RESUMO
Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.
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Calcinose , Disfunção Cognitiva , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Metformina , Estado Pré-Diabético , Calcificação Vascular , Masculino , Adulto , Humanos , Feminino , Diabetes Mellitus Tipo 2/complicações , Estado Pré-Diabético/complicações , Cálcio , Vasos Coronários , Estudos Transversais , Metformina/uso terapêutico , Disfunção Cognitiva/complicações , Calcinose/complicações , Cálcio da Dieta , Calcificação Vascular/complicações , Fatores de RiscoRESUMO
AIMS: We analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB). METHODS: The current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m2, with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD). RESULTS: At a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants. CONCLUSIONS: Development of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment. CLINICAL TRIAL REGISTRATIONS: Diabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992 DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727.
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Diabetes Mellitus Tipo 2 , Nefropatias , Metformina , Adulto , Humanos , Incidência , Estilo de Vida , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologiaRESUMO
INTRODUCTION: DNA methylation (DNAme) has been cross-sectionally associated with type 2 diabetes and hemoglobin A1c (HbA1c) in the general population. However, longitudinal data and data in type 1 diabetes are currently very limited. Thus, we performed an epigenome-wide association study (EWAS) in an observational type 1 diabetes cohort to identify loci with DNAme associated with concurrent and future HbA1cs, as well as other clinical risk factors, over 28 years. RESEARCH DESIGN AND METHODS: Whole blood DNAme in 683 597 CpGs was analyzed in the Pittsburgh Epidemiology of Diabetes Complications study of childhood onset (<17 years) type 1 diabetes (n=411). An EWAS of DNAme beta values and concurrent HbA1c was performed using linear models adjusted for diabetes duration, sex, pack years of smoking, estimated cell type composition variables, and technical/batch covariates. A longitudinal EWAS of subsequent repeated HbA1c measures was performed using mixed models. We further identified methylation quantitative trait loci (meQTLs) for significant CpGs and conducted a Mendelian randomization. RESULTS: DNAme at cg19693031 (Chr 1, Thioredoxin-Interacting Protein (TXNIP)) and cg21534330 (Chr 17, Casein Kinase 1 Isoform Delta) was significantly inversely associated with concurrent HbA1c. In longitudinal analyses, hypomethylation of cg19693031 was associated with consistently higher HbA1c over 28 years, and with higher triglycerides, pulse rate, and albumin:creatinine ratio (ACR) independently of HbA1c. We further identified 34 meQTLs in SLC2A1/SLC2A1-AS1 significantly associated with cg19693031 DNAme. CONCLUSIONS: Our results extend prior findings that TXNIP hypomethylation relates to worse glycemic control in type 1 diabetes by demonstrating the association persists over the long term. Additionally, the associations with triglycerides, pulse rate, and ACR suggest TXNIP DNAme could play a role in vascular damage independent of HbA1c. These findings strengthen potential for interventions targeting TXNIP to improve glycemic control in type 1 diabetes through its role in SLC2A1/glucose transporter 1-mediated glucose regulation.
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Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Metilação de DNA , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Hemoglobinas Glicadas , Epigênese Genética , Controle Glicêmico , Complicações do Diabetes/epidemiologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismoRESUMO
Background Utility of high-density lipoprotein cholesterol (HDL-C) in assessing the antiatherogenic properties of HDL may be limited in midlife women. Novel metrics of HDL function, lipid contents, and subclasses may better reflect the atheroprotective capacities of HDL, supporting the need to evaluate how cardiovascular health affects these metrics in women. We assessed the relationship of early midlife Life's Simple 7 (LS7) score and its health behavior components with future HDL function (HDL-cholesterol efflux capacity), HDL-phospholipid, HDL-triglyceride, HDL particles (HDL-P) and size, and the relationship between LS7 score and changes in HDL metrics over time. Methods and Results We analyzed 529 women (baseline age: 46.4 [2.6] years, 57% White) from the SWAN HDL (Study of Women's Health Across the Nation HDL) study who had baseline LS7 followed by future repeated HDL metrics. Multivariable linear mixed models were used. Higher LS7 score was associated with favorable future HDL profile (higher HDL-phospholipid, total HDL-P and large HDL-P, lower HDL-triglyceride, and larger overall HDL size). Ideal body mass index was associated with higher HDL-cholesterol efflux capacity, HDL-phospholipid, and large HDL-P, lower HDL-triglyceride and small HDL-P, and larger overall HDL size. Ideal physical activity was associated with higher HDL-phospholipid, and total, large, and medium HDL-P. Ideal smoking was associated with less HDL-triglycerides. Diet was not related to HDL metrics. Higher LS7 score and ideal body mass index were associated with slower progression of HDL size over time. Conclusions Novel HDL metrics may better reflect the clinical utility of HDL. Improving lifestyle at midlife, particularly maintaining ideal body mass index, is associated with better future HDL phenotype.
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Glicemia , Doenças Cardiovasculares , Feminino , Humanos , Pressão Sanguínea , Colesterol , Índice de Massa Corporal , Fosfolipídeos , Fatores de Risco , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controleRESUMO
BACKGROUND: We aimed to evaluate the risk of heart failure in young adults with childhood-onset type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. We also examined risk factors and microvascular disease burden associated with the incidence of heart failure. METHODS: Participants in the EDC study without known baseline heart failure (n = 655) were enrolled and then followed for 25 years. "Any" heart failure comprised the underlying cause of death, primary reason for hospitalization, EDC clinic examination findings or self-report of a physician diagnosis. "Hard" heart failure was determined only by the underlying cause of death or primary reason for hospitalization. Incidence rates for heart failure were estimated using Poisson models. Cox models were constructed to examine the associations between risk factors and microvascular disease burden with incident heart failure. RESULTS: The mean baseline age and diabetes duration were 27(8) years and 19 (8) years. Incidence for any and hard heart failure were 3.4 and 1.8/1000 person-years. Diabetes duration, ever smoking and triglycerides were significant risk factors of any heart failure; longer diabetes duration, lower estimated glomerular filtration rate and higher white blood cell count significantly predicted hard heart failure. A gradient association was observed between the number of microvascular disease (from 0 to 3) and "hard" heart failure endpoint but not "any" clinically defined heart failure. CONCLUSION: Young adults with long-duration type 1 diabetes had a high risk of heart failure. As microvascular disease burden increases so does the risk of heart failure independently of diabetes duration, A1c and coronary artery disease.
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Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Insuficiência Cardíaca , Criança , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/etiologia , Humanos , Incidência , Fatores de Risco , Adulto JovemRESUMO
CONTEXT: Novel metrics of high-density lipoprotein (HDL) (subclasses, lipid content, and function) may improve characterization of the anti-atherogenic features of HDL. In midlife women, changes in these metrics vary by time relative to the final menstrual period (FMP), supporting a contribution of estradiol (E2) and follicle-stimulating hormone (FSH). OBJECTIVE: We tested associations of endogenous E2 and FSH with novel HDL metrics and assessed whether these associations varied by time relative to FMP. METHODS: This study was a longitudinal analysis from the Study of Women's Health Across the Nation (SWAN) HDL study, using a community-based cohort of 463 women, baseline mean age 50.2 (2.7) years. The main outcome measures were HDL cholesterol efflux capacity (HDL-CEC), HDL phospholipids (HDL-PL), HDL triglycerides (HDL-Tg), HDL particles (HDL-P), HDL size, and HDL cholesterol (HDL-C). RESULTS: In multivariable analyses, E2 was positively associated with HDL size, large HDL-P, HDL-CEC, and HDL-Tg, but negatively with medium HDL-P (P valuesâ <â 0.05). The positive association between E2 and HDL-Tg was stronger 2 years post-FMP than before, (interaction Pâ =â 0.031). FSH was positively related to total and medium HDL-P, but negatively to HDL size, large HDL-P, and HDL-CEC per particle (P valuesâ <â 0.05). Associations of higher FSH with greater total HDL-P and smaller HDL size were only evident at/after menopause (interaction P valuesâ <â 0.05). CONCLUSION: Some of the associations linking E2 and FSH with novel HDL metrics were vulnerable to time relative to menopause onset. Whether a late initiation of hormone therapy relative to menopause could have a detrimental effect on lipid content of HDL particles should be tested in the future.
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Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Lipoproteínas HDL/sangue , Menopausa/metabolismo , Adulto , Estradiol/metabolismo , Feminino , Hormônio Foliculoestimulante/metabolismo , Humanos , Lipoproteínas HDL/metabolismo , Estudos Longitudinais , Menopausa/sangue , Pessoa de Meia-Idade , Saúde da MulherRESUMO
OBJECTIVE: Women with type 1 diabetes (T1D) are thought to experience menopause earlier than women without diabetes, although not all studies agree. We assessed metabolic predictors of the age at which natural menopause occurs among women with T1D participating in the Epidemiology of Diabetes Complications study. METHODS: Women with childhood-onset (<17ây) of T1D who underwent natural menopause without use of hormone therapy during their menopausal transition were included in the analysis (nâ=â105; mean baseline age, 29.5 and diabetes duration, 20.2ây). Self-reported reproductive history and the Women's Ischemia Syndrome Evaluation hormonal algorithms were used to determine menopause status. Linear regression was used to ascertain whether time-weighted metabolic factors (eg, BMI, lipids, HbA1c, insulin dose, albumin excretion rate [AER]) were associated with age at natural menopause. RESULTS: Univariately, only insulin dose (ßâ=â-4.87, Pâ=â0.04) and log (AER) (ßâ=â-0.62, Pâ=â0.02) were associated (negatively) with age at natural menopause. Adjusting for BMI, smoking status, lipids, HbA1c, number of pregnancies, and oral contraceptive use, each 0.1 unit increase in the daily dose of insulin per kilogram body weight was associated with 0.64âyears younger age at natural menopause (Pâ=â0.01), while for every 30% increase in AER, age at natural menopause decreased by 0.18âyears (Pâ=â0.03). CONCLUSION: Higher average levels of insulin dose and AER over time were significantly associated with a younger age at which natural menopause occurred among women with T1D. The biologic mechanisms underlying the observed associations between exogenous insulin dose and AER on reproductive health should be investigated among women with T1D.
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Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Adulto , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Insulina , Menopausa , Gravidez , História ReprodutivaRESUMO
AIMS/HYPOTHESIS: Type 1 diabetes increases CHD risk. We examined the use of the American Heart Association's cardiovascular health metrics (blood pressure, total cholesterol, glucose/HbA1c, BMI, physical activity, diet, smoking) to predict incidence of CHD among individuals with type 1 diabetes, with the hypothesis that a better American Heart Association health metric profile would be associated with lower incident CHD. METHODS: Prevalence of the seven cardiovascular health metrics was determined using first and second visits from adult participants (mean age 28.6 years) in the Epidemiology of Diabetes Complications prospective cohort study of childhood-onset type 1 diabetes. An ideal metric score (0-7) was defined as the sum of all metrics within the ideal range, and a total metric score (0-14) was calculated based on poor, intermediate and ideal categories for each metric. Incident CHD development (medical record-confirmed CHD death, myocardial infarction, revascularisation, ischaemic electrocardiogram changes or Epidemiology of Diabetes Complications physician-determined angina) over 25 years of follow-up was examined by metric scores. RESULTS: Among 435 participants, BMI, blood pressure, total cholesterol and smoking demonstrated the highest prevalence within the ideal range, while diet and HbA1c demonstrated the lowest. During 25 years of follow-up, 177 participants developed CHD. In Cox models, each additional metric within the ideal range was associated with a 19% lower risk (p = 0.01), and each unit increase in total metric score was associated with a 17% lower risk (p < 0.01) of CHD, adjusting for diabetes duration, estimated glomerular filtration rate, albumin excretion rate, triacylglycerols, depression and white blood cell count. CONCLUSIONS/INTERPRETATION: Among individuals with type 1 diabetes, higher cardiovascular health metric scores were associated with lower risk of incident CHD. The American Heart Association-defined cardiovascular health metrics provide straightforward goals for health promotion that may reduce CHD risk in the type 1 diabetes population. Graphical abstract.
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Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Nível de Saúde , Estilo de Vida Saudável , Adulto , Biomarcadores/sangue , Glicemia/análise , Pressão Sanguínea , Colesterol/sangue , Doença das Coronárias/diagnóstico , Diabetes Mellitus Tipo 1/diagnóstico , Dieta Saudável , Exercício Físico , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Indicadores Básicos de Saúde , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pennsylvania/epidemiologia , Prevalência , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Tempo , Adulto JovemAssuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , Carga Global da Doença , Comitês Consultivos , Doenças Cardiovasculares/mortalidade , Comorbidade , Gerenciamento de Dados , Complicações do Diabetes/economia , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/economia , Diabetes Gestacional/epidemiologia , Meio Ambiente , Feminino , Predisposição Genética para Doença , Saúde Global , Gastos em Saúde , Política de Saúde , Acessibilidade aos Serviços de Saúde , Humanos , Células Secretoras de Insulina/patologia , Cobertura do Seguro , Nefropatias/mortalidade , Estilo de Vida , Área Carente de Assistência Médica , Transtornos Mentais/epidemiologia , Múltiplas Afecções Crônicas/epidemiologia , Neoplasias/mortalidade , Obesidade/epidemiologia , Educação de Pacientes como Assunto , Dinâmica Populacional , Gravidez , Garantia da Qualidade dos Cuidados de Saúde , Medição de Risco , Fatores de Risco , Autogestão , Fatores Socioeconômicos , TelemedicinaRESUMO
BACKGROUND: A greater frequency of vasomotor symptoms (VMSs) has been associated with higher low-density lipoprotein cholesterol (LDL-C), but the association with high-density lipoprotein cholesterol (HDL-C) remains unclear. Endogenous estradiol (E2) levels are associated with both VMS and lipid levels and thus may confound such associations. OBJECTIVES: To assess the relationship of VMS frequency with HDL-C, LDL-C, and lipoprotein concentrations (HDL and LDL particles [HDL-P; LDL-P]) and lipoprotein sizes in midlife women and to evaluate whether these associations are explained by E2. METHODS: Participants were from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study who had both nuclear magnetic resonance (NMR) spectroscopy lipoprotein subclass metrics and self-reported frequency of VMS measured 2-5 times over the menopause transition. VMS frequency was categorized into none, 1-5 days (infrequent), or ≥6 days (frequent) within the past 2 weeks. RESULTS: We evaluated 522 women [at baseline: mean age 50.3 (SD: 2.8) years; infrequent VMS: 29.8%, frequent VMS: 16.5%]. Adjusting for potential confounders except E2, frequent VMS was associated with smaller HDL size [ß(SE): -0.06 (0.03); P = .04] and higher concentrations of LDL-C [ß(SE): 3.58 (1.77); P = .04] and intermediate LDL-P [ß(SE): 0.09 (0.05); P = .04] than no VMS. These associations were largely explained by E2, all P's > .05. CONCLUSIONS: Frequent VMSs were associated with smaller HDL size and higher concentrations of LDL-C and intermediate LDL-P. These associations were explained by endogenous E2. Whether treating frequent VMS with exogenous E2 could simultaneously improve lipids/lipoproteins profile should be assessed in future studies.
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Estradiol/sangue , Estrogênios/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Sistema Vasomotor/patologia , Adulto , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Prognóstico , Sistema Vasomotor/metabolismoRESUMO
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, ß-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, ß-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m2, higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.
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Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Neuropatias Diabéticas/patologia , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Glicemia , Estudos de Coortes , Feminino , Hemoglobinas Glicadas , Humanos , Estudos Longitudinais , Masculino , Análise Multivariada , Fatores de Risco , Adulto JovemRESUMO
AIM: To assess the role of periodontal disease (PD) as a predictor of coronary artery disease (CAD) and mortality in a prospective type 1 diabetes (T1D) cohort and to evaluate the role of smoking in this relationship. METHODS: Data were based on 320 participants of the Pittsburgh Epidemiology of Diabetes Complications study of T1D who, during 1992-94, received a partial mouth periodontal exam, and who were followed for up to 19â¯years to ascertain complication incidence. PD was defined as clinical attachment loss of ≥4â¯mm for at least 10% of the examined sites. Predictors of all-cause mortality; Hard CAD (CAD death, myocardial infarction or revascularization), and Total CAD (Hard CAD, angina, ischemic ECG) were assessed using Cox models. RESULTS: During 19â¯years of follow-up, 33.7% (97/288) developed CAD, 27.3% (83/304) developed Hard CAD, and 16.9% (54/320) died. Among current smokers, 46.4% (26/56) developed CAD, 42.7% (24/56) developed Hard CAD and 29.5% (18/61) died. PD was not associated with all-cause mortality, although it was a significant predictor of both CAD (HRâ¯=â¯1.12, CIâ¯=â¯1.01-1.23) and Hard CAD (HRâ¯=â¯1.30, CIâ¯=â¯1.11-1.51). As smoking modified the PD-CAD and PD-Hard CAD associations, analyses were stratified by smoking status. PD was associated with an increased risk of CAD (HRâ¯=â¯1.25, CIâ¯=â¯1.03-1.50) and Hard CAD (HRâ¯=â¯1.85, CIâ¯=â¯1.17-2.93) only among smokers. CONCLUSION: PD was a significant predictor of CAD and Hard CAD among current smokers with T1D.
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Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Doenças Periodontais/epidemiologia , Fumar/epidemiologia , Adulto , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Estudos ProspectivosRESUMO
AIMS/HYPOTHESIS: We compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. METHODS: The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. RESULTS: E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). CONCLUSIONS/INTERPRETATION: These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.
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Biomarcadores/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Metformina/uso terapêutico , Adiponectina/sangue , Quimiocina CCL2/sangue , Diabetes Mellitus/terapia , Selectina E/sangue , Fibrinogênio/metabolismo , Molécula 1 de Adesão Intercelular/sangue , Interleucina-6/sangue , Leptina/sangue , Ativador de Plasminogênio Tecidual/sangueRESUMO
In a recent Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study report, mean HbA1c was the strongest predictor of cardiovascular disease (CVD) after age. In DCCT/EDIC, mean diabetes duration was 6 years (median 4) at baseline and those with high blood pressure or cholesterol were excluded. We now replicate these analyses in the Pittsburgh Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset (at <17 years of age) type 1 diabetes, with similar age (mean 27 years in both studies) but longer diabetes duration (mean 19 years and median 18 years) and no CVD risk factor exclusion at baseline. CVD incidence (CVD death, myocardial infarction (MI), stroke, revascularization, angina, or ischemic electrocardiogram) was associated with diabetes duration, most recent albumin excretion rate (AER), updated mean triglycerides, baseline hypertension, baseline LDL cholesterol, and most recent HbA1c Major atherosclerotic cardiovascular events (CVD death, MI, or stroke) were associated with diabetes duration, most recent AER, baseline systolic blood pressure, baseline smoking, and updated mean HbA1c Compared with findings in DCCT/EDIC, traditional risk factors similarly predicted CVD; however AER predominates in EDC and HbA1c in DCCT/EDIC. Thus, the relative impact of HbA1c and kidney disease in type 1 diabetes varies according to diabetes duration.
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Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/etiologia , Adolescente , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/metabolismo , Criança , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: We assessed the predictive role of coronary artery calcification (CAC) in clinically relevant cognitive impairment in 148 middle-aged individuals with childhood-onset type 1 diabetes (T1D) from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. METHODS: Baseline CAC was measured in 1996-98 and repeated 4-8 years later. Per extensive neuropsychological testing in 2010-15, 28% (41/148) of participants met the study definition of clinically relevant cognitive impairment (two or more of 7 select test scores ≥1.5SD worse than demographically appropriate published norms). Logistic regression models with backward selection were constructed for statistical analysis. RESULTS: Mean age and T1D duration at first CAC measure were 37 and 29 years, respectively. A greater burden of initial CAC was associated with cognitive impairment determined 14 years later. Compared to Agatston scoreâ¯=â¯0, odds ratio (OR) and 95% confidence intervals (CI) of 0<-100, 100<-300 and >300 were 1.4 (0.6, 3.6), 2.3 (0.6, 9.7), and 7.9 (1.6, 38.5), respectively. With both initial and progression of CAC in the multivariable model, backward selection retained only CAC progression, showing it was significantly associated with cognitive impairment (OR [95% CI]: 1.7 [1.1, 2.9]). In those with an initial CAC>0, CAC density was marginally, inversely, associated with cognitive impairment when controlling for CAC volume (OR [95%CI]: 0.3 (0.1, 1.2), p valueâ¯=â¯0.078). CONCLUSIONS: Greater CAC burden was associated with clinically relevant cognitive impairment in middle-aged adults with childhood-onset T1D. CAC progression appears to be a more powerful predictor than initial calcification.
Assuntos
Calcinose/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Adolescente , Adulto , Índice Tornozelo-Braço , Calcinose/complicações , Criança , Disfunção Cognitiva/complicações , Doença da Artéria Coronariana/complicações , Complicações do Diabetes , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Valor Preditivo dos Testes , Estudos Prospectivos , Análise de Regressão , Medição de Risco , Adulto JovemRESUMO
BACKGROUND: Diabetic medications can cause hypoglycemia, which may lead to myocardial damage. OBJECTIVES: This study sought to determine whether hypoglycemia is associated with higher levels of high-sensitivity cardiac troponin T (hsTnT). METHODS: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial randomized patients with type 2 diabetes mellitus and stable coronary artery disease, and closely followed them for hypoglycemia over the first year. Hypoglycemia was classified by maximum severity and frequency. hsTnT was measured at baseline and 1 year, and analyzed using multivariable regression. RESULTS: Of 1,984 patients, follow-up hypoglycemia was absent in 1,026 (52%) patients, mild in 875 (44%), and severe in 83 (4%), and occurred less than weekly in 561 (28%) and greater than or equal to weekly in 397 (20%). hsTnT levels were associated with hypoglycemia: a median of 11.4 ng/l (interquartile range [IQR]: 8.1 to 17.3 ng/l) for none, 12.5 ng/l (IQR: 8.3 to 19.3 ng/l) for mild, and 13.7 ng/l (IQR: 9.9 to 24.9 ng/l) for severe hypoglycemia (p = 0.0001); and 12.5 ng/l (IQR: 8.3 to 18.1 ng/l) for less than weekly and 13.0 ng/l (IQR: 8.8 to 21.1 ng/l) for greater than or equal to weekly hypoglycemia (p = 0.0013). Severe hypoglycemia was associated with 34% higher 1-year hsTnT levels (p < 0.0001) in unadjusted analysis, 17% higher (p = 0.006) after adjustment for baseline factors unrelated to diabetes, and 6% higher (p = 0.23) after further adjustment for the duration and severity of diabetes. Hypoglycemia greater than or equal to weekly was associated with 14% higher hsTnT (p = 0.0003) in unadjusted analysis, 12% higher (p = 0.0002) after adjustment for baseline factors unrelated to diabetes, and 4% higher (p = 0.16) after adjustment for diabetes related factors. CONCLUSIONS: Hypoglycemia was associated with elevated hsTnT levels, but this may be due to more severe diabetes in patients who developed hypoglycemia, rather than the direct result of hypoglycemia. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI2D]; NCT00006305).
Assuntos
Glicemia/análise , Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Hipoglicemia , Troponina T/sangue , Idoso , Biomarcadores/análise , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Correlação de Dados , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Hipoglicemia/sangue , Hipoglicemia/etiologia , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Período Pós-Operatório , Medição de Risco , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Haptoglobin's (Hp) main role is to bind free hemoglobin (Hb), reducing its oxidative potential. The Hp-Hb complex formed is cleared from the circulation by macrophage receptor CD163. In diabetes, impaired Hp 2-2-Hb CD163 clearance and abnormal glomerular permeability allow the large Hp 2-2-Hb complex to cross the barrier, where its redox active iron leads to cellular toxicity. Although Hp 2-2 predicts renal function decline, whether renal iron deposition differs by Hp is unknown. We used renal quantitative T2* magnetic resonance imaging to estimate iron level in the cortex and medullar of type 1 diabetes (T1D) adults [15 Hp 1-1 and 15 Hp 2-2 carriers of similar age (53 years), duration (45 years), and gender]. Total kidney iron level was estimated as the sum of the cortex and medullar iron. Albuminuria was defined as urinary albumin to creatinine ratio >30 mg/g in two of three samples. Total kidney iron did not differ by gender or Hp but was higher in those with albuminuria (p = 0.05), an association confined to Hp 2-2 carriers (p = 0.04 vs. p = 0.51 in Hp 1-1). These data lead to the hypothesis that kidney iron deposition is increased among Hp 2-2 carriers with albuminuria in T1D. Antioxid. Redox Signal. 29, 735-741.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Haptoglobinas/genética , Heterozigoto , Ferro/análise , Ferro/metabolismo , Rim/metabolismo , Imageamento por Ressonância Magnética , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Haptoglobinas/metabolismo , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT: Growing evidence challenges the concept that high-density lipoprotein-cholesterol (HDL-C) is cardioprotective after menopause. HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) might be better predictors of cardiovascular risk. OBJECTIVE: Quantify alterations in HDL-P and CEC during menopause, correlating those changes with alterations in estradiol (E2) and FSH. DESIGN: Longitudinal study of HDL metrics before and after menopause as indexed by the final menstrual period (FMP). PARTICIPANTS: Forty-six women, mean baseline age 47.1 years, 33% black, 67% white. MAIN OUTCOMES AND MEASURES: HDL-P concentration (HDL-PIMA) by calibrated ion mobility analysis (IMA); macrophage CEC with cAMP-stimulated macrophages; ATP-binding cassette transporter A1 (ABCA1)-specific CEC with BHK cells expressing human ABCA1. RESULTS: After a median of 2.1 years since FMP, both HDL-C (P = .03) and HDL-PIMA (P = .01) increased, with a selective increase in large HDL-PIMA (P = .01), whereas sizes of medium and small HDL-PIMA were decreased (P < .05). These changes were independent of race, body mass index, and time difference. Macrophage CEC and ABCA1-specific CEC increased after FMP (both P < .001). Greater declines in E2 correlated with larger increases in small HDL-PIMA (P = .01), whereas greater increases in FSH associated with greater reductions in the size of medium HDL-PIMA (P = .04). Macrophage CEC and ABCA1-specific CEC correlated positively with E2 levels only before menopause (P = .04 and .009, respectively). CONCLUSIONS: Large HDL-PIMA and CEC increased significantly in the early phase of the menopausal transition. Whether patterns of these alterations differ in late postmenopause is unknown. Further exploration is needed to assess that and to determine whether the reported changes in HDL metrics associate with increased cardiovascular risk after menopause.
Assuntos
Doenças Cardiovasculares/fisiopatologia , HDL-Colesterol/sangue , Colesterol/sangue , Transportador 1 de Cassete de Ligação de ATP/sangue , Adulto , Biomarcadores/metabolismo , Células Cultivadas , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Macrófagos/citologia , Macrófagos/metabolismo , Menopausa , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Saúde da MulherRESUMO
OBJECTIVE: In addition to slowing diabetes development among participants in the Diabetes Prevention Program (DPP), intensive lifestyle change and metformin raised HDL-cholesterol (HDL-C) compared to placebo treatment. We investigated the lifestyle and metabolic determinants as well as effects of biomarkers of inflammation, endothelial dysfunction and coagulation and their changes resulting from lifestyle and metformin interventions on the increase in HDL-C in the DPP. METHODS: The effects of a 1year period of intensive lifestyle change aimed at achieving 7% weight loss or metformin 850mg twice daily versus placebo on HDL-C were assessed in 3070 participants with impaired glucose tolerance, and on HDL particle concentration (HDL-P) and size in a subgroup of 1645 individuals. Treatment-associated changes in lifestyle and metabolic factors as well as in novel biomarkers were investigated for their associations with change in HDL-C using multiple regression analysis. RESULTS: After adjusting for BMI, insulin resistance, glycemia, dietary saturated fat, alcohol intake, physical activity and nine different biomarkers, only adiponectin accounted for the effect of intensive lifestyle change on HDL-C via an increase in large HDL-P. By contrast baseline and change in BMI and tissue plasminogen activator levels attenuated the effect of metformin on HDL-C, with adiponectin having no specific effect. CONCLUSION: While both lifestyle and metformin interventions used to prevent diabetes increase HDL-C, the mechanisms involved differ between the two treatments and may have consequences for future risk of cardiovascular disease.
Assuntos
Adiponectina/sangue , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Estilo de Vida , Sobrepeso/terapia , Estado Pré-Diabético/terapia , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Terapia Combinada , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta com Restrição de Gorduras , Dieta Redutora , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Atividade Motora , Sobrepeso/sangue , Sobrepeso/dietoterapia , Sobrepeso/fisiopatologia , Estado Pré-Diabético/sangue , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/fisiopatologia , Fatores de Risco , Estados Unidos/epidemiologia , Redução de PesoRESUMO
OBJECTIVE: Low testosterone concentrations have been reported to be associated with increased risk of congestive heart failure, but the mechanisms are unclear. Our objective was to examine the relationship between endogenous testosterone and measures of cardiac mass and function among men with type 1 diabetes. DESIGN: Secondary analysis of a prospective observational study. PARTICIPANTS: Men (n = 508) in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial (DCCT). MEASUREMENTS: Testosterone assessed by liquid chromatography mass spectrometry at EDIC year 10 and cardiac magnetic resonance imaging (CMR) measures at EDIC years 14/15. Linear regression models were used to assess the relationship between testosterone, sex hormone binding globulin (SHBG) and left ventricular (LV) mass, volume, ejection fraction and cardiac index before and after adjustment for age, randomization arm, alcohol and cigarette use, macroalbuminuria, haemoglobin A1c, insulin dose, body mass index, lipids, blood pressure, use of antihypertensive medications and microvascular complications. RESULTS: In fully adjusted models, total testosterone concentrations were significantly associated with LV mass (P = 0·014), end-diastolic volume (P = 0·002), end-systolic volume (P = 0·012) and stroke volume (P = 0·022), but not measures of LV function after adjustment for cardiac risk factors. Bioavailable testosterone was associated with LV mass, but not volume or function, while SHBG was associated with volume, but not mass or function. CONCLUSIONS: Among men with type 1 diabetes, higher total testosterone was associated with higher LV mass and volume, but not with function. The clinical significance of this association remains to be established.