Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32.231
Filtrar
1.
Int J Nanomedicine ; 16: 297-314, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33488074

RESUMEN

The glucose-sensitive self-adjusting drug delivery system simulates the physiological model of the human pancreas-secreting insulin and then precisely regulates the release of hypoglycemic drugs and controls the blood sugar. Thus, it has good application prospects in the treatment of diabetes. Presently, there are three glucose-sensitive drug systems: phenylboronic acid (PBA) and its derivatives, concanavalin A (Con A), and glucose oxidase (GOD). Among these, the glucose-sensitive polymer carrier based on PBA has the advantages of better stability, long-term storage, and reversible glucose response, and the loading of insulin in it can achieve the controlled release of drugs in the human environment. Therefore, it has become a research hotspot in recent years and has been developed very rapidly. In order to further carry out a follow-up study, we focused on the development process, performance, and application of PBA and its derivatives-based glucose-sensitive polymer drug carriers, and the prospects for the development of this field.


Asunto(s)
Ácidos Borónicos/química , Diabetes Mellitus/tratamiento farmacológico , Portadores de Fármacos/química , Hipoglucemiantes/farmacología , Ácidos Borónicos/metabolismo , Diabetes Mellitus/metabolismo , Portadores de Fármacos/metabolismo , Estudios de Seguimiento , Glucosa/metabolismo , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Insulina/química , Insulina/farmacología , Insulina/uso terapéutico
2.
BMJ Open ; 10(9): e040644, 2020 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-32928868

RESUMEN

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.


Asunto(s)
Antagonistas de Receptores de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Infecciones por Coronavirus , Estrógenos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipoglucemiantes/farmacología , Pandemias , Peptidil-Dipeptidasa A/efectos de los fármacos , Neumonía Viral , Antiinflamatorios no Esteroideos/farmacología , Betacoronavirus/metabolismo , Regulación hacia Abajo , Péptido 1 Similar al Glucagón/agonistas , Humanos , Insulina/farmacología , Antagonistas de Receptores de Mineralocorticoides/farmacología , Peptidil-Dipeptidasa A/metabolismo , Tiazolidinedionas/farmacología , Reino Unido , Regulación hacia Arriba
3.
Diabetes Res Clin Pract ; 167: 108356, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32745695

RESUMEN

AIMS: Implementation of insulin therapy among those with diabetes is often suboptimal as a result of non-adherence or non-persistence. Studies regarding factors leading to insulin nonpersistence are limited. Therefore, we conducted this retrospective cohort study to determine the factors affecting insulin nonpersistence. METHODS: A total of 274,852 persons with type 2 diabetes mellitus under insulin therapy during the period 2000-2014 were enrolled. Persons who stopped insulin therapy for >90 days were defined as having insulin nonpersistence. We searched for factors associated with insulin nonpersistence during the long-term follow-up period. RESULTS: According to the multiple Cox regression model with a mean follow-up of 13.9 years, the factors associated with higher risk of insulin nonpersistence were age <40 years, men, residing in a rural area, Charlson comorbidity index score = 4, use of two or more oral antidiabetic drugs, and hypoglycemia during follow-up. The Kaplan-Meier graph showed that patients aged <40 years had significantly less insulin persistence. CONCLUSIONS: This nationwide cohort study indicated that persons with young-onset type 2 diabetes, less medical resources, and more comorbidities are at risk of insulin nonpersistence. Healthcare providers should regularly assess insulin persistence and help patients who are having difficulty with insulin-taking.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
4.
Diabetes Res Clin Pract ; 167: 108359, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32745699

RESUMEN

AIMS: Insulin resistance in people with type 1 diabetes (T1D) is associated with increased risk of chronic complications and death. The gold standard to quantify insulin sensitivity, a euglycaemic hyperinsulinaemic clamp, is not applicable to clinical practice. We have employed clamp studies to develop a panel of formulae to estimate insulin sensitivity in adults with T1D for use in clinical practice and trials. METHODS: Clamps were conducted in 28 adults with T1D, who were also characterised with 38 clinical and research biomarkers. Exhaustive search analysis was used to derive equations correlating with clamp-quantified glucose disposal rate (GDR), GDR/plasma insulin (M/I) and log10M/I. RESULTS: Measured insulin sensitivity correlated with BMI, WHR, HDL-C, adipokines and inflammation markers on univariate analysis. Exhaustive search analysis derived three formulae correlating with clamp-derived GDR and logM/I (p < 0.0001), accounting for ≈62% of their variability. A formula using gender, age, HDL-C, pulse pressure and WHR performed as well as those containing inflammation and adipokine measures. CONCLUSIONS: The performance of formulae using routinely available parameters with/without research biomarkers in clinical studies and trials, particularly related to future complications, relevant lifestyle interventions, insulin delivery modes and insulin sensitisers is merited.


Asunto(s)
Biomarcadores/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Técnica de Clampeo de la Glucosa/métodos , Resistencia a la Insulina/fisiología , Insulina/uso terapéutico , Adulto , Femenino , Humanos , Insulina/farmacología , Masculino , Persona de Mediana Edad , Adulto Joven
5.
Medicine (Baltimore) ; 99(34): e21821, 2020 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-32846824

RESUMEN

BACKGROUND: Traditional Chinese medicine Tongxinluo (TXL) has been widely used to treat coronary artery disease in China, since it could reduce myocardial infarct size and ischemia/reperfusion injury in both non-diabetic and diabetic conditions. It has been shown that TXL could regulate peroxisome proliferator activated receptor-α (PPAR-α), a positive modulator of angiopoietin-like 4 (Angptl4), in diabetic rats. Endothelial junction substructure components, such as VE-cadherin, are involved in the protection of reperfusion injury. Thus, we hypothesized cell-intrinsic and endothelial-specific Angptl4 mediated the protection of TXL on endothelial barrier under high glucose condition against ischemia/reperfusion-injury via PPAR-α pathway. METHODS: Incubated with high glucose medium, the human cardiac microvascular endothelial cells (HCMECs) were then exposed to oxygen-glucose-serum deprivation (2 hours) and restoration (2 hours) stimulation, with or without TXL, insulin, or rhAngptl4 pretreatment. RESULTS: TXL, insulin, and rhAngptl4 had similar protective effects on the endothelial barrier. TXL treatment reversed the endothelial barrier breakdown in HCMECs significantly as identified by decreasing endothelial permeability, upregulating the expression of JAM-A, VE-cadherin, and integrin-α5 and increasing the membrane location of VE-cadherin and integrin-α5, and these effects of TXL were as effective as insulin and rhAngptl4. However, Angptl4 knock-down with small interfering RNA (siRNA) interference and PPAR-α inhibitor MK886 partially abrogated these beneficial effects of TXL. Western blotting also revealed that similar with insulin, TXL upregulated the expression of Angptl4 in HCMECs, which could be inhibited by Angptl4 siRNA or MK886 exposure. TXL treatment increased PPAR-α activity, which could be diminished by MK886 but not by Angptl4 siRNA. CONCLUSION: These data suggest cell-intrinsic and endothelial-specific Angptl4 mediates the protection of TXL against endothelial barrier breakdown during oxygen-glucose-serum deprivation and restoration under high glucose condition partly via the PPAR-α/Angptl4 pathway.


Asunto(s)
Proteína 4 Similar a la Angiopoyetina/metabolismo , Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/efectos de los fármacos , Endotelio/efectos de los fármacos , Endotelio/fisiopatología , PPAR alfa/metabolismo , Proteína 4 Similar a la Angiopoyetina/genética , Proteína 4 Similar a la Angiopoyetina/farmacología , Cadherinas/metabolismo , Permeabilidad Capilar , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Vasos Coronarios/citología , Técnicas de Silenciamiento del Gen , Glucosa/metabolismo , Glucosa/farmacología , Humanos , Indoles/farmacología , Insulina/farmacología , Integrina alfa5/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Microvasos/citología , Oxígeno/metabolismo , Oxígeno/farmacología , Receptores de Superficie Celular/metabolismo , Daño por Reperfusión/metabolismo , Transducción de Señal
6.
Am J Pathol ; 190(11): 2237-2250, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32858016

RESUMEN

The insulin and Wnt signaling pathways are involved in cell proliferation, tissue homeostasis, and tumorigenesis. However, their interrelationship in the pathophysiological process of diabetic corneal injury remains unclear. In this study, the role of insulin in the diabetic cornea was investigated in vitro, using cultured TKE2 cells and trigeminal ganglion neurons, and in vivo, by assessing corneal wound-healing responses in diabetic mice. A selective Wnt antagonist (XAV-939) and activator (BML-284) were used to regulate the interactions between insulin and the Wnt pathway. The results demonstrated that insulin promoted corneal epithelial wound healing and sensation recovery, whereas the expression of molecules involved in the Wnt/ß-catenin pathway was also up-regulated in the injured corneal epithelium. However, XAV-939 limited the insulin-induced epithelial and corneal nerve repair. By contrast, BML-284 treatment promoted the healing of the corneal epithelium and corneal nerve repair in diabetic mice. These results indicate that insulin, via Wnt signaling, contributes to diabetic corneal epithelial wound healing and nerve injury recovery and is, therefore, a potential protective factor for diabetic corneal epithelial wounds and nerve injury.


Asunto(s)
Lesiones de la Cornea , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Insulina/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Córnea/metabolismo , Córnea/patología , Lesiones de la Cornea/tratamiento farmacológico , Lesiones de la Cornea/metabolismo , Lesiones de la Cornea/patología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Masculino , Ratones
8.
PLoS One ; 15(8): e0231806, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32817622

RESUMEN

The cAMP-dependent protein kinase (PKA) signaling pathway is the primary means by which the heart regulates moment-to-moment changes in contractility and metabolism. We have previously found that PKA signaling is dysfunctional in the diabetic heart, yet the underlying mechanisms are not fully understood. The objective of this study was to determine if decreased insulin signaling contributes to a dysfunctional PKA response. To do so, we isolated adult cardiomyocytes (ACMs) from wild type and Akita type 1 diabetic mice. ACMs were cultured in the presence or absence of insulin and PKA signaling was visualized by immunofluorescence microscopy using an antibody that recognizes proteins specifically phosphorylated by PKA. We found significant decreases in proteins phosphorylated by PKA in wild type ACMs cultured in the absence of insulin. PKA substrate phosphorylation was decreased in Akita ACMs, as compared to wild type, and unresponsive to the effects of insulin. The decrease in PKA signaling was observed regardless of whether the kinase was stimulated with a beta-agonist, a cell-permeable cAMP analog, or with phosphodiesterase inhibitors. PKA content was unaffected, suggesting that the decrease in PKA signaling may be occurring by the loss of specific PKA substrates. Phospho-specific antibodies were used to discern which potential substrates may be sensitive to the loss of insulin. Contractile proteins were phosphorylated similarly in wild type and Akita ACMs regardless of insulin. However, phosphorylation of the glycolytic regulator, PFK-2, was significantly decreased in an insulin-dependent manner in wild type ACMs and in an insulin-independent manner in Akita ACMs. These results demonstrate a defect in PKA activation in the diabetic heart, mediated in part by deficient insulin signaling, that results in an abnormal activation of a primary metabolic regulator.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Diabetes Mellitus/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Insulina/metabolismo , Insulina/farmacología , Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/fisiología , Inhibidores de Fosfodiesterasa/farmacología , Fosforilación/efectos de los fármacos , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos
9.
Acta Cir Bras ; 35(7): e202000704, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32813772

RESUMEN

Purpose Given the high prevalence of diabetes (D), several animal models have been analyzed. In the literature, most of the animal models have studied severe D. However, in clinical practice, most patients have moderate disease. Therefore, the present study aimed to describe a moderate D condition. Methods We analyzed 20 Wistar rats, age eight-weeks, weight between 200g-250g. All animals received an intravenous injection of Streptozotocin (55mg/kg weight). On the 15th day after D induction, the animals were divided into two groups: Group I - animals receiving a single daily dose of fast-acting insulin (FAIG) NPH (1UI,SC) for partial glycemic control, and Group II - animals receiving slow-acting insulin(SAIG) twice a week. We measured glycemia, weight, and adverse events every week during two months. Results Of the total of animals analyzed in the study, three animals died in the FAIG and two animals died in the SAIG. Regarding the glycemic level, results were 339.5 ± 125.4mg/dL (95CI 302.3402 to 376.6842) in the FAIG, and 367.8 ± 66.1mg/dL (95IC 333.7607 to 401.8978) in the SAIG. There was no difference between groups as to weight during the study. Conclusion The use of slow-acting-insulin is not inferior to the use of fast-acting-insulin in the management of partially insulin-controlled moderate diabetes in rats.


Asunto(s)
Diabetes Mellitus , Insulina/farmacología , Animales , Glucemia , Hemoglobina A Glucada , Hipoglucemiantes , Ratas , Ratas Wistar
10.
Lancet Neurol ; 19(9): 758-766, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32730766

RESUMEN

Insulin is a peptide secreted by the pancreas and plays an important role in the regulation of glucose metabolism in peripheral tissues. Although the role of insulin in the periphery is well understood, less is known about its multifactorial role in the brain. However, emerging evidence from human and animal studies indicate that insulin influences cerebral bioenergetics, enhances synaptic viability and dendritic spine formation, and increases turnover of neurotransmitters, such as dopamine. Insulin also has a role in proteostasis, influencing clearance of the amyloid ß peptide and phosphorylation of tau, which are hallmarks of Alzheimer's disease. Insulin also modulates vascular function through effects on vasoreactivity, lipid metabolism, and inflammation. Through these multiple pathways, insulin dysregulation could contribute to neurodegeneration. Thus, new approaches to restore cerebral insulin function that could offer therapeutic benefit to adults with Alzheimer's disease, vascular cognitive impairment, or related disorders are being investigated.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Encéfalo/metabolismo , Resistencia a la Insulina/fisiología , Conducta de Reducción del Riesgo , Animales , Encéfalo/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Humanos , Insulina/farmacología , Insulina/uso terapéutico
12.
Am J Physiol Heart Circ Physiol ; 319(1): H162-H170, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32502373

RESUMEN

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.


Asunto(s)
Presión Sanguínea , Gasto Cardíaco , Hiperinsulinismo/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Vasodilatación , Adrenérgicos/farmacología , Adulto , Animales , Arterias/efectos de los fármacos , Arterias/fisiología , Femenino , Humanos , Insulina/administración & dosificación , Insulina/farmacología , Pierna/irrigación sanguínea , Masculino , Ratones , Ratones Endogámicos C57BL , Flujo Sanguíneo Regional
13.
Nat Struct Mol Biol ; 27(7): 615-624, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32483339

RESUMEN

Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins-a human des-octapeptide insulin analog-as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24-PheB25-TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.


Asunto(s)
Antígenos CD/química , Insulina/química , Venenos de Moluscos/química , Venenos de Moluscos/metabolismo , Receptor de Insulina/química , Sustitución de Aminoácidos , Animales , Antígenos CD/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Insulina/análogos & derivados , Insulina/metabolismo , Insulina/farmacología , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación de Dinámica Molecular , Venenos de Moluscos/genética , Venenos de Moluscos/farmacología , Péptidos/química , Péptidos/genética , Péptidos/metabolismo , Conformación Proteica , Ratas Sprague-Dawley , Receptor de Insulina/metabolismo , Relación Estructura-Actividad , Tirosina
14.
Gene ; 754: 144903, 2020 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-32540374

RESUMEN

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among reproductive-age women. The circRNA-miRNA axis functions in various diseases progression have been partially revealed in the past two decades. However, little is known about the role of the circRNA-miRNA axis in PCOS progression. MicroRNA miR-760, which is characterized by tissue-specific, has been studied in several cancers. Firstly, we found that miR-760 expression was decreased in PCOS tissues insulin treated GCs, KGN and SVOG cells. Secondly, The CCK-8 and apoptosis experiment results suggested that downregulated miR-760 promoted cell proliferation ability and suppressed apoptosis activity in KGN and SVOG cells. Then, the bioinformatic analysis result indicated that circPUM1 was a potential sponge to miR-760. By performing AGO2-RIP, RNA pull-down, Luciferase reporter, and qRT-PCR experiments, we demonstrated that circPUM1 acted as a molecular sponge to miR-760, and decreased miR-760 expression. Moreover, it was found that the promotive effect of circPUM1 was mediated by regulating miR-760. Collectively, our findings suggest that circPUM1 promotes PCOS progression through sponging to miR-760. We may provide a promising therapeutic target for PCOS.


Asunto(s)
Regulación de la Expresión Génica , Células de la Granulosa/patología , MicroARNs/genética , Síndrome del Ovario Poliquístico/patología , ARN Circular/genética , Apoptosis , Proliferación Celular , Células Cultivadas , Progresión de la Enfermedad , Femenino , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insulina/farmacología , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo
15.
Nat Commun ; 11(1): 2186, 2020 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-32367034

RESUMEN

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/ß or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.


Asunto(s)
Calcio/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Homeostasis , Resistencia a la Insulina , Proteínas Musculares/metabolismo , Quinasa de Cadena Ligera de Miosina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Cardiomiopatías Diabéticas/genética , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Insulina/metabolismo , Insulina/farmacología , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Musculares/genética , Mutación , Quinasa de Cadena Ligera de Miosina/genética , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/genética , Retículo Sarcoplasmático/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transducción de Señal/genética
16.
Cardiovasc Drugs Ther ; 34(4): 487-501, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32377826

RESUMEN

BACKGROUND: Previous studies have demonstrated that a high-carbohydrate intake could induce metabolic syndrome (MetS) in male rats with marked cardiac functional abnormalities. In addition, studies mentioned some benefits of insulin application on these complications, but there are considerable disagreements among their findings. Therefore, we aimed to extend our knowledge on the in-vitro influence of insulin on left ventricular dysfunction and also in the isolated cardiomyocytes from MetS rats. RESULTS: At the organ function level, an acute insulin application (100-nM) provided an important beneficial effect on the left ventricular developed pressure in MetS rats. Furthermore, to treat the freshly isolated cardiomyocytes from MetS rats with insulin provided marked recoveries in elevated resting intracellular Ca2+-level, as well as significant prevention of prolonged action potential through an augmentation in depressed K+-channel currents. Insulin also normalized the cellular levels of increased ROS and phosphorylation of PKCα, together with normalizations of apoptotic markers in MetS cardiomyocytes through the insulin-mediated regulation of phospho-Akt. Since not only elevated PKCα-activity but also reductions in phospho-Akt are key modulators of titin-based cardiomyocyte stiffening in hyperglycemia, insulin treatment of the cardiomyocytes prevented the activation of titin via the above pathways. Furthermore, CK2α-activation and NOS-phosphorylation could be prevented with insulin treatment. Mechanistically, we found that impaired insulin signaling and elevated PKCα and CK2α activities, as well as depressed Akt phosphorylation, are key modulators of titin-based cardiomyocyte stiffening in MetS rats. CONCLUSION: We propose that restoring normal kinase activities and also increases in phospho-Akt by insulin can contribute marked recoveries in MetS heart function, indicating a promising approach to modulate titin-associated factors in heart dysfunction associated with type-2 diabetes mellitus. Graphical Abstract.


Asunto(s)
Quinasa de la Caseína II/metabolismo , Conectina/metabolismo , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Insulina/farmacología , Síndrome Metabólico/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Señalización del Calcio/efectos de los fármacos , Modelos Animales de Enfermedad , Preparación de Corazón Aislado , Masculino , Síndrome Metabólico/enzimología , Síndrome Metabólico/fisiopatología , Miocitos Cardíacos/enzimología , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Disfunción Ventricular Izquierda/enzimología , Disfunción Ventricular Izquierda/fisiopatología , Presión Ventricular/efectos de los fármacos
17.
Mol Cell ; 79(1): 43-53.e4, 2020 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-32464093

RESUMEN

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.


Asunto(s)
Tejido Adiposo/efectos de los fármacos , Hiperglucemia/patología , Insulina/farmacología , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Tejido Adiposo/metabolismo , Animales , Glucemia/análisis , Gluconeogénesis/genética , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Interleucina-10/fisiología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Noqueados , Periodo Posprandial , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/fisiología
18.
Life Sci ; 255: 117856, 2020 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-32473246

RESUMEN

BACKGROUND: Ferulic acid (FA) is a phenolic phytochemical known to protect against various diabetic complications. However, its role in diabetic neuropathy is still unclear. The present study investigated the potential protective effects of FA alone and its combination with insulin against streptozotocin (STZ)-induced diabetic neuropathy in rats. METHODS: STZ (55 mg/kg) was injected in adult Sprague-Dawley rats to induce diabetes. Diabetic rats were treated with FA (25, 50, and 100 mg/kg, p.o), insulin (10 IU/kg, s.c.) and the combination of FA (100 mg/kg, p.o.) with insulin (10 IU/kg, s.c.) for four weeks. Body weight, blood glucose, insulin, glycosylated hemoglobin, nerve conduction velocity and pain parameters were measured. Moreover, oxidative stress, inflammatory (TNF-α, IL-1ß, COX-2) and apoptotic markers (Bcl-2, Bax, caspase 3) were assessed in the sciatic nerve tissue. Na+-K+-ATPase activity and nerve growth factor (NGF) levels were also determined. RESULTS: FA attenuated STZ induced alteration in metabolic parameters, nociceptive threshold, motor nerve conduction velocity, NGF levels and Na+-K+-ATPase activity. In addition, FA boosted anti-oxidant defenses and suppressed oxidative stress, pro-inflammatory mediators and apoptotic markers. Furthermore, diabetic rats treated with insulin-FA (100 mg/kg) combination demonstrated more pronounced beneficial effects as compared to either agent alone. CONCLUSIONS: Collectively, our results suggest that FA either alone or in combination with insulin therapy could serve as an efficacious agent for treating diabetic neuropathy.


Asunto(s)
Ácidos Cumáricos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/farmacología , Insulina/farmacología , Animales , Antioxidantes/metabolismo , Glucemia/efectos de los fármacos , Ácidos Cumáricos/administración & dosificación , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estreptozocina
19.
Clin Exp Hypertens ; 42(7): 614-621, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-32349626

RESUMEN

OBJECTIVE: To investigate if insulin resistance per se or the accompanying hyperinsulinemia induced hypertension and its underlying mechanisms. METHODS: Sprague-Dawley rats were randomized into normal diet-fed group (ND group) and high-fat diet-fed group (HFD group). Then, the HFD group was further randomly divided into the control group (HFD_C group), the PIO group (treated with pioglitazone), the STZ_DM group (to induce diabetes with streptozotocin) and the DM+Ins group (streptozotocin injection followed by insulin treatment). Insulin sensitivity, plasma insulin, endothelin-1, norepinephrine, aldosterone, angiotensinⅡ and 24-h urinary sodium excretion (USE) levels of the groups were measured and analyzed. A multiple stepwise regression analysis method was applied to exam our hypothesis. RESULTS: Compared to HFD_C group, the groups with lower plasma insulin, the PIO group and STZ_DM group, showed higher USE and lower blood pressure. The groups with higher plasma insulin (but same level of insulin resistance), the HFD_C group and DM+Ins group, showed lower USE and higher blood pressure. The 24-h urinary sodium excretion was the most important contributor to the significant changes of blood pressure with an R2 of 25.2% in this animal experiment. CONCLUSIONS: It is the compensatory hyperinsulinemia rather than insulin resistance per se that causes blood pressure elevation. The urinary sodium excretion is the key mediator among the multiple mechanisms. Therapies targeting hyperinsulinemia and restricting salt intake may favor a better control of hypertension associated with insulin resistance.


Asunto(s)
Presión Sanguínea , Diabetes Mellitus Experimental/fisiopatología , Hiperinsulinismo/fisiopatología , Resistencia a la Insulina/fisiología , Insulina/sangre , Sodio/orina , Animales , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Dieta Alta en Grasa , Hiperinsulinismo/etiología , Hipertensión/complicaciones , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Pioglitazona/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
20.
Nat Biomed Eng ; 4(5): 507-517, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32393892

RESUMEN

Treatment of patients with diabetes with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. However, because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 h at 37 °C under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin from 0.4 ± 0.2 to 0.7 ± 0.1 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Composición de Medicamentos , Glucagón/metabolismo , Insulina/uso terapéutico , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Animales , Hidrocarburos Aromáticos con Puentes/química , Difusión , Vías de Administración de Medicamentos , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Imidazoles/química , Insulina/administración & dosificación , Insulina/farmacocinética , Insulina/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/administración & dosificación , Polipéptido Amiloide de los Islotes Pancreáticos/farmacocinética , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Masculino , Polietilenglicoles/química , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Porcinos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA