolismo , Animales , Línea Celular , Regulación de la Expresión Génica , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Insulina/agonistas , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Ácido Palmítico/antagonistas & inhibidores , Ácido Palmítico/farmacología , Ratas , Transducción de Señal , Superóxidos/antagonistas & inhibidores , Glutatión Peroxidasa GPX1RESUMEN
Diabetes has been cited as the most challenging health problem in the twenty-first century. Accordingly, it is urgent to develop a new type of efficient and low-toxic antidiabetic medication. Since vanadium compounds have insulin-mimetic and potential hypoglycemic activities for type 1 and type 2 diabetes, a new trend has been developed using vanadium and organic ligands to form a new compound in order to increase the intestinal absorption and reduce the toxicity of vanadium compound. In the current investigation, a new organic vanadium compounds, vanadyl rosiglitazone, was synthesized and determined by infrared spectra. Vanadyl rosiglitazone and three other organic vanadium compounds were administered to the diabetic mice through oral administration for 5 weeks. The results of mouse model test indicated that vanadyl rosiglitazone could regulate the blood glucose level and relieve the symptoms of polydipsia, polyphagia, polyuria, and weight loss without side effects and was more effective than the other three organic vanadium compounds including vanadyl trehalose, vanadyl metformin, and vanadyl quercetin. The study indicated that vanadyl rosiglitazone presents insulin-mimetic activities, and it will be a good potential candidate for the development of a new type of oral drug for type 2 diabetes.
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Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Homeostasis , Insulina/agonistas , Tiazolidinedionas/uso terapéutico , Vanadio/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Homeostasis/efectos de los fármacos , Masculino , Metformina/farmacología , Metformina/uso terapéutico , Ratones , Quercetina/farmacología , Quercetina/uso terapéutico , Rosiglitazona , Espectrofotometría Infrarroja , Tiazolidinedionas/farmacología , Trehalosa/farmacología , Trehalosa/uso terapéutico , Vanadio/farmacologíaRESUMEN
GPR142 is an islet-enriched G protein-coupled receptor that has been investigated as a novel therapeutic target for the treatment of type 2 diabetes by virtue of its insulin secretagogue activity. However, the signaling pathways downstream of GPR142 and whether its stimulation of insulin release is glucose-dependent remain poorly characterized. In this study, we show that both native and synthetic GPR142 agonists can activate Gq as well as Gi signaling when GPR142 is recombinantly expressed in HEK293 cells. However, in primary pancreatic islets, a native cellular system, the insulin secretagogue activity of GPR142 agonists only requires Gq activation. In addition, our results show that stimulation of insulin secretion by GPR142 in pancreatic islets is strictly glucose-dependent.
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Aminopiridinas/farmacología , Glucosa/farmacología , Insulina/agonistas , Subunidades de Proteína/agonistas , Pirazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Triptófano/farmacología , Animales , Colforsina/farmacología , AMP Cíclico/metabolismo , Regulación de la Expresión Génica , Glucosa/metabolismo , Células HEK293 , Humanos , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Cultivo Primario de Células , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Discovery of common pathways that mediate both pancreatic ß-cell function and end-organ function offers the opportunity to develop therapies that modulate glucose homeostasis and separately slow the development of diabetes complications. Here, we investigated the in vitro and in vivo effects of pharmacological agonism of the prostaglandin I2 (IP) receptor in pancreatic ß-cells and in glomerular podocytes. The IP receptor agonist MRE-269 increased intracellular 3',5'-cyclic adenosine monophosphate (cAMP), augmented glucose-stimulated insulin secretion (GSIS), and increased viability in MIN6 ß-cells. Its prodrug form, selexipag, augmented GSIS and preserved islet ß-cell mass in diabetic mice. Determining that this preservation of ß-cell function is mediated through cAMP/protein kinase A (PKA)/nephrin-dependent pathways, we found that PKA inhibition, nephrin knockdown, or targeted mutation of phosphorylated nephrin tyrosine residues 1176 and 1193 abrogated the actions of MRE-269 in MIN6 cells. Because nephrin is important to glomerular permselectivity, we next set out to determine whether IP receptor agonism similarly affects nephrin phosphorylation in podocytes. Expression of the IP receptor in podocytes was confirmed in cultured cells by immunoblotting and quantitative real-time PCR and in mouse kidneys by immunogold electron microscopy, and its agonism 1) increased cAMP, 2) activated PKA, 3) phosphorylated nephrin, and 4) attenuated albumin transcytosis. Finally, treatment of diabetic endothelial nitric oxide synthase knockout mice with selexipag augmented renal nephrin phosphorylation and attenuated albuminuria development independently of glucose change. Collectively, these observations describe a pharmacological strategy that posttranslationally modifies nephrin and the effects of this strategy in the pancreas and in the kidney.
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Nefropatías Diabéticas/prevención & control , Células Secretoras de Insulina/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Podocitos/efectos de los fármacos , Receptores de Epoprostenol/agonistas , Acetamidas/uso terapéutico , Acetatos/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/agonistas , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Fosforilación/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Podocitos/ultraestructura , Profármacos/uso terapéutico , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirazinas/farmacología , Pirazinas/uso terapéutico , Interferencia de ARN , Receptores de Epoprostenol/genética , Receptores de Epoprostenol/metabolismo , Insuficiencia Renal/complicaciones , Insuficiencia Renal/metabolismo , Insuficiencia Renal/patología , Insuficiencia Renal/prevención & controlRESUMEN
Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hormone after ghrelin. As we have previously reported, INSL5 is extremely difficult to assemble and oxidize into its two-chain three-disulfide structure. The focus of this study was to generate structure-activity relationships (SARs) of INSL5 and use it to develop a potent and simpler INSL5 mimetic with RXFP4 agonist activity. A series of human and mouse INSL5 (hINSL5/mINSL5) analogues were designed and chemically synthesized, resulting in a chimeric INSL5 analogue exhibiting more than 10-fold higher potency (0.35 nM) at human RXFP4 compared with native hINSL5 (4.57 nM). The SAR study also identified a key residue (K(A15)) in the A-chain of mINSL5 that contributes to improved RXFP4 affinity and potency of mINSL5 compared with hINSL5. This knowledge ultimately led us to engineer a minimized hINSL5 mimetic agonist that retains native hINSL5-like RXFP4 affinity and potency at human RXFP4. This minimized analogue was synthesized in 17.5-fold higher yield and in less time compared with hINSL5.
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Insulina/agonistas , Péptidos/farmacología , Ingeniería de Proteínas , Proteínas/agonistas , Animales , Células CHO , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Péptidos/síntesis química , Péptidos/química , Relación Estructura-ActividadRESUMEN
Determination of response of cortisol and its metabolites to different stimuli may be important for adrenal gland disorders. To date, only one metabolite, cortisone, has been followed in stimulation tests of the adrenal gland. We aimed to describe a response of cortisol metabolites to the standard short Synacthen test (HDST), insulin tolerance test (ITT), low dose Synacthen test (LDST) and medium dose Synacthen test (MDST). Sixty healthy subjects were investigated: 30 men and 30 women. Plasma for measurements of cortisol and its metabolites was obtained before and 30th and 60th min after Synacthen and insulin administration. The cut-off 500 nmol/l of cortisol was reached after stimulation in all of tests, the maximal stimulation level was reached in 60th min in all of the tests except for LDST. The response of cortisol and its metabolites at 30th and 60th min strongly correlated in all of the tests except for LDST. Cortisol and its metabolites increased after stimulation; in contrast, cortisone and its metabolites decreased. We showed that the response of the cortisol metabolites during the Synacthen tests and ITT well correlated, and the MDST showed similar response compared to HDST. The decrease in cortisone metabolites may correspond to the regeneration of cortisol from cortisone in response to stimulation test.