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1.
Diabetes Metab ; 45(3): 254-260, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29784563

RESUMO

BACKGROUND: The haemoglobin glycation index (HGI) has been proposed as a marker of interindividual differences in haemoglobin glycosylation. Previous studies have shown a relationship between high HGI and risk of cardiovascular disease (CVD) in patients with diabetes. However, no studies have investigated the role of previous CVD in this association. METHODS: The study cohort comprised patients with type 2 diabetes mellitus (T2DM; n=1910) included in the Second Manifestations of Arterial Disease (SMART) study. The relationship between either HGI or HbA1c and a composite of cardiovascular events as the primary outcome, and mortality, cardiovascular mortality, myocardial infarction and stroke as secondary outcomes, was investigated using Cox proportional-hazards models. Similar analyses were performed after stratification according to previous CVD. RESULTS: A 1-unit higher HGI was associated with a 29% greater risk of a composite of cardiovascular events (HR: 1.29, 95% CI: 1.06-1.57) in patients without previous CVD, whereas no such relationship was seen in patients with previous CVD (HR: 0.96, 95% CI: 0.86-1.08). The direction and magnitude of the hazard ratios (HRs) of HGI and HbA1c in relation to outcomes were similar. Additional adjustment for HbA1c in the association between HGI and outcomes lowered the HRs. CONCLUSION: Similar to HbA1c, higher HGI is related to higher risk of cardiovascular events in patients with T2DM without CVD. As HbA1c has proved to be a comparable risk factor, and obtaining and interpreting the HGI is complicated, any additional benefit of applying the HGI in clinical settings is likely to be limited.


Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Hemoglobina A Glicada/análise , Idoso , Glicemia , Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
2.
Adv Clin Chem ; 75: 99-158, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27346618

RESUMO

The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic ß-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of ß-cell function and survival and the causes of ß-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant ß-cell toxic chemicals as a model of ß-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations in the low to the high picomolar-femtomolar range and vary exposure time for up to 14-16h to reproduce the acute regulatory effects of systemic inflammation on ß-cell secretory responses, with a shift to inhibition at high picomolar concentrations or more than 16h of exposure to illustrate adverse effects of local, chronic islet inflammation. Since then, numerous studies have clarified how these bimodal responses depend on discrete signaling pathways. Most interest has been devoted to the proapoptotic response dependent upon mainly nuclear factor κ B and mitogen-activated protein kinase activation, leading to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential of anticytokine therapies has yet to be shown by testing the incremental effects of appropriate dosing, timing, and combinations of treatments. Due to the considerable translational importance of enhancing the precision, specificity, and safety of antiinflammatory treatments of diabetes, we review here the cellular, preclinical, and clinical evidence of which of the death pathways recently proposed in the Nomenclature Committee on Cell Death 2012 Recommendations are activated by inflammatory cytokines in the pancreatic ß-cell to guide the identification of antidiabetic targets. Although there are still scarce human data, the cellular and preclinical studies point to the caspase-dependent intrinsic apoptosis pathway as the prime effector of inflammatory ß-cell apoptosis.


Assuntos
Apoptose , Citocinas/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Citocinas/genética , Citocinas/farmacologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Estresse do Retículo Endoplasmático , Humanos
3.
Diabetes Obes Metab ; 17(7): 703-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25846481

RESUMO

Failure of pancreatic ß cells to compensate for insulin resistance is a prerequisite for the development of type 2 diabetes. Sustained elevated circulating levels of free fatty acids and glucose contribute to ß-cell failure. Selective inhibition of histone deacetylase (HDAC)-3 protects pancreatic ß cells against inflammatory and metabolic insults in vitro. In the present study, we tested the ability of a selective HDAC3 inhibitor, BRD3308, to reduce hyperglycaemia and increase insulin secretion in a rat model of type 2 diabetes. At diabetes onset, an ambulatory hyperglycaemic clamp was performed. HDAC3 inhibition improved hyperglycaemia over the study period without affecting weight gain. At the end of the hyperglycaemic clamp, circulating insulin levels were significantly higher in BRD3308-treated rats. Pancreatic insulin staining and contents were also significantly higher. These findings highlight HDAC3 as a key therapeutic target for ß-cell protection in type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Obesidade/tratamento farmacológico , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos não Esterificados/metabolismo , Técnica Clamp de Glucose , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/uso terapêutico , Hiperglicemia/tratamento farmacológico , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Obesidade/sangue , Obesidade/complicações , Ratos , Ratos Zucker , Ganho de Peso
4.
Eur J Endocrinol ; 172(2): 107-13, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25378371

RESUMO

OBJECTIVE: Body weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis. DESIGN: Multicentre longitudinal study carried out at diagnosis and up to 1-year follow-up. METHODS: Data on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (<5 years, n=126; >5 years <10 years, n=295; >10 years <18 years, n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c. RESULTS: In individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10-18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (ß 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m(2) higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (ß=0.026, 95% CI=0.0097, 0.042; P=0.002). CONCLUSIONS: These observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10-18 years. This should be considered in studies of ß-cell function in type 1 diabetes.


Assuntos
Índice de Massa Corporal , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Adolescente , Biomarcadores/sangue , Contagem de Células/métodos , Criança , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino
5.
Acta Physiol (Oxf) ; 210(4): 717-32, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24521359

RESUMO

The interest in the role of ferrous iron in diabetes pathophysiology has been revived by recent evidence of iron as an important determinant of pancreatic islet inflammation and as a biomarker of diabetes risk and mortality. The iron metabolism in the ß-cell is complex. Excess free iron is toxic, but at the same time, iron is required for normal ß-cell function and thereby glucose homeostasis. In the pathogenesis of diabetes, iron generates reactive oxygen species (ROS) by participating in the Fenton chemistry, which can induce oxidative damage and apoptosis. The aim of this review is to present and discuss recent evidence, suggesting that iron is a key pathogenic factor in both type 1 and type 2 diabetes with a focus on inflammatory pathways. Pro-inflammatory cytokine-induced ß-cell death is not fully understood, but may include iron-induced ROS formation resulting in dedifferentiation by activation of transcription factors, activation of the mitochondrial apoptotic machinery or of other cell death mechanisms. The pro-inflammatory cytokine IL-1ß facilitates divalent metal transporter 1 (DMT1)-induced ß-cell iron uptake and consequently ROS formation and apoptosis, and we propose that this mechanism provides the relay between inflammation and oxidative ß-cell damage. Iron chelation may be a potential therapeutic approach to reduce disease severity and mortality among diabetes patients. However, the therapeutic effect and safety of iron reduction need to be tested in clinical trials before dietary interventions or the use of iron chelation therapy titrated to avoid anaemia.


Assuntos
Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Ferro/metabolismo , Transporte Biológico , Humanos , Células Secretoras de Insulina/metabolismo , Ferro na Dieta/metabolismo
6.
Diabetes Obes Metab ; 16(3): 262-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24118704

RESUMO

AIMS: C-peptide secretion is currently the only available clinical biomarker to measure residual ß-cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. METHODS: We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on ß-cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. RESULTS: Fasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (p < 0.0001). CONCLUSIONS: This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of ß-cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.


Assuntos
Envelhecimento , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/metabolismo , Hipoglicemiantes/uso terapêutico , Anticorpos Anti-Insulina/sangue , Células Secretoras de Insulina/metabolismo , Insulina/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idade de Início , Envelhecimento/metabolismo , Biomarcadores/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Relação Dose-Resposta a Droga , Europa (Continente) , Jejum , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino
7.
Diabetes Obes Metab ; 15 Suppl 3: 176-84, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24003935

RESUMO

With the worldwide increase in diabetes prevalence there is a pressing unmet need for novel antidiabetic therapies. Insufficient insulin production due to impaired ß-cell function and apoptotic reduction of ß-cell mass is a common denominator in the pathogenesis of diabetes. Current treatments are directed at improving insulin sensitivity, and stimulating insulin secretion or replacing the hormone, but do not target progressive apoptotic ß-cell loss. Here we review the current development of small-molecule inhibitors designed to rescue ß-cells from apoptosis. Several distinct classes of small molecules have been identified that protect ß-cells from inflammatory, oxidative and/or metabolically induced apoptosis. Although none of these have yet reached the clinic, ß-cell protective small molecules alone or in combination with current therapies provide exciting opportunities for the development of novel treatments for diabetes.


Assuntos
Anti-Inflamatórios/farmacologia , Hipoglicemiantes/farmacologia , Inflamação/prevenção & controle , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Citocinas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Bibliotecas de Moléculas Pequenas/farmacologia
8.
Diabetologia ; 56(6): 1356-63, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23494449

RESUMO

AIMS/HYPOTHESIS: Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes. METHODS: The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-ß1-3) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA1c and fasting blood glucose. RESULTS: High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p < 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-ß1 and TGF-ß2 were associated with lower fasting and stimulated C-peptide levels (p < 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased (p < 0.001) while those of IL-10 and TGF-ß1 decreased (p < 0.02) and IL-1RA and TGF-ß2 remained unchanged. CONCLUSIONS/INTERPRETATION: The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.


Assuntos
Citocinas/sangue , Diabetes Mellitus Tipo 1/sangue , Jejum , Regulação da Expressão Gênica , Células Secretoras de Insulina/citologia , Adolescente , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Peptídeo C/sangue , Criança , Diabetes Mellitus Tipo 1/metabolismo , Dieta , Feminino , Humanos , Inflamação , Masculino , Fatores de Tempo , Adulto Jovem
9.
Diabetologia ; 55(9): 2421-31, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22772764

RESUMO

AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. METHODS: The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. RESULTS: Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the pro-inflammatory mediators Il1α, Il1ß, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. CONCLUSIONS/INTERPRETATION: These data demonstrate non-redundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.


Assuntos
Apoptose , Diabetes Mellitus Tipo 1/metabolismo , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Animais , Apoptose/genética , Criança , Pré-Escolar , Citocinas , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Lactente , Masculino , NF-kappa B/metabolismo , Pâncreas/patologia , RNA Interferente Pequeno , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
10.
Diabetologia ; 53(12): 2569-78, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20878317

RESUMO

AIMS/HYPOTHESIS: Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated. METHODS: The beta cell line INS-1 and intact rat and human islets were exposed to cytokines with or without ITF2357. Expression of mRNA was assessed by real-time PCR and selected targets validated at the protein level by immunoblotting. Effects on cytokine-induced toxicity were investigated by in vitro assays. RESULTS: Hdac1 to Hdac11 were expressed and differentially regulated by cytokines in INS-1 cells and rat islets. HDAC1, -2, -6 and -11 were found to be expressed and regulated by cytokines in human islets. ITF2357 protected against cytokine-induced beta cell apoptosis and counteracted cytokine-induced attenuation of basal insulin secretion. In addition, cytokine-induced regulation of Hdac2 and Hdac6, but not Hdac1 and Hdac11, was reduced by KDAC inhibition. CONCLUSIONS/INTERPRETATION: All classical KDAC genes are expressed by beta cells and differentially regulated by cytokines. Based on the relative expression levels and degree of regulation by cytokines, we propose that HDAC1, -2, -6 and -11 are of particular importance for beta cell function. These observations may help in the design of specific KDAC inhibitors to prevent beta cell destruction in situ and in islet grafts.


Assuntos
Citocinas/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Mediadores da Inflamação/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lisina/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ratos , Ratos Wistar , Fatores de Tempo
11.
Diabetologia ; 53(10): 2129-33, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20607514

RESUMO

AIMS/HYPOTHESIS: Endothelial progenitor cells (EPC) augment vascular repair and neovascularisation. Patients with type 2 diabetes have reduced EPC and increased risk of cardiovascular disease (CVD), which is reduced by multifactorial intervention. Our aim, therefore, was to evaluate in type 2 diabetic patients whether the numbers of EPC derived from peripheral blood mononuclear cells is influenced by a multifactorial treatment strategy. METHODS: We enrolled 28 patients newly referred for initiation of multifactorial treatment, which consisted of improving glycaemic, lipid and blood pressure control, as well as antithrombotic therapy and lifestyle modification. EPC count was assessed by in vitro cultures at baseline and after 90 days of treatment. After 7 days in culture, we identified EPC by fluorescent staining of attached cells. Patients were treated with metformin, aspirin, statins and angiotensin II receptor blockers, and divided accordingly into groups of mono-, dual-, triple- or quadruple therapy. RESULTS: After 90 days of treatment, glycaemic control improved and total cholesterol decreased. Multifactorial intervention for 90 days significantly increased EPC count in cultures by 35% (from 105 [SE 8] to 140 [11] cells per field [p = 0.002]). The change in EPC among patients with quadruple therapy was higher (63%) than in untreated patients (-32%, p = 0.043). CONCLUSIONS/INTERPRETATION: Numbers of EPC derived from peripheral blood mononuclear cells increased significantly after multifactorial intervention in type 2 diabetic patients. It remains to be shown whether these changes contribute to the beneficial effects of multifactorial intervention on diabetic micro- and macroangiopathy.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Células Endoteliais/citologia , Células-Tronco/citologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Aspirina/uso terapêutico , Contagem de Células , Células Cultivadas , Dieta Redutora , Terapia por Exercício , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Leucócitos Mononucleares/citologia , Estilo de Vida , Masculino , Metformina/uso terapêutico , Resultado do Tratamento
12.
Diabetologia ; 53(1): 10-20, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19890624

RESUMO

The recent major increase in the global incidence of type 2 diabetes suggests that most cases of this disease are caused by changes in environment and lifestyle. All major risk factors for type 2 diabetes (overnutrition, low dietary fibre, sedentary lifestyle, sleep deprivation and depression) have been found to induce local or systemic low-grade inflammation that is usually transient or milder in individuals not at risk for type 2 diabetes. By contrast, inflammatory responses to lifestyle factors are more pronounced and prolonged in individuals at risk of type 2 diabetes and appear to occur also in the pancreatic islets. Chronic low-grade inflammation will eventually lead to overt diabetes if counter-regulatory circuits to inflammation and metabolic stress are compromised because of a genetic and/or epigenetic predisposition. Hence, it is not the lifestyle change per se but a deficient counter-regulatory response in predisposed individuals which is crucial to disease pathogenesis. Novel approaches of intervention may target these deficient defence mechanisms.


Assuntos
Diabetes Mellitus/epidemiologia , Inflamação/epidemiologia , Estilo de Vida , Diabetes Mellitus/etiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Surtos de Doenças , Saúde Global , Glucose/metabolismo , Humanos , Inflamação/complicações , Inflamação/imunologia , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Obesidade/complicações , Obesidade/epidemiologia , Prevalência , Amido/metabolismo , Organização Mundial da Saúde
13.
Diabetes Obes Metab ; 11(3): 196-203, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19215277

RESUMO

AIMS/HYPOTHESIS: The suppressor of cytokine signalling 1 (SOCS1) is a natural inhibitor of cytokine and insulin signalling pathways and may also play a role in obesity. In addition, SOCS1 is considered a candidate gene in the pathogenesis of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective was to perform mutation analysis of SOCS1 and to test the identified variations for association to T2D-related quantitative traits, T2D or T1D. METHODS: Mutation scanning was performed by direct sequencing in 27 white Danish subjects. Genotyping was carried out by TaqMan allelic discrimination. A total of more than 8100 individuals were genotyped. RESULTS: Eight variations were identified in the 5' untranslated region (UTR) region. Two of these had allele frequencies below 1% and were not further examined. The six other variants were analysed in groups of T1D families (n = 1461 subjects) and T2D patients (n = 1430), glucose tolerant first-degree relatives of T2D patients (n = 212) and normal glucose tolerant (NGT) subjects. The rs33977706 polymorphism (-820G > T) was associated with a lower body mass index (BMI) (p = 0.004). In a second study (n = 4625 NGT subjects), significant associations of both the rs33977706 and the rs243330 (-1656G > A) variants to obesity were found (p = 0.047 and p = 0.015) respectively. The rs33977706 affected both binding of a nuclear protein to and the transcriptional activity of the SOCS1 promoter, indicating a relationship between this polymorphism and gene regulation. CONCLUSIONS/INTERPRETATION: This study demonstrates that functional variations in the SOCS1 promoter may associate with alterations in BMI in the general white population.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Resistência à Insulina/genética , Obesidade/genética , Polimorfismo Genético/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/metabolismo
14.
Diabetologia ; 52(2): 281-8, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19002429

RESUMO

AIMS/HYPOTHESIS: Chemokines recruit activated immune cells to sites of inflammation and are important mediators of insulitis. Activation of the pro-apoptotic receptor Fas leads to apoptosis-mediated death of the Fas-expressing cell. The pro-inflammatory cytokines IL-1beta and IFN-gamma regulate the transcription of genes encoding the Fas receptor and several chemokines. We have previously shown that suppressor of cytokine signalling (SOCS)-3 inhibits IL-1beta- and IFN-gamma-induced nitric oxide production in a beta cell line. The aim of this study was to investigate whether SOCS-3 can influence cytokine-induced Fas and chemokine expression in beta cells. METHODS: Using a beta cell line with inducible Socs3 expression or primary neonatal rat islet cells transduced with a Socs3-encoding adenovirus, we employed real-time RT-PCR analysis to investigate whether SOCS-3 affects cytokine-induced chemokine and Fas mRNA expression. The ability of SOCS-3 to influence the activity of cytokine-responsive Fas and Mcp-1 (also known as Ccl2) promoters was measured by reporter analysis. RESULTS: IL-1beta induced a time-dependent increase in Mcp-1 and Mip-2 (also known as Cxcl2) mRNA expression after 6 h of stimulation in insulinoma (INS)-1 and neonatal rat islet cells. This induction was inhibited when Socs3 was expressed in the cells. In INS-1 cells, IL-1beta + IFN-gamma induced a tenfold and eightfold increase of Fas mRNA expression after 6 and 24 h, respectively. This induction was inhibited at both time-points when expression of Socs3 was induced. In promoter studies SOCS-3 significantly inhibited the cytokine-induced activity of Mcp-1 and Fas promoter constructs. CONCLUSIONS/INTERPRETATION: SOCS-3 inhibits the expression of cytokine-induced chemokine and death-receptor Fas mRNA.


Assuntos
Quimiocinas/genética , Células Secretoras de Insulina/fisiologia , Interleucina-1beta/farmacologia , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Animais , Linhagem Celular , Quimiocina CCL2/genética , Insulina/biossíntese , Células Secretoras de Insulina/efeitos dos fármacos , Interferon gama/farmacologia , RNA Mensageiro/genética , Ratos , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Transcrição Genética/efeitos dos fármacos
15.
Diabetologia ; 51(10): 1873-82, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18648765

RESUMO

AIMS/HYPOTHESIS: The pro-inflammatory cytokines IL-1 and IFNgamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS3 in primary rodent beta cells and diabetic animal models. METHODS: Using mice with beta cell-specific Socs3 expression and a Socs3-encoding adenovirus construct, we characterised the protective effect of SOCS3 in mouse and rat islets subjected to cytokine stimulation. In transplantation studies of NOD mice and alloxan-treated mice the survival of Socs3 transgenic islets was investigated. RESULTS: Socs3 transgenic islets showed significant resistance to cytokine-induced apoptosis and impaired insulin release. Neither glucose-stimulated insulin release, insulin content or glucose oxidation were affected by SOCS3. Rat islet cultures transduced with Socs3-adenovirus displayed reduced cytokine-induced nitric oxide and apoptosis associated with inhibition of the IL-1-induced nuclear factor-kappaB and mitogen-activated protein kinase (MAPK) pathways. Transplanted Socs3 transgenic islets were not protected in diabetic NOD mice, but showed a prolonged graft survival when transplanted into diabetic allogenic BALB/c mice. CONCLUSIONS/INTERPRETATION: SOCS3 inhibits IL-1-induced signalling through the nuclear factor-kappaB and MAPK pathways and apoptosis induced by cytokines in primary beta cells. Moreover, Socs3 transgenic islets are protected in an allogenic transplantation model. SOCS3 may represent a target for pharmacological or genetic engineering in islet transplantation for treatment of type 1 diabetes mellitus.


Assuntos
Apoptose/fisiologia , Citocinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Aloxano , Animais , Animais Recém-Nascidos , Apoptose/genética , Western Blotting , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/fisiopatologia , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/fisiologia , Humanos , Marcação In Situ das Extremidades Cortadas , Ilhotas Pancreáticas/citologia , Transplante das Ilhotas Pancreáticas/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Transplante Homólogo
16.
Cell Mol Life Sci ; 65(7-8): 1248-55, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18278435

RESUMO

An insufficient number of insulin-producing beta-cells is a major cause of defective control of blood glucose in both type 1 and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024, but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines interleukin-1beta, interferon- gamma and tumor necrosis factor-alpha. These effects did not involve changes in nitric oxide production but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the treatment of diabetes.


Assuntos
Imidazóis/farmacologia , Indóis/farmacologia , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Animais , Benzofuranos/farmacologia , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Óxido Nítrico/biossíntese
17.
Diabetologia ; 51(1): 91-100, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17994216

RESUMO

AIMS/HYPOTHESIS: The aim of the study was to determine whether purified beta cells can replicate in vitro and whether this is enhanced by extracellular matrix (ECM) and growth factors. METHODS: Human beta cells were purified by FACS by virtue of their high zinc content using Newport Green, and excluding ductal and dead cells. Rat beta cells were sorted by autofluorescence or using the same method developed for human cells. Cells were plated on poly-L-lysine or ECMs from rat or human bladder carcinoma cells or bovine corneal ECM and incubated in the presence of BrdU with or without growth factors. RESULTS: The newly developed method for sorting human beta cells yields a population containing 91.4 +/- 2.8% insulin-positive cells with a low level of spontaneous apoptosis and a robust secretory response to glucose. Beta cells from 8-week-old rats proliferated in culture and this was increased by ECM. Among growth factors, only human growth hormone (hGH) and the glucagon-like peptide-1 analogue liraglutide enhanced proliferation of rat beta cells, with a significant increase on both poly-L-lysine and ECM. By contrast, sorted adult human beta cells from 16 donors aged 48.9 +/- 14.3 years (range 16-64 years) failed to replicate demonstrably in vitro regardless of the substratum or growth factors used. CONCLUSIONS/INTERPRETATION: These findings indicate that, in our conditions, the fully differentiated human adult insulin-producing beta cell was unable to proliferate in vitro. This has important implications for any attempt to expand cells from pancreases of donors of this age group. By contrast, the rat beta cells used here were able to divide in vitro, and this was enhanced by ECM, hGH and liraglutide.


Assuntos
Técnicas de Cultura de Células/métodos , Diabetes Mellitus/terapia , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Adolescente , Adulto , Animais , Diferenciação Celular , Separação Celular , Matriz Extracelular , Citometria de Fluxo/métodos , Humanos , Transplante das Ilhotas Pancreáticas/métodos , Pessoa de Meia-Idade , Ratos , Especificidade da Espécie
18.
Diabet Med ; 24(5): 512-20, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17381505

RESUMO

AIMS: We tested the hypothesis that systemic concentrations of cytokines, chemokines or soluble cytokine receptors predict or accompany clinical remission in Type 1 diabetes (T1D). METHODS: In a prospective, multicentre study, 48 patients with newly diagnosed T1D and 55 age-matched healthy control subjects were investigated. Blood was drawn 3-7 days after the diagnosis and then 3-4 months later. Patients were grouped into partial remitters or non-remitters by the degree of clinical improvement defined by HbA(1c) (threshold 7.5%) and daily insulin dose (threshold 0.38 IU/kg/day). Systemic concentrations of 17 immune mediators were analysed in serum or plasma. In addition, autoantibodies against insulin (IAA), IA-2 (IA-2A) and GAD65 (GADA) were quantified. RESULTS: All 17 immune mediators showed remarkable intra-individual stability in their systemic concentrations over time. As a consequence, partial remission was not accompanied by changes in mediator levels except for a moderate decrease of interleukin (IL)-1ra concentrations (P = 0.02) and IL-10 concentrations (P = 0.01) in non-remitters. Baseline levels were associated with the later clinical course in that low levels of interferon gamma (P = 0.01), IL-10 (P = 0.03) and IL-1R1 (P = 0.009) concentrations were observed in partial remitters. CONCLUSIONS: We conclude that the systemic immunoregulatory state at diagnosis of T1D is predictive of clinical improvement during the remission phase. There was no general change in systemic immune reactivity in the months after diagnosis and initiation of insulin therapy.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Receptores de Citocinas/sangue , Adolescente , Adulto , Biomarcadores/sangue , Quimiocinas/análise , Citocinas/análise , Feminino , Humanos , Masculino , Estudos Prospectivos , Receptores de Citocinas/análise , Indução de Remissão
19.
Diabetologia ; 50(4): 779-89, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17265033

RESUMO

AIMS/HYPOTHESIS: The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1beta and IFNgamma, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFkappaB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of pro-apoptotic genes. NFkappaB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. MATERIALS AND METHODS: The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1beta and IFNgamma. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFkappaB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. RESULTS: HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1beta induced a bi-phasic phosphorylation of inhibitor protein kappa Balpha (IkappaBalpha) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IkappaBalpha degradation and NFkappaB DNA binding. CONCLUSIONS/INTERPRETATION: HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFkappaB transactivating activity.


Assuntos
Citocinas/metabolismo , Regulação Enzimológica da Expressão Gênica , Inibidores de Histona Desacetilases , Células Secretoras de Insulina/metabolismo , Animais , Apoptose , Sobrevivência Celular , Inibidores Enzimáticos/farmacologia , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Proteínas Recombinantes/química , Transdução de Sinais
20.
Clin Exp Immunol ; 145(3): 480-4, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16907917

RESUMO

We studied whether serum interferon (IFN)-gamma or interleukin (IL)-10 levels and their corresponding functional polymorphic genotypes are associated with partial remission of type 1 diabetes (T1D). A multi-centre study was undertaken in patients with newly diagnosed T1D and matched controls. T1D patients were followed for 3 months and characterized for remission status. Partial clinical remission was defined as a daily insulin dose

Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Interferon gama/genética , Interleucina-10/genética , Análise de Variância , Biomarcadores/sangue , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Predisposição Genética para Doença , Genótipo , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Remissão Espontânea , Tamanho da Amostra
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