RESUMO
AIM: To examine the association between early onset of type 2 diabetes mellitus (DM) and clinical and behavioural risk factors for later complications of diabetes. METHODS: We conducted a cross-sectional study of 5115 persons with incident type 2 DM enrolled during 2010-2015 in the Danish Centre for Strategic Research in Type 2 Diabetes-cohort. We compared risk factors at time of diagnosis among those diagnosed at ≤45 years (early onset) with diagnosis age 46 to 55, 56 to 65 (average onset = reference), 66 to 75, and >75 years (late onset). Prevalence ratios (PRs) were computed by using Poisson regression. RESULTS: Poor glucose control, ie, HbA1c ≥ 75 mmol/mol (≥9.0%) in the early-, average-, and late-onset groups was observed in 12%, 7%, and 1%, respectively (PR 1.70 [95% confidence intervals (CI) 1.27, 2.28] and PR 0.17 [95% CI 0.06, 0.45]). A similar age gradient was observed for severe obesity (body mass index > 40 kg/m2 : 19% vs. 8% vs. 2%; PR 2.41 [95% CI 1.83, 3.18] and 0.21 (95% CI 0.08, 0.57]), dyslipidemia (90% vs. 79% vs. 68%; PR 1.14 [95% CI 1.10, 1.19] and 0.86 [95% CI 0.79, 0.93]), and low-grade inflammation (C-reactive protein > 3.0 mg/L: 53% vs. 38% vs. 26%; PR 1.41 [95% CI 1.12, 1.78] and 0.68 [95% CI 0.42, 1.11]). Daily smoking was more frequent and meeting physical activity recommendations less likely in persons with early-onset type 2 DM. CONCLUSIONS: We found a clear age gradient, with increasing prevalence of clinical and behavioural risk factors the younger the onset age of type 2 DM. Younger persons with early-onset type 2 DM need clinical awareness and support.
Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Fatores Etários , Idade de Início , Idoso , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoAssuntos
Diabetes Mellitus/prevenção & controle , Saúde Global/normas , Política de Saúde , Atenção Primária à Saúde , Berlim , Diabetes Mellitus/epidemiologia , Promoção da Saúde/organização & administração , Promoção da Saúde/normas , Direitos Humanos , Humanos , Cazaquistão , Medicina Preventiva/métodos , Medicina Preventiva/organização & administração , Medicina Preventiva/normas , Atenção Primária à Saúde/organização & administração , Atenção Primária à Saúde/normasRESUMO
Telemonitoring of home blood pressure measurements (TBPM) is a new and promising supplement to diagnosis, control and treatment of hypertension. We wanted to compare the outcome of antihypertensive treatment based on TBPM and conventional monitoring of blood pressure. Participants were recruited from a prevalence study among citizens aged 55-64 years in the municipality of Holstebro, Denmark. The study was a randomized, controlled, unblinded 3 months' trial. In the intervention group, antihypertensive treatment was based on TBPM with transmission of the measurements and subsequent communication by telephone or e-mail. In the control group, patients received usual care. Primary outcome was reduction in daytime ambulatory blood pressure measurements (ABPM) from baseline to 3 months' follow-up. Of 375 participants randomized, primary outcome data were available for 356 (95%). In both groups, daytime ABPM decreased significantly. The decrease in daytime ABPM in the intervention group was systolic/diastolic, -8±12/-4±7 mm Hg. This did not differ significantly from the control group's -8±13/-4±8 mm Hg. An equal number of participants obtained normal daytime ABPM, in the intervention group 17% (31/175) versus control 21% (37/181), P=0.34. We found that both TBPM patients and controls achieved a significant blood pressure reduction in this randomized, controlled, unblinded 3-month trial. We found no difference in blood pressure reduction or number of patients reaching blood pressure goals. Further information and education of some general practitioners seem to be relevant regarding blood pressure management and control of hypertension.
Assuntos
Monitorização Ambulatorial da Pressão Arterial/estatística & dados numéricos , Telemedicina/estatística & dados numéricos , Monitorização Ambulatorial da Pressão Arterial/instrumentação , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria 5 years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management. METHODS: In 1826 participants with newly diagnosed, screen-detected diabetes without albuminuria, we explored associations between risk of new albuminuria (≥2.5 mg mmol-1 for males and ≥3.5 mg mmol-1 for females) and (1) baseline cardio-metabolic risk factors and (2) changes from baseline to 1 year in systolic blood pressure (ΔSBP) and glycated haemoglobin (ΔHbA1c ) using logistic regression. RESULTS: Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in 5 years after detection of diabetes. In a model adjusted for age, gender, baseline HbA1c and blood pressure, a 1% decrease in HbA1c and 5-mm Hg decrease in SBP during the first year were independently associated with lower risks of albuminuria (odds ratio), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively. Further adjustment did not materially change these estimates. There was no interaction between ΔSBP and ΔHbA1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease. CONCLUSIONS: Baseline measurements and changes in HbA1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria 4 years later. Established multifactorial treatment for diabetes applies to cases identified through screening.
Assuntos
Albuminúria/epidemiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/epidemiologia , Idoso , Albuminúria/fisiopatologia , Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/fisiopatologia , Feminino , Hemoglobinas Glicadas/análise , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
AIMS: The glycolysis-derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6-year follow-up in 1481 people with screen-detected Type 2 diabetes, as part of the Danish arm of the ADDITION-Europe trial (ADDITION-DK). METHODS: Biobank serum samples collected at ADDITION-DK baseline (2001-2006) and follow-up (2009-2010) were used in the current analysis of methylglyoxal. We assessed cross-sectional baseline and longitudinal associations between methylglyoxal and urinary albumin-to-creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR. RESULTS: Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow-up was inversely associated with change in eGFR (-1.6 ml/min/1.73 m2 per doubling in methylglyoxal change), in models adjusted for age, sex, HbA1c , systolic blood pressure, anti-hypertensive treatment, LDL-cholesterol, lipid-lowering treatment, C-reactive protein and smoking. CONCLUSIONS: In a population of people with screen-detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6-year change in methylglyoxal was inversely associated with 6-year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Aldeído Pirúvico/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Albuminúria/fisiopatologia , Creatinina/urina , Estudos Transversais , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: Cardiovascular autonomic neuropathy and diabetic peripheral neuropathy are common diabetic complications and independent predictors of cardiovascular disease. The glucose metabolite methylglyoxal has been suggested to play a causal role in the pathogeneses of diabetic peripheral neuropathy and possibly diabetic cardiovascular autonomic neuropathy. The aim of this study was to investigate the cross-sectional association between serum methylglyoxal and diabetic peripheral neuropathy and cardiovascular autonomic neuropathy in a subset of patients in the ADDITION-Denmark study with short-term screen-detected Type 2 diabetes (duration ~ 5.8 years). METHODS: The patients were well controlled with regard to HbA(1c), lipids and blood pressure. Cardiovascular autonomic neuropathy was assessed by measures of resting heart rate variability and cardiovascular autonomic reflex tests. Diabetic peripheral neuropathy was assessed by vibration detection threshold (n = 319), 10 g monofilament (n = 543) and the Michigan Neuropathy Screening Instrument questionnaire (n = 966). Painful diabetic neuropathy was assessed using the Brief Pain Inventory short form (n = 882). RESULTS: No associations between methylglyoxal and cardiovascular autonomic reflex tests or any measures of diabetic peripheral neuropathy or painful diabetic neuropathy were observed. However, a positive association between methylglyoxal and several heart rate variability indices was observed, although these associations were not statistically significant when corrected for multiple testing. CONCLUSION: Serum methylglyoxal is not associated with cardiovascular autonomic neuropathy, diabetic peripheral neuropathy or painful diabetic neuropathy in this cohort of well-treated patients with short-term diabetes.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Neuropatias Diabéticas/sangue , Aldeído Pirúvico/sangue , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/epidemiologia , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: To investigate whether intensive multifactorial treatment can reverse the predisposed adverse phenotype of people with Type 2 diabetes who have a family history of diabetes. METHODS: Data from the randomized controlled trial ADDITION-Denmark were used. A total of 1441 newly diagnosed patients with diabetes (598 with family history of diabetes) were randomized to intensive treatment or routine care. Family history of diabetes was defined as having one parent and/or sibling with diabetes. Linear mixed-effects models were used to assess the changes in risk factors (BMI, waist circumference, blood pressure, lipids and HbA1c ) after 5 years of follow-up in participants with and without a family history of diabetes. An interaction term between family history of diabetes and treatment group was included in the models to test for a modifying effect of the intervention. All analyses were adjusted for age, sex, baseline value of the risk factor and general practice (random effect). RESULTS: At baseline, participants with a family history of diabetes were younger and had a 1.1 mmol/mol (0.1%) higher HbA1c concentration at the time of diagnosis than those without a family history of diabetes. Family history of diabetes modified the effect of the intervention on changes in HbA1c levels. In the group receiving routine care, participants with a family history of diabetes experienced an improvement in HbA1c concentration that was 3.3 mmol/mol (0.3%) lower than the improvement found in those without a family history of diabetes after 5 years of follow-up. In the intensive treatment group, however, there was no difference in HbA1c concentrations between participants with and without a family history of diabetes after 5 years of treatment. CONCLUSIONS: Intensive treatment of diabetes may partly remove the adverse effects of family history of diabetes on glycaemic control. The effect of this improvement on long-term diabetic complications warrants further investigation.
Assuntos
Anti-Hipertensivos/uso terapêutico , Aspirina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Aconselhamento/métodos , Diabetes Mellitus Tipo 2/terapia , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Pressão Sanguínea , Índice de Massa Corporal , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Terapia Combinada , Dinamarca , Diabetes Mellitus Tipo 2/genética , Família , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Comportamento de Redução do Risco , Resultado do Tratamento , Triglicerídeos/metabolismo , Circunferência da CinturaRESUMO
AIMS: To examine the short- and long-term cost-effectiveness of intensive multifactorial treatment compared with routine care among people with screen-detected Type 2 diabetes. METHODS: Cost-utility analysis in ADDITION-UK, a cluster-randomized controlled trial of early intensive treatment in people with screen-detected diabetes in 69 UK general practices. Unit treatment costs and utility decrement data were taken from published literature. Accumulated costs and quality-adjusted life years (QALYs) were calculated using ADDITION-UK data from 1 to 5 years (short-term analysis, n = 1024); trial data were extrapolated to 30 years using the UKPDS outcomes model (version 1.3) (long-term analysis; n = 999). All costs were transformed to the UK 2009/10 price level. RESULTS: Adjusted incremental costs to the NHS were £285, £935, £1190 and £1745 over a 1-, 5-, 10- and 30-year time horizon, respectively (discounted at 3.5%). Adjusted incremental QALYs were 0.0000, - 0.0040, 0.0140 and 0.0465 over the same time horizons. Point estimate incremental cost-effectiveness ratios (ICERs) suggested that the intervention was not cost-effective although the ratio improved over time: the ICER over 10 years was £82,250, falling to £37,500 over 30 years. The ICER fell below £30 000 only when the intervention cost was below £631 per patient: we estimated the cost at £981. CONCLUSION: Given conventional thresholds of cost-effectiveness, the intensive treatment delivered in ADDITION was not cost-effective compared with routine care for individuals with screen-detected diabetes in the UK. The intervention may be cost-effective if it can be delivered at reduced cost.
Assuntos
Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/economia , Diabetes Mellitus Tipo 2/terapia , Assistência Centrada no Paciente , Idoso , Análise por Conglomerados , Estudos de Coortes , Terapia Combinada/economia , Análise Custo-Benefício , Complicações do Diabetes/economia , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Custos de Cuidados de Saúde , Humanos , Incidência , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/economia , Assistência Centrada no Paciente/economia , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologiaRESUMO
AIMS: To examine variation between general practices in the prescription of lipid-lowering treatment to people with screen-detected Type 2 diabetes, and associations with practice and participant characteristics and risk of cardiovascular events and all-cause mortality. METHODS: Observational cohort analysis of data from 1533 people with screen-detected Type 2 diabetes aged 40-69 years from the ADDITION-Denmark study. One hundred and seventy-four general practices were cluster randomized to receive: (1) routine diabetes care according to national guidelines (623 individuals), or (2) intensive multifactorial target-driven management (910 individuals). Multivariable logistic regression was used to quantify the association between the proportion of individuals in each practice who redeemed prescriptions for lipid-lowering medication in the two years following diabetes diagnosis and a composite cardiovascular disease (CVD) outcome, adjusting for age, sex, prevalent chronic disease, baseline CVD risk factors, smoking and lipid-lowering medication, and follow-up time. RESULTS: The proportion of individuals treated with lipid-lowering medication varied widely between practices (0-100%). There were 118 CVD events over 9431 person-years of follow-up. For the whole trial cohort, the risk of CVD was significantly higher in practices in the lowest compared with the highest quartile for prescribing lipid-lowering medication [adjusted odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6-7.3]. Similar trends were found for all-cause mortality. CONCLUSIONS: More frequent prescription of lipid-lowering treatment was associated with a lower incidence of CVD and all-cause mortality. Improved understanding of factors underlying practice variation in prescribing may enable more frequent use of lipid-lowering treatment. The results highlight the benefits of intensive treatment of people with screen-detected diabetes (Clinical Trials Registry No; NCT 00237549).
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Gerenciamento Clínico , Feminino , Humanos , Incidência , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Mortalidade , Fatores de RiscoRESUMO
BACKGROUND: Diurnal variation in serum growth hormone (s-GH) levels after exogenous GH delivery has previously been reported in patients with no endogenous GH secretion. Changes in postural position or physical activity, leading to changes in blood flow and/or lymphatic drainage may be underlying explanations. PRIMARY OBJECTIVES: The primary aim of this study is to study a possible impact of exercise and supine rest on pharmacokinetics (PK) and day-to-day variation of subcutaneously (s.c.) administered GH in adult GH deficient (AGHD) patients. SECONDARY OBJECTIVE: The secondary aim of this study is to compare s-IGF-I, s-insulin, and plasma (p)-glucose profiles after a carbohydrate rich breakfast following s.c. GH injection vs. continuous infusion. DESIGN AND METHODS: During supine rest eight AGHD males (59.8±8 years, BMI 29.7±4.9 kg/m(2)) were treated with one daily s.c. GH injections of 3 mg/24 h for 48 h (treatment sessions A, B) or a continuous s.c. GH infusion of 3 mg/24 h for 60 h (treatment sessions C, D). Exercise comprised 1 h bicycling with 50 W load on two consecutive days during treatment sessions B and D. RESULTS: Administration of GH as a bolus injection, but not as a continuous GH infusion, resulted in about 32% higher s-GH levels during exercise (60 min) as well as 30 min after (s-GH logAUC(B-A) difference was 0.28; 95% CI: 0.14-0.4; p<0.001). However, the total s-GH(AUC 0-24 h) (p=0.75) and s-IGF-I(AUC0-48 h) levels (p=0.51) remained unchanged between the two occasions. P-glucose and insulin profiles were significantly higher after carbohydrate rich breakfast before first and second dosing both following s.c. GH injection and continuous infusion (p<0.05). CONCLUSIONS: Moderate exercise intermittently increased s-GH levels. These changes seem to have no clinical short-term relevance, since total s-GH(24 h) and s-IGF-I(48 h) levels were unaffected.
Assuntos
Exercício Físico/fisiologia , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/farmacocinética , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/metabolismo , Descanso/fisiologia , Decúbito Dorsal/fisiologia , Adulto , Idoso , Glicemia/metabolismo , Ritmo Circadiano , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Humanos , Hipopituitarismo/sangue , Injeções Subcutâneas , Insulina/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic ß-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans. METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*104) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*104) but again not in men (P = 0.34). CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.
Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Dopamina D2/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Dinamarca , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Loci Gênicos , Humanos , Hiperglicemia/sangue , Hiperglicemia/genética , Hiperglicemia/metabolismo , Insulina/sangue , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Países Baixos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Dopamina D2/metabolismo , Caracteres SexuaisRESUMO
AIM: To assess whether a 12-week participant-driven health education programme offered to individuals with screening-detected hyperglycaemia in Danish primary care would lead to improvements in cardiovascular risk factors, health behaviour and patient-reported outcomes after 3 years. METHODS: We conducted a randomized controlled trial in 509 patients with screening-detected hyperglycaemia (impaired fasting glucose, impaired glucose tolerance or type 2 diabetes) from 33 general practices in Denmark. Individuals were pre-randomized to receive (i) routine care (n = 187), or (ii) an invitation to participate in the Ready to Act health education programme (n = 322). The programme was delivered over 12 weeks in primary care and focused on motivation, action experience, informed decision-making and social involvement to promote health behaviour change. The primary outcome was 10-year modelled cardiovascular risk. RESULTS: Of 322 individuals, 123 (38%) received the intervention and 436/509 individuals (86%) returned for follow-up assessment. There was no difference between the trial groups in modelled cardiovascular risk at 3 years (relative difference: 1.01; 95% CI: 0.84 to 1.23). Total cholesterol was lower (-0.24mmol/l, 95% CI: -0.45 to -0.03, P = 0.027), and patient activation was higher in the intervention than in the control group (5.3, 95% CI: 0.97 to 9.7). No other between-group differences were observed for any cardiovascular risk factor, health behaviour or patient-reported outcome variables. Subgroup analyses suggested that the intervention was more beneficial in those with impaired fasting glucose/impaired glucose tolerance than in those with type 2 diabetes. CONCLUSION: For patients with screening-detected hyperglycaemia, a participant-driven health education programme was not associated with improvements in most clinical, behavioural and patient-reported outcomes after 3 years of follow-up.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/terapia , Intolerância à Glucose/terapia , Educação de Pacientes como Assunto , Medicina de Precisão , Estado Pré-Diabético/terapia , Atenção Primária à Saúde , Adulto , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/etiologia , Terapia Combinada , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Angiopatias Diabéticas/complicações , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Feminino , Seguimentos , Intolerância à Glucose/sangue , Intolerância à Glucose/diagnóstico , Intolerância à Glucose/fisiopatologia , Comportamentos Relacionados com a Saúde , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/etiologia , Hipercolesterolemia/prevenção & controle , Estilo de Vida , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Estado Pré-Diabético/sangue , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/fisiopatologia , Fatores de RiscoRESUMO
AIMS: Little is known about the long-term effects of intensive multifactorial treatment early in the diabetes disease trajectory. In the absence of long-term data on hard outcomes, we described change in 10-year modelled cardiovascular risk in the 5 years following diagnosis, and quantified the impact of intensive treatment on 10-year modelled cardiovascular risk at 5 years. METHODS: In a pragmatic, cluster-randomized, parallel-group trial in Denmark, the Netherlands and the UK, 3057 people with screen-detected Type 2 diabetes were randomized by general practice to receive (1) routine care of diabetes according to national guidelines (1379 patients) or (2) intensive multifactorial target-driven management (1678 patients). Ten-year modelled cardiovascular disease risk was calculated at baseline and 5 years using the UK Prospective Diabetes Study Risk Engine (version 3ß). RESULTS: Among 2101 individuals with complete data at follow up (73.4%), 10-year modelled cardiovascular disease risk was 27.3% (sd 13.9) at baseline and 21.3% (sd 13.8) at 5-year follow-up (intensive treatment group difference -6.9, sd 9.0; routine care group difference -5.0, sd 12.2). Modelled 10-year cardiovascular disease risk was lower in the intensive treatment group compared with the routine care group at 5 years, after adjustment for baseline cardiovascular disease risk and clustering (-2.0; 95% CI -3.1 to -0.9). CONCLUSIONS: Despite increasing age and diabetes duration, there was a decline in modelled cardiovascular disease risk in the 5 years following diagnosis. Compared with routine care, 10-year modelled cardiovascular disease risk was lower in the intensive treatment group at 5 years. Our results suggest that patients benefit from intensive treatment early in the diabetes disease trajectory, where the rate of cardiovascular disease risk progression may be slowed.
Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Angiopatias Diabéticas/prevenção & controle , Adulto , Idoso , Terapia Combinada/estatística & dados numéricos , Diagnóstico Precoce , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Resultado do TratamentoRESUMO
BACKGROUND: Previous studies in growth hormone (GH)-deficient (GHD) patients have indicated a possible diurnal variation in the pharmacokinetics (PK) of GH after subcutaneous (sc) GH administration. Thus, higher GH levels were observed during the night with continuous sc infusion, and increased GH bioavailability was reported following daily sc injections in the evening compared to morning. OBJECTIVE: The aim was to study whether diurnal variability in the PK of sc administered exogenous GH can be reproduced under standard conditions for all study participants, e.g. supine rest. DESIGN AND METHODS: Eight male GHD patients (59.8 ± 8 years, body mass index 29.7 ± 4.9 kg/m(2)) received a continuous sc infusion of GH (3mg/24h) for 60 h on two different occasions. Diurnal variation in PK of GH was studied during steady state in the last 24h of the infusion period. RESULTS: Median GH levels were higher at night time (23:00 h-07:00 h) than during the day (10:00 h-18:00 h) for visit 1 [5.1 (4.5-7.2 ng/ml/0.5h) vs. 4.6 (3.7-5.7 ng/ml/0.5h); p<0.05], and reproducible results of diurnal GH variation were obtained during visit 2 [5.7 (4.6-7.4) ng/ml/0.5h vs. 4.6 (3.8-6.0) ng/ml/0.5h, p<0.05]. Reproducible results between days 1 and 2 were also obtained during 08:30 h-20:30 h and 20:30 h-08:30 h, respectively. CONCLUSIONS: Previous findings of higher nocturnal GH levels were confirmed during steady state continuous sc GH infusion under standard conditions. The underlying mechanisms, e.g. whether GH absorption, distribution or elimination is primarily affected need to be further elucidated.
Assuntos
Ritmo Circadiano/fisiologia , Transtornos do Crescimento/metabolismo , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/farmacocinética , Adulto , Idoso , Área Sob a Curva , Estudos Cross-Over , Feminino , Seguimentos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Imunoensaio , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Prognóstico , Distribuição TecidualRESUMO
AIMS/HYPOTHESIS: Recent evidence links the soluble urokinase plasminogen activator receptor (suPAR), a stable biomarker of systemic immune activation, to several chronic diseases, including type 2 diabetes. suPAR is also associated with adiposity and smoking. We hypothesised that this biomarker would be linked to incident type 2 diabetes in individuals with impaired glucose regulation and that this association would be modified by smoking and body weight status. METHODS: The study included 1,933 participants with impaired glucose regulation, who were drawn from the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION) and for whom data on suPAR, BMI and smoking were available. Logistic regression analysis was used to estimate the odds for incident type 2 diabetes per twofold increase in suPAR levels. Interactions between both smoking and body weight status and suPAR were tested. RESULTS: During a 3-year follow-up (599 incident diabetes cases), there was a 48% overall increase in the odds of developing type 2 diabetes per twofold increase in suPAR (p = 0.006). This association was modified by body weight status in overweight, but not in obese individuals (OR 2.36, 95% CI 1.48, 3.76 in overweight group), and by smoking status (OR 2.05, 95% CI 1.20, 3.51 in non-smokers). After adjustment for other diabetes risk factors, the association between suPAR and type 2 diabetes was attenuated in the whole sample and among non-smokers, but remained robust among overweight participants. CONCLUSIONS/INTERPRETATION: suPAR may be a good novel biomarker for systemic sub-clinical inflammation and immune activation linked to incident type 2 diabetes risk in overweight individuals and non-smokers. The observed interactions with adiposity and smoking should be investigated further.
Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Sobrepeso/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Fumar/efeitos adversos , Índice de Massa Corporal , Peso Corporal/fisiologia , Feminino , Humanos , MasculinoRESUMO
AIMS/HYPOTHESIS: There is limited evidence on how multifactorial treatment improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. Cardiac autonomic neuropathy (CAN) in people with diabetes indicates widespread damage to the autonomic nervous system, which may severely affect health and quality of life. We examined effects of early detection and subsequent intensive treatment of type 2 diabetes in primary care on the prevalence of CAN at the 6-year follow-up examination in a pragmatic cluster-randomised parallel group trial. METHODS: One hundred and ninety general practices were randomised to deliver either intensive multifactorial treatment (IT) or routine care (RC) as recommended by national guidelines to patients with type 2 diabetes, identified through a stepwise screening programme in the primary care setting. 1533 people (IT, n = 910; RC, n = 623) were identified and included. At the 6-year follow-up examination, measures of CAN were applied in an unselected subsample of 777 participants using heart rate variability analysis and standard tests of CAN. RESULTS: At the 6-year follow-up examination, the prevalence of early CAN was 15.1% in the RC group and 15.5% in the IT group, while manifest CAN was present in 7.1% and 7.3%, respectively. We found no statistically significant effect of intensive treatment on the prevalence of CAN compared with routine care. CONCLUSIONS/INTERPRETATION: In the Danish arm of the ADDITION Study, signs of CAN were highly prevalent 6 years after a screening-based diagnosis of type 2 diabetes. Intensive multifactorial treatment did not significantly affect the prevalence of CAN compared with routine care. However, at follow-up the level of medication was also high in the RC group.
Assuntos
Doenças do Sistema Nervoso Autônomo/prevenção & controle , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Cardiomiopatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/prevenção & controle , Adulto , Idoso , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/epidemiologia , Estudos de Coortes , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/diagnóstico , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/fisiopatologia , Diagnóstico Precoce , Feminino , Seguimentos , Medicina Geral , Frequência Cardíaca , Humanos , Hipoglicemiantes/uso terapêutico , Incidência , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prevalência , Atenção Primária à Saúde , Índice de Gravidade de DoençaRESUMO
CONTEXT: Uncoupling protein 2 (UCP2) is involved in regulating ATP synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in ß-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus. OBJECTIVE: To determine the influence of a functional UCP2 promoter polymorphism (-866G>A, rs659366) on obesity, type 2 diabetes and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes. DESIGN: We genotyped UCP2 rs659366 in a total of 17 636 Danish individuals and established case-control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analysed within separate study populations. RESULTS: We found no consistent associations between the UCP2 -866G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12 984 subjects showed an association with obesity (GA vs GG odds ratio (OR) (95% confidence interval (CI)): 0.894(0.826-0.968) P=0.00562, and AA vs GG OR(95% CI): 0.892(0.800-0.996), P=0.0415. Moreover, a meta-analysis for type 2 diabetes of 15 107 individuals showed no association. The -866G-allele was associated with elevated fasting serum insulin levels (P=0.002) and HOMA insulin resistance index (P=0.0007). Insulin sensitivity measured during intravenous glucose tolerance test in young Caucasian subjects (n=377) was decreased in carriers of the GG genotype (P=0.05). CONCLUSIONS: The UCP2 -866G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Resistência à Insulina , Canais Iônicos/sangue , Proteínas Mitocondriais/sangue , Obesidade/sangue , Polimorfismo de Nucleotídeo Único , População Branca/genética , Alelos , Animais , Glicemia/metabolismo , Estudos de Casos e Controles , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Resistência à Insulina/genética , Canais Iônicos/genética , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Obesidade/epidemiologia , Obesidade/genética , Regiões Promotoras Genéticas , Proteína Desacopladora 2RESUMO
AIMS: To describe the total cardiovascular burden (cardiovascular morbidity or mortality, revascularization or non-traumatic amputation) in individuals with screen-detected diabetes in the ADDITION-Europe trial and to quantify the impact of the intervention on multiple cardiovascular events over 5 years. METHODS: In a pragmatic, cluster-randomized, parallel-group trial in four centres (Denmark; Cambridge, UK; the Netherlands; and Leicester, UK), 343 general practices were randomized to screening plus routine care (n = 1379 patients), or screening and promotion of target-driven, intensive treatment of multiple risk factors (n = 1678). We estimated the effect of the intervention on multiple cardiovascular events after diagnosis of diabetes using the Wei, Lin and Weissfeld method. RESULTS: Over 5.3 years, 167 individuals had exactly one cardiovascular event, 53 exactly two events, and 18 three or more events. The incidence rates (95% CI) of first events and any event per 1000 person-years were 14.6 (12.8-16.6) and 20.4 (18.2-22.6), respectively. There were non-significant reductions in the risk of a first (hazard ratio 0.83, 95% CI 0.65-1.05) and second primary endpoint (hazard ratio 0.70, 95% CI 0.43-1.12). The overall average hazard ratio for any event was 0.77 (95% CI 0.58-1.02). CONCLUSIONS: Early intensive multifactorial treatment was not associated with a significant reduction in total cardiovascular burden at 5 years. Focusing on first events in cardiovascular disease prevention trials underestimates the total cardiovascular burden to patients and the health service.
Assuntos
Amputação Cirúrgica/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Adulto , Idoso , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Análise por Conglomerados , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/prevenção & controle , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/prevenção & controle , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Risco , Reino Unido/epidemiologiaRESUMO
AIMS/HYPOTHESIS: There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits. METHODS: OxPhos gene variants (n = 10) that had been nominally associated (p < 0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n = 10,108) were selected for follow-up in 3,599 type 2 diabetic and 4,956 glucose-tolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study. RESULTS: The minor alleles of COX10 rs9915302 (p = 0.02) and COX5B rs1466100 (p = 0.005) showed nominal association with type 2 diabetes in our Danish cohort. However, in the meta-analysis, none of the investigated variants showed a robust association with type 2 diabetes after correction for multiple testing. Among the alleles potentially associated with type 2 diabetes, none negatively influenced surrogate markers of insulin sensitivity in non-diabetic participants, while the minor alleles of UQCRC1 rs2228561 and COX10 rs10521253 showed a weak (p < 0.01 to p < 0.05) negative influence on indices of glucose-stimulated insulin secretion. CONCLUSIONS/INTERPRETATION: We cannot rule out the possibility that common variants in or near OxPhos genes may influence beta cell function in non-diabetic individuals. However, our quantitative trait studies and a sufficiently large meta-analysis indicate that common variation in proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Variação Genética , Resistência à Insulina , Oxigênio/química , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Dinamarca , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Humanos , Mitocôndrias/metabolismo , Modelos Biológicos , Modelos Genéticos , Fosforilação Oxidativa , Fosforilação , Locos de Características QuantitativasRESUMO
AIMS/HYPOTHESIS: The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits. METHODS: GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified. Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes. RESULTS: When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean ± SD, 4.8 ± 1.2 vs 5.5 ± 0.8 mmol/l, p = 0.004); fasting serum insulin (22 ± 14 vs 42 ± 27 pmol/l, p = 0.04); glucose-stimulated serum insulin (159 ± 83 vs 290 ± 183 pmol/l, p = 0.01) and adult height (165 ± 10 vs 172 ± 9 cm, p = 0.0009) compared with A allele carriers. During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730 ± 69 vs 1,334 ± 288 pmol/l × min, p = 0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were â¼50% decreased (p < 0.001) among three homozygous carriers compared with nine matched wild-type carriers. rs7581952, Ile158Val and Trp169Ter (where 'Ter' indicates 'termination') variants of GCG did not significantly associate or co-segregate with the metabolic traits examined. CONCLUSIONS/INTERPRETATION: Re-sequencing of GCG revealed a low frequency intronic variant, rs4664447, and follow-up physiological studies suggest that this variant in homozygous form may cause decreased fasting and stimulated levels of insulin, glucagon and GLP-1. Overall, our findings suggest that variation in GCG has no major impact on carbohydrate metabolism in the study populations examined.