RESUMO
Type 2 diabetes is a global health priority, given that it is driven, in part, by an ageing population, the role of immune senescence has been overlooked. This is surprising, as the functional impairments of senescent T cells show strong similarities to patients with hyperglycaemia. Immune senescence is typified by alterations in T cell memory, such as the accumulation of highly differentiated end-stage memory T cells, as well as a constitutive low-grade inflammation, which drives further immune differentiation. We show here in a preliminary study that people living with type 2 diabetes have a higher circulating volume of senescent T cells accompanied with a higher level of systemic inflammation. This inflammatory environment drives the expression of a unique array of chemokine receptors on senescent T cells, most notably C-X-C motif chemokine receptor type 2. However, this increased expression of migratory markers does not translate to improved extravasation owing to a lack of glucose uptake by the T cells. Our results therefore demonstrate that the presence of senescent T cells has a detrimental impact on immune function during type 2 diabetes.
Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Senescência Celular/imunologia , Diabetes Mellitus Tipo 2/imunologia , Idoso , Movimento Celular/imunologia , Feminino , Glucose/metabolismo , Humanos , Memória Imunológica/imunologia , Inflamação/imunologia , Resistência à Insulina/fisiologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Receptores de Quimiocinas/análiseRESUMO
AIMS: To investigate the effect of short-term vitamin D supplementation on cardiometabolic outcomes among individuals with an elevated risk of diabetes. METHODS: In a double-blind placebo-controlled randomized trial, 340 adults who had an elevated risk of type 2 diabetes (non-diabetic hyperglycaemia or positive diabetes risk score) were randomized to either placebo, 100,000 IU vitamin D2 (ergocalciferol) or 100,000 IU vitamin D3 (cholecalciferol), orally administered monthly for 4 months. The primary outcome was change in glycated haemoglobin (HbA1c) between baseline and 4 months, adjusted for baseline. Secondary outcomes included: blood pressure; lipid levels; apolipoprotein levels; C-reactive protein levels; pulse wave velocity (PWV); anthropometric measures; and safety of the supplementation. RESULTS: The mean [standard deviation (s.d.)] 25-hydroxyvitamin D [25(OH)D]2 concentration increased from 5.2 (4.1) to 53.9 (18.5) nmol/l in the D2 group, and the mean (s.d.) 25(OH)D3 concentration increased from 45.8 (22.6) to 83.8 (22.7) nmol/l in the D3 group. There was no effect of vitamin D supplementation on HbA1c: D2 versus placebo: -0.05% [95% confidence interval (CI) -0.11, 0.02] or -0.51 mmol/mol (95% CI -1.16, 0.14; p = 0.13); D3 versus placebo: 0.02% (95% CI -0.04, 0.08) or 0.19 mmol/mol (95% CI -0.46, 0.83; p = 0.57). There were no clinically meaningful effects on secondary outcomes, except PWV [D2 versus placebo: -0.68 m/s (95% CI -1.31, -0.05); D3 versus placebo -0.73 m/s (95% CI -1.42, -0.03)]. No important safety issues were identified. CONCLUSIONS: Short-term supplementation with vitamin D2 or D3 had no effect on HbA1c. The modest reduction in PWV with both D2 and D3 relative to placebo suggests that vitamin D supplementation has a beneficial effect on arterial stiffness.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Colecalciferol/uso terapêutico , Diabetes Mellitus Tipo 2/prevenção & controle , Suplementos Nutricionais , Ergocalciferóis/uso terapêutico , 25-Hidroxivitamina D 2/sangue , Adulto , Idoso , Calcifediol/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Colecalciferol/administração & dosagem , Colecalciferol/efeitos adversos , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Inglaterra/epidemiologia , Ergocalciferóis/administração & dosagem , Ergocalciferóis/efeitos adversos , Estudos de Viabilidade , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Risco , Rigidez VascularRESUMO
AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Assuntos
Exoma/genética , Polimorfismo Genético/genética , Diabetes Mellitus Tipo 2/genética , Frequência do Gene/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Diabetes UK is the charity that cares for, connects with and campaigns on behalf of all people affected by and at risk of diabetes. Founded in 1934 by the novelist H. G. Wells and Dr R. D. Lawrence, the charity has always combined the expertise of lay and professional members to achieve its mission to improve the lives of people with diabetes and to work towards a future without diabetes.
RESUMO
AIM: Genome-wide association studies have identified >30 common variants associated with Type 2 diabetes (>5% minor allele frequency). These variants have small effects on individual risk and do not account for a large proportion of the heritable component of the disease. Monogenic forms of diabetes are caused by mutations that occur in <1:2000 individuals and follow strict patterns of inheritance. In contrast, the role of low frequency genetic variants (minor allele frequency 0.1-5%) in Type 2 diabetes is not known. The aim of this study was to assess the role of low frequency PDX1 (also called IPF1) variants in Type 2 diabetes. METHODS: We sequenced the coding and flanking intronic regions of PDX1 in 910 patients with Type 2 diabetes and 878 control subjects. RESULTS: We identified a total of 26 variants that occurred in 5.3% of individuals, 14 of which occurred once. Only D76N occurred in >1%. We found no difference in carrier frequency between patients (5.7%) and control subjects (5.0%) (P=0.46). There were also no differences between patients and control subjects when analyses were limited to subsets of variants. The strongest subset were those variants in the DNA binding domain where all five variants identified were only found in patients (P=0.06). CONCLUSION: Approximately 5% of UK individuals carry a PDX1 variant, but there is no evidence that these variants, either individually or cumulatively, predispose to Type 2 diabetes. Further studies will need to consider strategies to assess the role of multiple variants that occur in <1 in 1000 individuals.
Assuntos
Diabetes Mellitus Tipo 2/genética , Proteínas de Homeodomínio/genética , Polimorfismo de Nucleotídeo Único/genética , Transativadores/genética , População Branca/genética , Adolescente , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência de DNA , Reino Unido/epidemiologia , Adulto JovemAssuntos
Auditoria Clínica , Pé Diabético/terapia , Qualidade de Vida , Cicatrização , Feminino , Humanos , MasculinoAssuntos
Diabetes Mellitus Tipo 2/terapia , Guias de Prática Clínica como Assunto , Qualidade da Assistência à Saúde/normas , Terapia Combinada/normas , Consenso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Governo Federal , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Reino UnidoAssuntos
Automonitorização da Glicemia/economia , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/metabolismo , Sistemas de Infusão de Insulina/economia , Insulina/administração & dosagem , Insulina/uso terapêutico , Monitorização Fisiológica/métodos , Avaliação de Resultados em Cuidados de Saúde/economia , Feminino , Humanos , MasculinoRESUMO
AIMS/HYPOTHESIS: Controversy surrounds whether the ratio of apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) is the best lipoprotein discriminator of CHD risk in non-diabetic populations, but the issue has never been investigated in type 2 diabetes. METHODS: In 2,627 participants without known vascular disease in the Collaborative Atorvastatin Diabetes Study, ApoB, ApoA-I, LDL-cholesterol (LDLC) and HDL-cholesterol (HDLC) were assayed at baseline. RESULTS: There were 108 CHD and 59 stroke endpoints over 3.9 years. The ApoB:A-I ratio at baseline was the lipoprotein variable most closely predicting CHD risk both by comparison of the hazard ratio for a 1 SD change or tertiles of frequency distribution. The areas under the receiver-operator curve for the ApoB:ApoA-I and the LDLC to HDLC [corrected] ratios, although not significantly different from each other, were greater (p = 0.0005 and p = 0.0125 respectively) than that of non-HDLC:HDLC. The 27% decrease in the ApoB:ApoA-I ratio on atorvastatin predicted a 32% (95% CI 5.4-51.2%) risk reduction in CHD, close to the 36% decrease observed. Neither the ApoB:ApoA-I nor any other lipoprotein concentration or ratio predicted the stroke outcome. CONCLUSIONS/INTERPRETATION: Overall, the ApoB:ApoA-I ratio improved on the non-HDLC:HDLC ratio in predicting CHD, but, depending on the assessment chosen, its superiority over LDLC:HDLC may be marginal. The statin-induced decrease in stroke risk may not be lipoprotein mediated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327418. FUNDING: The study was supported by unrestricted grants from Diabetes UK, the Department of Health and Pfizer to the University of Manchester and to University College, London.