RESUMO
AIM: Angiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3-deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d-lactate, reflecting greater methylglyoxal flux. METHODS: We analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs and d-lactate using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA. RESULTS: There was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907-1509) nmol/l vs. irbesartan 300 mg 1053 (820-1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d-lactate levels at either 1 or 2 years. CONCLUSION: Irbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs or d-lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915).
Assuntos
Albuminúria/tratamento farmacológico , Desoxiglucose/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glioxal/sangue , Irbesartana/uso terapêutico , Aldeído Pirúvico/sangue , Albuminúria/sangue , Albuminúria/etiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Biomarcadores/sangue , Cromatografia Líquida , Desoxiglucose/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Fatores de Tempo , Resultado do TratamentoRESUMO
AIM: Acute oxygen inhalation and slow deep breathing improve measures of autonomic function transiently in individuals with short-duration type 1 diabetes. Our aims were to examine these interventions and changes in autonomic function in individuals with long-duration type 1 diabetes and to explore interactions with the presence of macroalbuminuria or existing cardiovascular autonomic neuropathy. METHODS: Individuals with type 1 diabetes (n = 54) were exposed to acute oxygen inhalation, slow deep breathing and a combination of both (hereafter 'the combination'). Primary outcomes were change in baroreflex sensitivity and heart rate variability. Associations between changes in outcomes were evaluated using mixed effects models. RESULTS: Mean age ± sd was 60 ± 10 years and diabetes duration was 38 ± 14 years. Changes are presented as per cent difference from baseline with 95% confidence intervals. Acute oxygen inhalation, slow deep breathing and the combination increased baroreflex sensitivity by 21 (10, 34)%, 32 (13, 53)% and 30 (10, 54)%, respectively. Acute oxygen inhalation trended towards increasing heart rate variability 8 (-1, 17)% (P = 0.056), and slow deep breathing and the combination increased heart rate variability by 33 (18, 49)% and 44 (27, 64)% respectively. Macroalbuminuria or cardiovascular autonomic neuropathy did not modify results. CONCLUSION: Autonomic function is improved transiently in individuals with long-duration type 1 diabetes and normoalbuminuria or macroalbuminuria by acute oxygen inhalation and slow deep breathing. There is a risk of survival bias. Autonomic dysfunction might be a reversible condition, and hypoxia might represent a target of intervention.
Assuntos
Doenças do Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/fisiologia , Exercícios Respiratórios , Diabetes Mellitus Tipo 1/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Frequência Cardíaca/fisiologia , Hiperóxia , Oxigenoterapia , Idoso , Albuminúria/etiologia , Sistema Nervoso Autônomo/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Dephosphorylated uncarboxylated matrix Gla-protein (dp-ucMGP) is a biomarker of functional vitamin K status. High plasma dp-ucMGP concentrations reflect a low vitamin K status and have been related to vascular calcification. Our aims were to assess plasma levels of dp-ucMGP and their association with cardiovascular risk in a general population. METHODS: Plasma dp-ucMGP measurements were performed using the IDS-iSYS InaKtif MGP assay in 491 consecutive participants in a Danish general population study (229 males and 262 females, aged 19-71 years). Multivariable linear and logistic regressions were used to assess the association between dp-ucMGP levels and cardiovascular risk factors. RESULTS: Mean ± standard deviation (SD) for dp-ucMGP was 465 ± 181 pmol/L, and upper 95th percentile was 690 pmol/L. In logistic regression analyses, an increase in dp-ucMGP category (<300, 300-399, 400-499, ≥500 pmol/L) was positively associated with obesity, odds ratio (OR) 2.27 (95% confidence interval (CI) 1.54-3.33), history of cardiovascular disease, OR 1.77 (CI 1.02-3.05), and above-median estimated pulse wave velocity (ePWV), OR 1.54 (CI 1.21-1.96), when adjusted for age, sex, and lifestyle factors. 1 SD increase in diastolic and systolic blood pressure (BP) corresponded to a 5.5% (CI 2.9-8.0%) and 4.7% (CI 2.1-7.4%) increase in dp-ucMGP, respectively, when adjusted for age and sex. CONCLUSION: Plasma dp-ucMGP levels were positively associated with obesity, BP, ePWV, and history of cardiovascular disease. These findings support that dp-ucMGP is a biomarker of cardiovascular risk, and that vitamin K status could play a role in vascular calcification. The strong association with obesity deserves further attention.
Assuntos
Proteínas de Ligação ao Cálcio/sangue , Doenças Cardiovasculares/sangue , Proteínas da Matriz Extracelular/sangue , Deficiência de Vitamina K/sangue , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Dinamarca/epidemiologia , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade , Razão de Chances , Calcificação Vascular/sangue , Deficiência de Vitamina K/complicações , Adulto Jovem , Proteína de Matriz GlaRESUMO
AIM: To investigate the association between cardiovascular autonomic neuropathy and bone metabolism in people with Type 1 diabetes. METHODS: We assessed cardiovascular autonomic neuropathy in 329 people with Type 1 diabetes according to heart rate response to deep breathing, to standing and to the Valsalva manoeuvre, and 2-min resting heart rate. More than one pathological non-resting test was defined as cardiovascular autonomic neuropathy. Bone mineral density of the femoral neck (BMDfn) was assessed by dual energy X-ray absorptiometry. Serum parathyroid hormone levels and other bone markers were measured. RESULTS: The mean (sd) age of the participants was 55.6 (9.4) years, 52% were men, and the mean (sd) diabetes duration was 40 (8.9) years, HbA1c 62 (9) mmol/mol and estimated GFR 78 (26) ml/min/1.73m2 . In all, 36% had cardiovascular autonomic neuropathy. Participants with cardiovascular autonomic neuropathy had 4.2% (95% CI -8.0 to -0.2; P=0.038) lower BMDfn and 33.6% (95% CI 14.3 to 53.8; P=0.0002) higher parathyroid hormone levels compared with participants without cardiovascular autonomic neuropathy in adjusted models. Higher resting heart rate remained associated with higher parathyroid hormone level and lower BMDfn after additional adjustment for eGFR (P<0.0001 and P = 0.042, respectively). CONCLUSIONS: The presence of cardiovascular autonomic neuropathy was associated with reduced BMDfn and increased levels of parathyroid hormone. Kidney function may either confound or mediate these findings. Cardiovascular autonomic neuropathy could be associated with increased risk of osteoporosis in Type 1 diabetes. Whether cardiovascular autonomic neuropathy directly affects bone metabolism detrimentally or if this association is mediated via decreased kidney function should be investigated further.
Assuntos
Doenças do Sistema Nervoso Autônomo/epidemiologia , Osso e Ossos/metabolismo , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Angiopatias Diabéticas/epidemiologia , Osteoporose/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças do Sistema Nervoso Autônomo/complicações , Densidade Óssea , Doenças Cardiovasculares/complicações , Estudos de Casos e Controles , Estudos Transversais , Angiopatias Diabéticas/complicações , Angiopatias Diabéticas/metabolismo , Neuropatias Diabéticas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/metabolismo , Fatores de Risco , Adulto JovemRESUMO
AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/urina , Hipoglicemiantes/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Proteoma/análise , Adolescente , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteoma/metabolismo , Proteômica/métodos , Medição de Risco , Urinálise/métodos , Adulto JovemRESUMO
AIMS: To investigate depolarization and repolarization durations in people with Type 1 diabetes, including the relationship to age. METHODS: 855 persons with Type 1 diabetes without known heart disease were included and matched with 1710 participants from a general population study. Clinical examinations, questionnaires and biochemistry were assessed. A 10-second 12-lead ECG was performed and analysed digitally. RESULTS: QTc was longer in people with Type 1 diabetes compared to controls (414±16 vs. 411±19 ms, P <0.001), and particularly so in young people with Type 1 diabetes. The fully adjusted increase was 13.8 ms (95% confidence interval (CI): 8.6-19.0 ms, P <0.001) at age 20 years and 3.4 ms (CI: 1.5-5.3 ms, P<0.001) at age 40 years. The rate-corrected QRSc was increased in people with Type 1 diabetes (97±11 vs. 95±11 ms, P <0.001) and was age-independent (P =0.5). JTc was increased in the young people with Type 1 diabetes (10.7 ms (CI: 5.4-16.0 ms, P <0.001) at age 20 years), but not in older people with Type 1 diabetes (interaction age-diabetes, P <0.01). CONCLUSIONS: For people with Type 1 diabetes, cardiac depolarization is increased at all ages, whereas repolarization is increased only relatively in young people with Type 1 diabetes. Hence, young people with Type 1 diabetes may be more prone to ventricular arrhythmias. The findings contribute to the understanding of sudden cardiac death in young people with Type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Coração/fisiopatologia , Volume Sistólico/fisiologia , Adulto , Fatores Etários , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/fisiopatologia , Doenças Assintomáticas , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/fisiopatologia , Eletrocardiografia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
AIMS: Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes. METHODS: Post hoc analysis of a trial of losartan in diabetic nephropathy, mean follow-up 3â¯years (IQR 1.5-3.5). UA was measured at baseline. Primary end-point was change in measured GFR. UA was tested in a linear regression model adjusted for known progression factors (gender, HbA1c, systolic blood pressure, cholesterol, baseline GFR and baseline urinary albumin excretion rate (UAER)). RESULTS: Baseline UA was 0.339â¯mmol/l (SD ±0.107), GFR 87â¯ml/min/1.73â¯m2 (±23), geometric mean UAER 1023â¯mg/24â¯h (IQR, 631 - 1995). Mean rate of decline in GFR was 4.6 (3.7) ml/min/year. In the upper quartile of baseline UA the mean decline in GFR from baseline to the end of the study was 6.2 (4.9) ml/min/1.73â¯m2 and 4.1 (3.1) ml/min/1.73â¯m2 in the three lower quartiles of UA, (pâ¯=â¯0.088). In a linear model including baseline covariates (UAER, GFR, total cholesterol, HDL cholesterol) UA was associated with decline in GFR (r2â¯=â¯0.45, pâ¯<â¯0.001). CONCLUSION: Uric acid was weakly associated with decline in GFR in type 1 diabetic patients with overt nephropathy.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Losartan/uso terapêutico , Ácido Úrico/sangue , Albuminúria/sangue , Albuminúria/complicações , Albuminúria/tratamento farmacológico , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Prognóstico , Resultado do TratamentoRESUMO
AIMS: Advanced glycation endproducts (AGEs) and altered extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) are associated with vascular complications in type 1 diabetes. Experimental studies have shown that AGEs regulate the production of MMPs and/or TIMP-1. Therefore, we investigated associations between specific AGEs and MMP-1, -2, -3, -9, and -10, and TIMP-1 in individuals with type 1 diabetes. METHODS: In 670 type 1 diabetic individuals we determined serum levels of protein-bound AGEs Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1) and pentosidine, and MMP-1, -2, -3, -9, and -10, and TIMP-1. We performed linear regression analyses to investigate associations between AGEs and markers of the MMP-TIMP system. Analyses were adjusted for age, sex, HbA1c and duration of diabetes, and additionally for other potential confounders and presence of vascular complication. RESULTS: After full adjustment, levels of CML were positively associated with levels of MMP-2 and inversely with MMP-9. CEL was positively associated with MMP-3 and TIMP-1. MG-H1 was only associated with TIMP-1, whereas pentosidine was not associated with MMPs or TIMP-1. CONCLUSIONS: We showed independent associations between several AGEs and markers of the MMP-TIMP system, which indicate specific AGE-MMP/TIMP-1 interactions potentially contributing to vascular complications in patients with type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/enzimologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/enzimologia , Produtos Finais de Glicação Avançada/sangue , Metaloproteinases da Matriz Secretadas/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Angiopatias Diabéticas/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Albuminúria/tratamento farmacológico , Alopurinol/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Fármacos Renais/uso terapêutico , Ácido Úrico/metabolismo , Creatinina/urina , Estudos Cross-Over , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Altered regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular events and all-cause mortality in type 1 diabetic patients. METHODS: We prospectively followed 337 type 1 diabetic patients [mean age 41.4 years (9.6), 39% female], 170 with and 167 without diabetic nephropathy, with median follow-up of 12.3 years. Survival analyses were applied to investigate differences in plasma MMP-1, -2, -3, -9, -10, and TIMP-1-levels in patients with and without a cardiovascular event and in those who died vs survivors. All analyses were adjusted for age, sex, duration of diabetes, HbA1c, nephropathy and for other conventional cardiovascular risk factors. RESULTS: After adjustment for potential confounders, higher MMP-2 plasma levels were significantly associated with higher incidence of cardiovascular events [HR 1.49 (95% CI 1.11; 1.99)], and higher plasma levels of MMP-1 [1.38 (1.07; 1.78)], MMP-2 [1.60 (1.19; 2.15)] and MMP-3 [1.39 (1.05; 1.85)] were associated with all-cause mortality. All associations were independent of low-grade inflammation and endothelial dysfunction as estimated by plasma markers. Associations between MMP-2 and cardiovascular events and between MMP-3 and mortality were attenuated after further adjustment for eGFR and changes in eGFR. CONCLUSIONS: Higher levels of MMP-2 are associated with CVD and higher MMP-1, -2 and -3 with all-cause mortality. In addition, associations between MMP-2 and CVD, and MMP-3 and mortality were attenuated after adjustment for eGFR while both MMPs were associated with eGFR decline, indicating a possible mediating role of eGFR.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/mortalidade , Metaloproteinases da Matriz Secretadas/sangue , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/enzimologia , Causas de Morte , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/enzimologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Incidência , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/sangueRESUMO
BACKGROUND: Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, eg, mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria. METHODS: Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study. RESULTS: Seventy-five participants (28%) developed microalbuminuria during follow-up. MBL-associated protein 19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268 ng/mL [95% CI, 243-293] vs 236 ng/mL [95% CI, 223-250], P = .02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower 3 quartiles in unadjusted Cox analysis, hazard ratio 1.86 ([95% CI, 1.17-2.96], P = .009). This remained significant in adjusted models, eg, adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MBL-associated serine protease concentration was not associated with incidence of microalbuminuria. CONCLUSIONS: In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.
Assuntos
Albuminúria/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Adolescente , Adulto , Albuminúria/epidemiologia , Albuminúria/metabolismo , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
AIM: To investigate whether inclusion of quantitative data on blood flow distribution compared with visual qualitative evaluation improve the reliability and diagnostic performance of 99 m Tc-hydroxymethylene diphosphate three-phase bone scintigraphy (TPBS) in patients suspected for charcot neuropathic osteoarthropathy (CNO) of the foot. METHOD: A retrospective cohort study of TPBS performed on 148 patients with suspected acute CNO referred from a single specialized diabetes care centre. The quantitative blood flow distribution was calculated based on the method described by Deutsch et al. All scintigraphies were re-evaluated by independent, blinded observers twice with and without quantitative data on blood flow distribution at ankle and focus level, respectively. The diagnostic validity of TPBS was determined by subsequent review of clinical data and radiological examinations. RESULTS: A total of 90 patients (61%) had confirmed diagnosis of CNO. The sensitivity, specificity and accuracy of three-phase bone scintigraphy without/with quantitative data were 89%/88%, 58%/62% and 77%/78%, respectively. The intra-observer agreement improved significantly by adding quantitative data in the evaluation (Kappa value 0·79/0·94). The interobserver agreement was not significantly improved. CONCLUSION: Adding quantitative data on blood flow distribution in the interpretation of TBPS improves intra-observer variation, whereas no difference in interobserver variation was observed. The sensitivity of TPBS in the diagnosis of CNO is high, but holds limited specificity. Diagnostic performance does not improve using quantitative data in the evaluation. This may be due to the reference intervals applied in the study or the absence of a proper gold standard diagnostic procedure for comparison.
Assuntos
Artropatia Neurogênica/diagnóstico por imagem , Pé Diabético/diagnóstico por imagem , Ossos do Pé/irrigação sanguínea , Ossos do Pé/diagnóstico por imagem , Imagem de Perfusão/métodos , Cintilografia , Compostos Radiofarmacêuticos/administração & dosagem , Medronato de Tecnécio Tc 99m/administração & dosagem , Idoso , Área Sob a Curva , Artropatia Neurogênica/fisiopatologia , Pé Diabético/fisiopatologia , Feminino , Câmaras gama , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Imagem de Perfusão/instrumentação , Valor Preditivo dos Testes , Curva ROC , Cintilografia/instrumentação , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
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
BACKGROUND AND AIM: The bone-related peptide osteoprotegerin has been linked to vascular calcification and peripheral vascular disease. We investigated the association between osteoprotegerin and development of foot complications in persons with type 1 diabetes. MATERIALS AND METHODS: Prospective observational study of 573 persons with type 1 diabetes, 225 women; age [mean±SD] 42.3±10.3years. Plasma osteoprotegerin was measured by ELISA. RESULTS: Median (IQR) osteoprotegerin was 2.80(2.35-3.63)µg/L and follow-up time (median (range)) was 12.7(0.1-15.6)years. Endpoints included: new foot ulceration (n=153), Charcot foot (n=14), vascular surgery/amputation (n=53), loss of foot pulse (n=57), and peripheral neuropathy (n=99). In unadjusted analyses, higher osteoprotegerin was associated with development of all endpoints (p≤0.026). Higher osteoprotegerin remained associated with development of foot ulcer, and the combination of vascular surgery/amputation, loss of foot pulse and neuropathy (p≤0.001) in a sex and age adjusted model. After further adjustment (nephropathy status, smoking, HbA1c, systolic blood pressure, serum cholesterol, high sensitivity C-reactive protein, eGFR, and presence of neuropathy and/or claudication and/or foot ulcer at baseline), higher osteoprotegerin remained associated with development of foot ulcer (HR (95% CI) per doubling: 1.75 (1.04-2.97); p=0.037). CONCLUSION: Higher osteoprotegerin levels were associated with development of foot ulcer, even after comprehensive adjustment.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Pé Diabético/sangue , Osteoprotegerina/sangue , Adulto , Amputação Cirúrgica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Pulse pressure (PP) remains an elusive cardiovascular risk factor with inconsistent findings. We clarified the prognostic value in patients with type 2 diabetes, chronic kidney disease (CKD) and anemia in the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin alfa) Therapy. In 4038 type 2 diabetes patients, darbepoetin alfa treatment did not affect the primary outcome. Risk related to PP at randomization was evaluated in a multivariable model including age, gender, kidney function, cardiovascular disease (CVD) and other conventional risk factors. End points were myocardial infarction (MI), stroke, end stage renal disease (ESRD) and the composite of cardiovascular death, MI or hospitalization for myocardial ischemia, heart failure or stroke (CVD composite). Median (interquartile range) age, gender, eGFR and PP was 68 (60-75) years, 57.3% women, 33 (27-42) ml min(-1) per 1.73 m2 and 60 (50-74) mm Hg. During 29.1 months (median) follow-up, the number of events for composite CVD, MI, stroke and ESRD was 1010, 253, 154 and 668. In unadjusted analyses, higher quartiles of PP were associated with higher rates per 100 years of follow-up of all end points (P⩽0.04), except stroke (P=0.52). Adjusted hazard ratios (95% confidence interval) per one quartile increase in PP were 1.06 (0.99-1.26) for MI, 0.96 (0.83-1.11) for stroke, 1.01 (0.94-1.09) for ESRD and 1.01 (0.96-1.07) for CVD composite. Results were similar in continuous analyses of PP (per 10 mm Hg). In patients with type 2 diabetes, CKD and anemia, PP did not independently predict cardiovascular events or ESRD. This may reflect confounding by aggressive antihypertensive treatment, or PP may be too rough a risk marker in these high-risk patients.
Assuntos
Anemia/tratamento farmacológico , Anemia/epidemiologia , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Darbepoetina alfa/uso terapêutico , Diabetes Mellitus Tipo 2/epidemiologia , Hematínicos/uso terapêutico , Falência Renal Crônica/epidemiologia , Fatores Etários , Idoso , Anemia/complicações , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Falência Renal Crônica/complicações , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Fatores Sexuais , Resultado do TratamentoRESUMO
AIM: The effect of insulin pump [continuous subcutaneous insulin infusion (CSII)] treatment on diabetes complications in a modern clinical setting is largely unknown. We investigated the effect of 4 years CSII treatment on HbA(1c), albuminuria and kidney function compared with multiple daily injections (MDI) in a single-centre clinical setting. METHODS: All patients initiating CSII treatment from 2004 to 2010 and followed for at least 4 years were included in the study: 193 people with Type 1 diabetes were matched (1 : 2) with 386 patients treated with MDI in the same period. Matching was based on diabetes duration, gender, HbA(1c) and normo-, micro- or macroalbuminuria at baseline. Urinary albumin/creatinine ratio (UACR) was measured yearly and annual change assessed from linear regression. RESULTS: CSII- vs. MDI-treated patients were comparable at baseline. After 4 years, HbA(1c) was 62 ± 11 vs. 68 ± 11 mmol/mol (7.8 ± 1.0 vs. 8.4 ± 1.0%) (P < 0.001). Annual UACR change in CSII- vs. MDI-treated patients was [mean (95% confidence interval)] -10.1 (-13.3; -6.8) vs. -1.2 (-3.6; 0.9)% (P < 0.001). Reduction in UACR was significantly associated with CSII treatment after adjustment for age, gender, diabetes duration, estimated GFR, UACR, mean arterial pressure, HbA(1c), cholesterol, renin-angiotensin-aldosterone system inhibition, anti-hypertensive treatment and smoking (P < 0.001). This remained significant (P < 0.001) when only including patients on stable renin-angiotensin-aldosterone system inhibition during follow-up (n = 465). CONCLUSIONS: Treatment with CSII over 4 years independently reduced HbA(1c) and UACR compared with MDI. Reduced UACR may be due to less glycaemic variability because the effect of CSII on HbA(1c) could only partially explain the effect. This needs confirmation in randomized controlled trials.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Rim/efeitos dos fármacos , Adulto , Albuminúria/complicações , Albuminúria/epidemiologia , Albuminúria/prevenção & controle , Estudos de Coortes , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Rim/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/complicações , Insuficiência Renal/epidemiologia , Insuficiência Renal/prevenção & controle , RiscoRESUMO
AIM: To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction. METHODS: The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n = 823 individuals with diabetic kidney disease) vs. control (n = 903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates. RESULTS: A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease. CONCLUSIONS: Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/genética , Falência Renal Crônica/genética , Mitocôndrias/genética , Adulto , Idoso , Estudos de Casos e Controles , Nefropatias Diabéticas/etiologia , Feminino , Predisposição Genética para Doença , Genoma Mitocondrial , Humanos , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genéticaRESUMO
AIM: To evaluate the effects of therapy with the vitamin D analogue paricalcitol on markers of cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy. METHODS: In a double-blind, randomized placebo-controlled, crossover trial, 48 participants on stable renin angiotensin aldosterone system blockade and diuretics were assigned, in random order, to 12 weeks of paricalcitol and 12 weeks of placebo therapy, separated by a 4-week washout period. Primary and secondary endpoints were changes in plasma N-terminal probrain natriuretic peptide and urinary albumin excretion rate obtained before and after each intervention. Glomerular filtration rates were estimated and measured ((51) Cr-EDTA plasma clearance glomerular filtration rate) after each intervention. RESULTS: The mean (sd) age of the participants was 57 (9) years, the baseline geometric mean (95% CI) urinary albumin excretion rate was 148 (85-259) mg/24 h, the mean (sd) HbA1c was 70 (9) mmol/mol [8.6 (3)%], the mean (sd) estimated glomerular filtration rate was 47 (15) ml/min/1.73 m(2) and the mean (sd) 24-h blood pressure was 135 (17)/74 (10) mmHg. Compared with placebo therapy, vitamin D analogue therapy had no significant effect on plasma N-terminal probrain natriuretic peptide concentration (P = 0.6), urinary albumin excretion rate was reduced by 18% (P = 0.03 for comparison), estimated glomerular filtration rate was reduced by 5 ml/min/1.73 m(2) (P < 0.001) and measured glomerular filtration rate was reduced by 1.5 ml/min/1.73 m(2) (P = 0.2). CONCLUSIONS: Paricalcitol therapy did not affect plasma N-terminal probrain natriuretic peptide concentration in people with Type 1 diabetes and diabetic nephropathy; however, the urinary albumin excretion rate was significantly lowered.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/prevenção & controle , Ergocalciferóis/farmacologia , Ergocalciferóis/uso terapêutico , Rim/efeitos dos fármacos , Vitamina D/análogos & derivados , Adulto , Idoso , Albuminúria/epidemiologia , Albuminúria/urina , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Estudos Cross-Over , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Progressão da Doença , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glicopeptídeos/sangue , Humanos , Incidência , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fatores de RiscoRESUMO
AIMS: Glucagon-like peptide-1 receptor agonist studies have revealed clinically significant reductions in systolic blood pressure (SBP). The aim was to investigate the time course of the anti-hypertensive effect of liraglutide treatment and potential underlying mechanisms. METHODS: We used an open-label, single-centre trial; 31 participants with Type 2 diabetes and hypertension completed the study. All participants were treated with liraglutide escalated to a maximum dose of 1.8 mg/day for 7 weeks, followed by a 21-day washout period. The primary outcome was a change in 24-h SBP. RESULTS: Twenty-four-h SBP increased by 10 mmHg on day 3 (P = 0.008) and 7 mmHg on day 7 (P = 0.033, 0.6 mg/day). On day 29, (1.8 mg/day), 24-h SBP was 7 mmHg lower compared with baseline (P = 0.11). Following the treatment period (day 49) and after washout (day 70), 24-h BP was equivalent to baseline. In addition, extracellular volume (ECV) was reduced by 2.0 l [95% confidence interval (CI) = 1.0-3.1 l, P < 0.001] and midregional-pro-atrial natriuretic peptide (MR-proANP) was reduced by 20% (95% CI = 12-28%, P < 0.001). Also, urinary albumin excretion declined by 30% (95% CI = 12-44%, P = 0.003), GFR by 11 ml/min/1.73 m(2) (95% CI = 7.2-14.4 ml/min/1.73 m(2) , P < 0.001) and fractional albumin excretion by 29% (95% CI = 3-48%, P = 0.032). CONCLUSIONS: Liraglutide treatment was associated with an initial increase in 24-h SBP, followed by a 7 mmHg reduction after escalation to 1.8 mg/day. This effect subsided after 4 weeks of maximum dose. Reductions in ECV and MR-proANP may explain the anti-hypertensive potential. Liraglutide treatment was associated with reversible reductions in albuminuria and GFR, which has to be confirmed in randomized trials.