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1.
Ars pharm ; 62(1): 52-65, ene.-mar. 2021. tab, graf
Artigo em Inglês | IBECS-Express | IBECS | ID: ibc-ET6-1768

RESUMO

INTRODUCTION: The prevalence of diabetes type 2 is increasing worldwide, thus the search of novel alternative ther¬apies is needed. According to their traditional use, we selected five Bolivian plants Chenopodium quinoa (CQ) Ama¬ranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) and Smallanthus sonchifolius (SS) that are traditionally used to control glycemia. METHODS: The effect of a single oral administration of Ethanolic (EtOH), hydro-ethanolic (EtOH70) and aqueous (Aq) extracts from all plant species were tested for their effect on blood glucose in non-fasted mice and during the oral glucose tolerance test (OGTT). The effect on insulin secretion was evaluated in mice pancreatic islets. RESULTS: EtOH70 extracts of all the plants showed glucose-reducing effect at the highest dose evaluated (2000 mg/ kg b.w.). EtOH70 extracts improved the glucose tolerance evaluated by the OGTT in mice fasted for 12 hours. The extracts have different effects on glucose homeostasis since just extracts of AC, LM and CQ but not CP and SS in¬creased insulin secretion as shown on mice pancreatic islets. The phytochemical qualitative characterization of EtOH70 extracts detected phenolic acids and flavonoids in AC, CP and CQ; alkaloids in LM and anthocyanidins in SS. None of EtOH70 extracts tested showed in vitro or in vivo acute toxicity at concentrations where they exhibit glucose lowering effects. CONCLUSIONS: We report here that extracts from AC, CQ, CP, LM and SS exhibit glucose lowering effect while just AC, CQ and LM stimulate directly the insulin secretion


INTRODUCCIÓN: La prevalencia de diabetes tipo 2 está aumentando en todo el mundo, por lo que se necesita la búsqueda de nuevas terapias alternativas. Según su uso tradicional, seleccionamos cinco plantas bolivianas Chenopodium quinoa (CQ) Amaranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) y Smallanthus sonchifolius (SS) que se usan tradicionalmente para controlar la glucemia. MÉTODOS: Se evaluó el efecto de la administración oral única de extractos etanólicos (EtOH), hidroetanólicos (EtOH70) y acuosos (Aq) de las plantas mencionadas para determinar su efecto sobre la glucosa en sangre en ratones en o sin ayunas y durante la prueba de tolerancia a la glucosa oral (PTGO). El efecto sobre la secreción de insulina se evaluó en islotes pancreáticos de ratones. RESULTADOS: Los extractos de EtOH70 de todas las plantas disminuyeron la glucemia a la dosis más alta evaluada (2000 mg / kg b.w.). Los extractos de EtOH70 mejoraron la tolerancia a la glucosa evaluada mediante la PTGO en ratones con ayuno de 12 horas. Los extractos tienen diferentes efectos sobre la homeostasis de la glucosa, ya que solo los extractos de AC, LM y CQ pero no CP y SS aumentaron la secreción de insulina como se muestra en los islotes pancreáticos de los ratones. La caracterización cualitativa fitoquímica de extractos de EtOH70 detectó ácidos fenólicos y flavonoides en AC, CP y CQ, alcaloides en LM y antocianidinas en SS. Ninguno de los extractos de EtOH70 probados mostró toxicidad aguda in vitro o in vivo a concentraciones en las que exhiben efectos reductores de glucosa. CONCLUSIÓN: Los extractos de AC, CQ, CP, LM y SS exhiben un efecto reductor de la glucosa, mientras que solo AC, CQ y LM estimulan directamente la secreción de insulina

2.
Commun Biol ; 3(1): 768, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318569

RESUMO

Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. In diabetes, hyperglycemia impairs the adaptive responses to hypoxia with profound negative effects on different cellular compartments of wound healing. miR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Here, we show that hyperglycemia blunted the hypoxia-dependent induction of miR-210 both in vitro and in human and mouse diabetic wounds. The impaired regulation of miR-210 in diabetic wounds is pathogenic, since local miR-210 administration accelerated wound healing specifically in diabetic but not in non-diabetic mice. miR-210 reconstitution restores the metabolic balance in diabetic wounds by reducing oxygen consumption rate and ROS production and by activating glycolysis with positive consequences on cellular migration. In conclusion, miR-210 accelerates wound healing specifically in diabetes through improvement of the cellular metabolism.

3.
Front Endocrinol (Lausanne) ; 11: 575469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193091

RESUMO

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic ß cells. Further, patients with T1D have 3-4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the IL2RA and PTPN2 gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that IL2RA and PTPN2 gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.

4.
J Invest Dermatol ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32949564

RESUMO

Persistent and impaired inflammation impedes tissue healing and is characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. Here we show that in human wound-edge keratinocytes, the expression of miR-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, is upregulated during wound repair. However, their levels are lower in chronic ulcers than acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound-edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines/cytokines by keratinocytes. Thus, as crucial regulators of wound inflammation, lack of miR-19a/b and miR-20a may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.

5.
Int Rev Neurobiol ; 155: 91-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32854860

RESUMO

There is a large unmet medical need to find disease modifying therapies against neurodegenerative diseases. This review summarizes data indicating that insulin resistance occurs in neurodegeneration and strategies to normalize insulin sensitivity in neurons may provide neuroprotective actions. In particular, recent preclinical and clinical studies in Parkinson's disease and Alzheimer's disease have indicated that glucagon-like peptide 1 (GLP1) agonism and dipeptidyl peptidase-4 inhibition may exert neuroprotection. Mechanistic insights from these studies and future directions for drug development against neurodegeneration based on GLP1 agonism are discussed.

6.
Sci Rep ; 10(1): 11561, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665614

RESUMO

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.


Assuntos
Peptídeo C/sangue , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 1/genética , Nucleotídeos/sangue , Idoso , Biomarcadores/sangue , Glicemia , Complicações do Diabetes/sangue , Complicações do Diabetes/patologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/patologia , Feminino , Predisposição Genética para Doença , Humanos , Resistência à Insulina/genética , Fígado/metabolismo , Masculino , Metabolômica , Pessoa de Meia-Idade , Nucleotídeos/biossíntese
7.
Ann Rheum Dis ; 78(12): 1621-1631, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31481351

RESUMO

OBJECTIVES: Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) might contribute to bone loss and arthralgia before the onset of joint inflammation. We aimed to dissect additional mechanisms by which ACPAs might contribute to development of joint pathology. METHODS: Fibroblast-like synoviocytes (FLS) were isolated from the synovial membrane of patients with RA. The FLS cultures were stimulated with polyclonal ACPAs (anti-CCP-2 antibodies) purified from the peripheral blood of patients with RA or with monoclonal ACPAs derived from single synovial fluid B cells. We analysed how ACPAs modulate FLS by measuring cell adhesion and mobility as well as cytokine production. Expression of protein arginine deiminase (PAD) enzymes and protein citrullination were analysed by immunofluorescence, and signal transduction was studied using immunoblotting. RESULTS: Challenge of FLS by starvation-induced stress or by exposure to the chemokine interleukin-8 was essential to sensitise the cells to ACPAs. These challenges led to an increased PAD expression and protein citrullination and an ACPA-mediated induction of FLS migration through a mechanism involving phosphoinositide 3-kinase activation. Inhibition of the PAD enzymes or competition with soluble citrullinated proteins or peptides completely abolished the ACPA-induced FLS migration. Different monoclonal ACPAs triggered distinct cellular effects in either fibroblasts or osteoclasts, suggesting unique roles for individual ACPA clones in disease pathogenesis. CONCLUSION: We propose that transient synovial insults in the presence of a certain pre-existing ACPA repertoire might result in an ACPA-mediated increase of FLS migration.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Líquido Sinovial/metabolismo , Membrana Sinovial/patologia , Sinoviócitos/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Western Blotting , Movimento Celular , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Microscopia Confocal , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo
8.
EBioMedicine ; 44: 489-501, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31221584

RESUMO

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.


Assuntos
Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Antígenos CD/genética , Antígenos de Neoplasias/genética , Metabolismo Energético/genética , Hipóxia/metabolismo , Paniculite/genética , Paniculite/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Matriz Extracelular , Feminino , Fibrose , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Paniculite/patologia , Transdução de Sinais
9.
J Diabetes Res ; 2019: 2936962, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214621

RESUMO

Objective: Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method: 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results: We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion: The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatologia , Retinopatia Diabética/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Nefropatias Diabéticas/genética , Feminino , Genótipo , Glucose/análise , Células HEK293 , Humanos , Hiperglicemia/genética , Hiperglicemia/fisiopatologia , Hipóxia , Masculino , Pessoa de Meia-Idade , Mutação , Prolina/genética , Fatores de Risco , Serina/genética , Ativação Transcricional , Adulto Jovem
10.
Proc Natl Acad Sci U S A ; 116(14): 6985-6994, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30886104

RESUMO

Diabetic foot ulcerations (DFUs) represent a major medical, social, and economic problem. Therapeutic options are restricted due to a poor understanding of the pathogenic mechanisms. The Notch pathway plays a pivotal role in cell differentiation, proliferation, and angiogenesis, processes that are profoundly disturbed in diabetic wounds. Notch signaling is activated upon interactions between membrane-bound Notch receptors (Notch 1-4) and ligands (Jagged 1-2 and Delta-like 1, 3, 4), resulting in cell-context-dependent outputs. Here, we report that Notch1 signaling is activated by hyperglycemia in diabetic skin and specifically impairs wound healing in diabetes. Local inhibition of Notch1 signaling in experimental wounds markedly improves healing exclusively in diabetic, but not in nondiabetic, animals. Mechanistically, high glucose levels activate a specific positive Delta-like 4 (Dll4)-Notch1 feedback loop. Using loss-of-function genetic approaches, we demonstrate that Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4-Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of DFUs.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Pé Diabético/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Cicatrização , Proteínas Adaptadoras de Transdução de Sinal , Idoso , Animais , Proteínas de Ligação ao Cálcio , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Pé Diabético/genética , Pé Diabético/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Receptor Notch1/genética
11.
Diab Vasc Dis Res ; 16(1): 22-27, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30309264

RESUMO

PURPOSE: Copeptin and insulin-like growth factor binding protein-1 analysed at admission for a myocardial infarction in patients with type 2 diabetes mellitus predicts cardiovascular events. The present aim was to study the association between copeptin and insulin-like growth factor binding protein-1, the development of the levels over time, and if the predictive value remained when measured at hospital discharge and 3 months thereafter. METHODS: Copeptin and insulin-like growth factor binding protein-1 were analysed in patients (median age = 70, male = 68%) with type 2 diabetes mellitus + myocardial infarction at admission (n = 393), discharge (n = 309) and 3 months later (n = 288). The primary endpoint was cardiovascular event (cardiovascular death/non-fatal myocardial infarction/stroke) with the three time points as separate baselines. RESULTS: The median copeptin levels were 21.8 pmol/L at admission, 8.5 pmol/L at discharge and 8.4 pmol/L after 3 months, while insulin-like growth factor binding protein-1 levels continued to increase. There were significant correlations between the biomarkers at all occasions. During an average follow-up of 2.5 years, copeptin, but not insulin-like growth factor binding protein-1, predicted cardiovascular event at all occasions in unadjusted analyses. Copeptin remained as a predictor at discharge and after 3 months in the final multiple model (including: heart failure/age/creatinine clearance). CONCLUSION: The relationship between copeptin and insulin-like growth factor binding protein-1 during the initial phase of a myocardial infarction persisted in a less-stressful situation, and copeptin remained as a prognostic indicator at discharge and 3 months later.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Glicopeptídeos/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Infarto do Miocárdio/sangue , Idoso , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Glucose/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Alta do Paciente , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Suécia/epidemiologia , Fatores de Tempo , Resultado do Tratamento
12.
JACC Basic Transl Sci ; 3(4): 450-463, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30175269

RESUMO

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.

13.
Nutrients ; 10(7)2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30037028

RESUMO

Lupinus mutabilis (LM) is a legume part of Bolivian traditional diet that has a nutraceutical property reducing blood glucose levels. The prevalence of type 2 diabetes is increasing worldwide thus; the search for novel anti-diabetic drugs is needed. Based on its traditional use, we evaluated the anti-diabetic effect of LM in the spontaneously diabetic Goto-Kakizaki (GK) rat, a model of type 2 diabetes and in Wistar (W) rats as healthy control. LM seeds hydroethanolic extract, analyzed by gas chromatography-mass spectrometry and high-performance liquid chromatography-high resolution mass spectrometry, is a complex mixture of volatile and non-volatile components. A single oral administration of LM extract (2000 mg/kg b.w.) improved glucose tolerance during the oral glucose tolerance test (OGTT) (30⁻120 min) in GK and W rats (p < 0.0001). The long-term treatment with LM (1000 mg/kg b.w.), for 21 days, improved the area under the curve (AUC) of glucose during OGTT at day 20, in both GK (p < 0.01) and W rats (p < 0.01). The HbA1c (GK rats, p < 0.05 and W rats, p < 0.0001) and the non-fasting glucose (GK rats, p < 0.05) were also reduced. LM increased both serum insulin levels (2.4-fold in GK rats and 2.5-fold W rats), and the glucose-induced (16.7 mM glucose) insulin release in isolated islets from treated animals (6.7-fold in GK rats, and 6.6-fold in W rats). Moreover, LM (10 mg/mL) stimulated in vitro glucose induced (16.7 mM glucose) insulin release in batch incubated GK and W rat islets (p < 0.0001). In perifused GK rat islets, insulin release in 16.7 mM glucose was increased 95.3-fold compared to untreated islets (p < 0.0001), while no significant differences were found in perifused W rat islets. The LM mechanism of action, evaluated using inhibitory compounds of the insulin secretion pathway, showed that LM-dependent insulin secretion was reduced 42% by diazoxide (p < 0.001), 70% by nifedipine (p < 0.001), 86.7% by H89 (p < 0.0001), 70.8% by calphostine-C (p < 0.0001) and 93% by pertussis toxin (p < 0.0001). A similar effect was observed in W rats islets. Our findings provide evidence that LM has an anti-diabetic effect through stimulation of insulin release. The effect is-dependent on L-type calcium channel, protein kinase A and C systems, and G protein-coupled exocytosis and is partially mediated by K-ATP channels.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Lupinus , Fitoterapia , Animais , Área Sob a Curva , Canais de Cálcio Tipo L/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Exocitose , Teste de Tolerância a Glucose , Hemoglobina A Glicada/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Canais KATP/metabolismo , Masculino , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos Wistar
14.
PLoS One ; 13(3): e0193084, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29534073

RESUMO

OBJECTIVE: IGF-I is a growth factor, which is expressed in virtually all tissues. The circulating IGF-I is however derived mainly from the liver. IGF-I promotes wound healing and its levels are decreased in wounds with low regenerative potential such as diabetic wounds. However, the contribution of circulating IGF-I to wound healing is unknown. Here we investigated the role of systemic IGF-I on wound healing rate in mice with deficiency of liver-derived IGF-I (LI-IGF-I-/- mice) during normal (normoglycemic) and impaired wound healing (diabetes). METHODS: LI-IGF-I-/- mice with complete inactivation of the IGF-I gene in the hepatocytes were generated using the Cre/loxP recombination system. This resulted in a 75% reduction of circulating IGF-I. Diabetes was induced with streptozocin in both LI-IGF-I-/- and control mice. Wounds were made on the dorsum of the mice, and the wound healing rate and histology were evaluated. Serum IGF-I and GH were measured by RIA and ELISA respectively. The expression of IGF-I, IGF-II and the IGF-I receptor in the skin were evaluated by qRT-PCR. The local IGF-I protein expression in different cell types of the wounds during wound healing process was analyzed using immunohistochemistry. RESULTS: The wound healing rate was similar in LI-IGF-I-/- mice to that in controls. Diabetes significantly delayed the wound healing rate in both LI-IGF-I-/- and control mice. However, no significant difference was observed between diabetic animals with normal or reduced hepatic IGF-I production. The gene expression of IGF-I, IGF-II and IGF-I receptor in skin was not different between any group of animals tested. Local IGF-I levels in the wounds were similar between of LI-IGF-I-/- and WT mice although a transient reduction of IGF-I expression in leukocytes in the wounds of LI-IGF-I-/- was observed seven days post wounding. CONCLUSION: Deficiency in the liver-derived IGF-I does not affect wound healing in mice, neither in normoglycemic conditions nor in diabetes.


Assuntos
Complicações do Diabetes , Diabetes Mellitus Experimental , Hepatócitos , Fator de Crescimento Insulin-Like I/deficiência , Fígado/metabolismo , Pele , Cicatrização , Animais , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Pele/lesões , Pele/metabolismo , Pele/patologia
15.
Endocrine ; 60(1): 185-192, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29380231

RESUMO

BACKGROUND: Riedel´s thyroiditis (RT) is a rare inflammatory disease of the thyroid gland, causing compression and fibrosis of adjacent tissues. Typically the goiter is hard and firm. Hoarseness, dyspnea, and dysphagia may be present. METHODS: We retrospectively reviewed all patients known by us with RT in addition to all patients with appropriate ICD-10 codes evaluated at the Karolinska University Hospital 2003-2015. Clinical, biochemical, and histological data of patients with RT were recorded in detail. Histological preparations were re-examined when available. RESULTS: RT was diagnosed in six patients. Five were females and the median age at first presentation was 50 years (25-81 years). Median follow-up time was 3.75 years (1-22 years). At diagnosis five had hypothyroidism. Four had extrathyroidal manifestations, and one of these had also distant fibrosis. One patient had a clear IgG4/IgG ratio over 40%. One patient was treated with tracheostomy, one with isthmectomy and one with total thyroidectomy. Four had been treated with glucocorticoids, four with tamoxifen, and two with both drugs. One had also been treated with mycophenolate mofetil combined with Rituximab. At the end of follow-up four was doing fine, one had recurrent episodes of inflammation and one had died of possible complications to RT. CONCLUSION: It is important to recognize RT and give adequate treatment. Steroids are still the mainstay of therapy but other medications against fibrosclerosis can be considered. Wakefulness of other fibrosing manifestations is essential. Immunohistochemistry can show whether IgG-4 plasma cells are increased which could lead to fibrosis in other organs.


Assuntos
Glucocorticoides/uso terapêutico , Tamoxifeno/uso terapêutico , Tireoidectomia , Tireoidite/diagnóstico , Traqueostomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tireoidite/tratamento farmacológico , Tireoidite/cirurgia , Resultado do Tratamento
16.
Nutrients ; 10(1)2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29342984

RESUMO

Diabetes Mellitus Type 2 prevalence is increasing worldwide; thus efforts to develop novel therapeutic strategies are required. Amaranthus caudatus (AC) is a pseudo-cereal with reported anti-diabetic effects that is usually consumed in food preparations in Bolivia. This study evaluated the anti-diabetic nutraceutical property of an AC hydroethanolic extract that contains mainly sugars and traces of polyphenols and amino acids (as shown by nalysis with liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR)), in type 2 diabetic Goto-Kakizaki (GK) rats and healthy Wistar (W) rats. A single oral administration of AC extract (2000 mg/kg body weight) improved glucose tolerance during Oral Glucose Tolerance Tests (OGTT) in both GK rats and in W rats. Long-term treatment (21 days) with AC (1000 mg/kg b.w.) improved the glucose tolerance evaluated by the area under the curve (AUC) of glucose levels during the OGTT, in both GK and W rats. The HbA1c levels were reduced in both GK (19.83%) and W rats (10.7%). This effect was secondary to an increase in serum insulin levels in both GK and W rats and confirmed in pancreatic islets, isolated from treated animals, where the chronic AC exposure increased the insulin production 4.1-fold in GK and 3.7-fold in W rat islets. Furthermore, the effect of AC on in vitro glucose-dependent insulin secretion (16.7 mM glucose) was concentration-dependent up to 50 mg/mL, with 8.5-fold increase in GK and 5.7-fold in W rat islets, and the insulin secretion in perifused GK and W rat islets increased 31 and nine times, respectively. The mechanism of action of AC on insulin secretion was shown to involve calcium, PKA and PKC activation, and G-protein coupled-exocytosis since the AC effect was reduced 38% by nifedipine (L-type channel inhibitor), 77% by H89 (PKA inhibitor), 79% by Calphostine-C (PKC inhibitor) and 20% by pertussis toxin (G-protein suppressor).


Assuntos
Amaranthus/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/sangue , Insulina/metabolismo , Extratos Vegetais/farmacologia , Animais , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Hemoglobina A Glicada/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Ratos , Ratos Wistar
17.
J Clin Endocrinol Metab ; 103(1): 179-186, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29069385

RESUMO

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1. Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE. Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure. Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.


Assuntos
Doença de Addison/diagnóstico , Autoanticorpos/sangue , Biomarcadores/sangue , Citocinas/imunologia , Programas de Rastreamento , Poliendocrinopatias Autoimunes/diagnóstico , Sistema de Registros , Doença de Addison/sangue , Doença de Addison/imunologia , Autoanticorpos/imunologia , Estudos de Casos e Controles , Seguimentos , Humanos , Poliendocrinopatias Autoimunes/sangue , Poliendocrinopatias Autoimunes/imunologia , Prognóstico , Suécia
18.
J Invest Dermatol ; 137(12): 2630-2638, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28807666

RESUMO

Chronic wounds represent a major and rising health and economic burden worldwide. There is a continued search toward more effective wound therapy. We found significantly reduced microRNA-132 (miR-132) expression in human diabetic ulcers compared with normal skin wounds and also in skin wounds of leptin receptor-deficient (db/db) diabetic mice compared with wild-type mice. Local replenishment of miR-132 in the wounds of db/db mice accelerated wound closure effectively, which was accompanied by increased proliferation of wound edge keratinocytes and reduced inflammation. The pro-healing effect of miR-132 was further supported by global transcriptome analysis, which showed that several inflammation-related signaling pathways (e.g., NF-κB, NOD-like receptor, toll-like receptor, and tumor necrosis factor signaling pathways) were the top ones regulated by miR-132 in vivo. Moreover, we topically applied liposome-formulated miR-132 mimics mixed with pluronic F-127 gel on human ex vivo skin wounds, which promoted re-epithelialization. Together, our study showed the therapeutic potential of miR-132 in chronic wounds, which warrants further evaluation in controlled clinical trials.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Pé Diabético/metabolismo , MicroRNAs/metabolismo , Cicatrização , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Diabetes Mellitus Tipo 2/complicações , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , Transcriptoma
19.
Exp Cell Res ; 358(2): 129-139, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28602625

RESUMO

Hes1 is a Notch target gene that plays a major role during embryonic development. Previous studies have shown that HIF-1α can interact with the Notch intracellular domain and enhance Notch target gene expression. In this study, we have identified a Notch-independent mechanism that regulates the responsiveness of the Hes1 gene to hypoxia. Using P19 cells we show that silencing the Notch DNA binding partner CSL does not prevent hypoxia-dependent upregulation of Hes1 expression. In contrast to CSL, knockdown of HIF-1α or Arnt expression prevents Hes1 induction in hypoxia. Deletion analysis of the Hes1 promoter identified a minimal region near the transcription start site that is still responsive to hypoxia. In addition, we show that mutating the GA-binding protein (GABP) motif significantly reduced Hes1 promoter-responsiveness to hypoxia or to HIF-1 overexpression whereas mutation of the hypoxia-responsive element (HRE) present in this region had no effect. Chromatin immunoprecipitation assays demonstrated that HIF-1α binds to the proximal region of the Hes1 promoter in a Notch-independent manner. Using the same experimental approach, the presence of GABPα and GABPß1 was also observed in the same region of the promoter. Loss- and gain-of-function studies demonstrated that Hes1 gene expression is upregulated by hypoxia in a GABP-dependent manner. Finally, co-immunoprecipitation assays demonstrated that HIF-1α but not HIF-2α is able to interact with either GABPα or GABPß1. These results suggest a Notch-independent mechanism where HIF-1 and GABP contribute to the upregulation of Hes1 gene expression in response to hypoxia.


Assuntos
Regulação da Expressão Gênica/fisiologia , Fatores de Transcrição HES-1/genética , Transcrição Genética/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular , Linhagem Celular , Imunoprecipitação da Cromatina/métodos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Regiões Promotoras Genéticas/genética , Receptores Notch/metabolismo , Fatores de Transcrição HES-1/metabolismo
20.
J Clin Endocrinol Metab ; 102(2): 379-389, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27870550

RESUMO

Context: Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality. Objective: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors. Design, Setting, and Participants: A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008-2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls. Main Outcome Measures: The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. Results: The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8 ± 4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046). Conclusions: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.


Assuntos
Doença de Addison/imunologia , Doença de Addison/complicações , Doença de Addison/tratamento farmacológico , Doença de Addison/epidemiologia , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Esquema de Medicação , Feminino , Terapia de Reposição Hormonal/métodos , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/uso terapêutico , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Suécia/epidemiologia , Adulto Jovem
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