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1.
Diabet Med ; 35(11): 1596-1604, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29999549

RESUMEN

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.


Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/epidemiología , Huesos/metabolismo , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Angiopatías Diabéticas/epidemiología , Osteoporosis/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Densidad Ósea , Enfermedades Cardiovasculares/complicaciones , Estudios de Casos y Controles , Estudios Transversales , Angiopatías Diabéticas/complicaciones , Angiopatías Diabéticas/metabolismo , Neuropatías Diabéticas/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/etiología , Osteoporosis/metabolismo , Factores de Riesgo , Adulto Joven
2.
Diabet Med ; 32(3): 343-52, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25251901

RESUMEN

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.


Asunto(s)
Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipertensión/prevención & control , Riñón/efectos de los fármacos , Liraglutida/farmacología , Liraglutida/uso terapéutico , Adulto , Anciano , Albuminuria/epidemiología , Albuminuria/orina , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Comorbilidad , Diabetes Mellitus Tipo 2/epidemiología , Relación Dosis-Respuesta a Droga , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Incidencia , Riñón/fisiología , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento
3.
Diabet Med ; 32(8): 1104-9, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25819010

RESUMEN

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.


Asunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/genética , Fallo Renal Crónico/genética , Mitocondrias/genética , Adulto , Anciano , Estudios de Casos y Controles , Nefropatías Diabéticas/etiología , Femenino , Predisposición Genética a la Enfermedad , Genoma Mitocondrial , Humanos , Fallo Renal Crónico/etiología , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Polimorfismo de Nucleótido Simple , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/genética
4.
Diabet Med ; 31(9): 1138-47, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24661264

RESUMEN

AIMS: Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro- or macroalbuminuria. METHODS: Patients with Type 2 diabetes (n = 90) and hypertension (n = 150) were selected from the community-cohort 'Prevention of REnal and Vascular End-stage Disease' (PREVEND) and the Steno Diabetes Center for this case-control study. Cases transitioned in albuminuria stage (from normo- to microalbuminuria or micro- to macroalbuminuria). Controls, matched for age, gender, and baseline albuminuria stage, remained in normo- or microalbuminuria stage during follow-up. Median follow-up was 2.9 years. Metabolomics were performed on plasma and urine. The predictive performance of a metabolite for albuminuria transition was assessed by the integrated discrimination index. RESULTS: In patients with Type 2 diabetes with normoalbuminuria, no metabolites discriminated cases from controls. In patients with Type 2 diabetes with microalbuminuria, plasma histidine was lower (fold change = 0.87, P = 0.02) and butenoylcarnitine was higher (fold change = 1.17, P = 0.007) in cases vs. controls. In urine, hexose, glutamine and tyrosine were lower in cases vs. controls (fold change = 0.20, P < 0.001; 0.32, P < 0.001; 0.51, P = 0.006, respectively). Adding the metabolites to a model of baseline albuminuria and estimated glomerular filtration rate metabolites improved risk prediction for macroalbuminuria transition (plasma integrated discrimination index = 0.28, P < 0.001; urine integrated discrimination index = 0.43, P < 0.001). These metabolites did not differ between hypertensive cases and controls without Type 2 diabetes. CONCLUSIONS: Type 2 diabetes-specific plasma and urine metabolites were discovered that predict the development of macroalbuminuria beyond established renal risk markers. These results should be confirmed in a large, prospective cohort.


Asunto(s)
Albuminuria/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Hipertensión/metabolismo , Anciano , Albuminuria/fisiopatología , Biomarcadores/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/fisiopatología , Diagnóstico Precoz , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos
5.
Diabetologia ; 56(2): 323-9, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23111731

RESUMEN

AIMS/HYPOTHESIS: Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. METHODS: We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmö Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts. RESULTS: In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, ß ± SEM, -3.7 ± 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, ß ± SEM, -0.008 ± 0.003 ml/min (log( e )), p = 0.006). CONCLUSIONS/INTERPRETATION: These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Proteína HMGA2/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética
6.
Diabetologia ; 56(2): 259-67, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23086559

RESUMEN

AIMS/HYPOTHESIS: Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria. METHODS: We conducted a prospective case-control study. Cases (n = 44) and controls (n = 44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides. RESULTS: The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p = 0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p = 0.002; integrated discrimination index [IDI]: 0.105, p = 0.002). Fragments of collagen and α-2-HS-glycoprotein showed significantly different expression between cases and controls. CONCLUSIONS/INTERPRETATION: Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes.


Asunto(s)
Albuminuria/orina , Biomarcadores/orina , Diabetes Mellitus Tipo 2/orina , Péptidos/orina , Anciano , Albuminuria/patología , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteómica/métodos
7.
Diabetologia ; 56(2): 298-310, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23160641

RESUMEN

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.


Asunto(s)
Exoma/genética , Polimorfismo Genético/genética , Diabetes Mellitus Tipo 2/genética , Frecuencia de los Genes/genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipertensión/genética , Polimorfismo de Nucleótido Simple/genética
8.
Diabet Med ; 29(3): 337-44, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21988672

RESUMEN

AIMS: Placental growth factor is a vascular endothelial growth factor involved in angiogenesis, vascular inflammation and plaque formation. Soluble Fms-like tyrosine kinase 1 is a decoy receptor for placental growth factor, reducing its activity. The aim of this study is to evaluate the predictive value of placental growth factor and soluble Fms-like tyrosine kinase 1 in relation to all-cause and cardiovascular mortality and decline in kidney function in Type 1 diabetes. METHODS: This was a prospective, observational follow-up study with 8 (0-13) years [median (range)] of follow-up, including patients with Type 1 diabetes, of whom 458 had diabetic nephropathy [278 men; age 42 ± 11 years (mean ± sd), diabetes duration 28 ± 9 years, glomerular filtration rate 76 ± 33 ml min(-1) 1.73 m(-2) ] and 442 had long-standing normoalbuminuria (234 men; age 45 ± 12 years, diabetes duration 28 ± 10 years). RESULTS: Placental growth factor and soluble Fms-like tyrosine kinase 1 levels measured at baseline were higher in patients with diabetic nephropathy compared with patients with long-standing normoalbuminuria [median (range)] 15 (4-131) vs. 11 (7-64) ng/l, (P < 0.001) and 86 (42-3462) vs. 77 (43-1557) ng/l (P < 0.001), respectively. In patients with diabetic nephropathy, high levels of placental growth factor predicted all-cause and cardiovascular mortality [hazard ratio 1.94 (1.16-3.24) and hazard ratio 2.91 (1.45-5.85)] after adjustment for sex, age, smoking, systolic blood pressure, HbA(1c) , cholesterol, glomerular filtration rate and previous cardiovascular disease. High levels of placental growth factor predicted increased risk of end-stage renal disease [hazard ratio 2.77 (1.47-5.14)], but covariate adjustments attenuated the association [hazard ratio 1.89 (0.91-3.95)]. Among patients with long-standing normoalbuminuria, placental growth factor levels predicted fatal and non-fatal cardiovascular events [hazard ratio 1.97 (1.03-3.76)], but not all-cause mortality. Baseline soluble Fms-like tyrosine kinase 1 levels did not predict outcome in either group after adjustment. CONCLUSION: Placental growth factor is elevated in patients with Type 1 diabetes and diabetic nephropathy and predicts all-cause and cardiovascular mortality, but not deterioration of kidney function.


Asunto(s)
Enfermedades Cardiovasculares/sangre , Diabetes Mellitus Tipo 1/sangre , Angiopatías Diabéticas/sangre , Nefropatías Diabéticas/sangre , Fallo Renal Crónico/sangre , Proteínas Gestacionales/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Biomarcadores/sangre , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/fisiopatología , Angiopatías Diabéticas/prevención & control , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/fisiopatología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/fisiopatología , Masculino , Factor de Crecimiento Placentario , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo
9.
Diabet Med ; 29(8): 990-4, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22414297

RESUMEN

AIMS: To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes. METHODS: Prospective, observational study, median (range) follow-up 8 (0-13) years, 900 patients with Type 1 diabetes, 458 with diabetic nephropathy, mean ± SD age 44 ± 11 years. RESULTS: During follow-up, we recorded 178 (20%) all-cause deaths, 109 (12%) cardiovascular deaths, 213 (24%) cardiovascular events and 73 (16%) progressed to end-stage renal disease. Elevated pulse pressure predicted all-cause and cardiovascular mortality and cardiovascular events [Hazard Ratio (HR) (95% CI) per 10 mmHg increase]: HR 1.2 (1.1-1.3), 1.3 (1.2-1.5) and 1.2 (1.1-1.3), P<0.001 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, creatinine, smoking, previous cardiovascular disease and nephropathy status). Furthermore, pulse pressure predicted the development of end-stage renal disease in patients with diabetic nephropathy: HR 1.2 (1.1-1.4), P=0.011 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, previous cardiovascular disease and glomerular filtration rate). In a two-hit model, patients with pulse pressure and placental growth factor levels above the median vs. below the median had increased risk of all-cause and cardiovascular mortality, cardiovascular events and progression to end-stage renal disease: adjusted HRs 2.3 (1.2-4.2), 4.2 (1.6-11.0), 2.3 (1.3-4.1) and 3.5 (1.0-11.8),P<0.05. CONCLUSIONS: Elevated pulse pressure independently predicts mortality, cardiovascular events and progression to end-stage renal disease in patients with Type 1 diabetes. Placental growth factor adds to the predictive value of pulse pressure on cardiovascular and renal outcome.


Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Angiopatías Diabéticas/fisiopatología , Nefropatías Diabéticas/fisiopatología , Endotelio Vascular/fisiología , Fallo Renal Crónico/fisiopatología , Rigidez Vascular/fisiología , Adulto , Presión Sanguínea/fisiología , Diabetes Mellitus Tipo 1/mortalidad , Angiopatías Diabéticas/mortalidad , Nefropatías Diabéticas/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Factor de Crecimiento Placentario , Proteínas Gestacionales/metabolismo , Estudios Prospectivos
10.
Diabetologia ; 53(1): 45-8, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19802713

RESUMEN

AIMS/HYPOTHESIS: Type 1 diabetic patients with diabetic nephropathy have increased mortality and morbidity compared with normoalbuminuric patients. Telomere length in proliferative cells is inversely related to the total number of cell divisions, and therefore to biological age. We aimed to evaluate differences in telomere length in patients with type 1 diabetes with or without diabetic nephropathy; we also evaluated the prognostic value of telomere length. METHODS: In a prospective follow-up study, 157 type 1 diabetic patients with diabetic nephropathy and a control group of 116 patients with type 1 diabetes and normoalbuminuria were followed for 11.1 years (range 0.2-12.9). Telomere length was measured from DNA samples extracted from white blood cells at baseline. RESULTS: The mean telomere length did not differ between patients with or without diabetic nephropathy, and was similar in men and women, but was inversely correlated with age and systolic blood pressure, p < 0.05. When dividing patients into tertiles after telomere length, 36 (37%) patients died in the tertile with the shortest telomere length, 24 (28%) died in the middle tertile, and 15 (17%) of patients in the tertile with the longest telomere length died, log rank test p = 0.017. After adjustment for traditional risk factors, telomere length was still predictive of all-cause mortality. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes we found no differences in telomere length between patients with or without diabetic nephropathy. We also found that telomere length was associated with all-cause mortality; however, confirmative studies are needed to verify our findings.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/mortalidad , Telómero/ultraestructura , Emparejamiento Base , División Celular , ADN/genética , Diabetes Mellitus Tipo 1/patología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/mortalidad , Nefropatías Diabéticas/fisiopatología , Estudios de Seguimiento , Tasa de Filtración Glomerular , Hemoglobina Glucada/análisis , Frecuencia Cardíaca , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Secuencias Repetitivas de Ácidos Nucleicos
11.
Diabetologia ; 53(10): 2129-33, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20607514

RESUMEN

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


Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/terapia , Células Endoteliales/citología , Células Madre/citología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Aspirina/uso terapéutico , Recuento de Células , Células Cultivadas , Dieta Reductora , Terapia por Ejercicio , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Leucocitos Mononucleares/citología , Estilo de Vida , Masculino , Metformina/uso terapéutico , Resultado del Tratamiento
12.
Diabet Med ; 27(10): 1144-50, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20854382

RESUMEN

AIMS: Our aim was to evaluate the markers of tubulointerstitial damage, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule1 (KIM1) in Type 1 diabetic patients with different levels of albuminuria and in control subjects. In addition, the effect of renoprotective treatment on urinary NGAL was evaluated in diabetic nephropathy. METHODS: This was a cross-sectional study in 58 normoalbuminuric (u-albumin <30 mg/24 h), 45 microalbuminuric (30-300 mg/24 h) and 45 macroalbuminuric (>300 mg/24 h) Type 1 diabetic patients and 55 non-diabetic control subjects. Furthermore, in a second study, urine-NGAL was measured in a randomized cross-over study of 56 Type 1 diabetic patients with diabetic nephropathy treated with lisinopril 20, 40 and 60 mg daily. RESULTS: Urine-NGAL levels were [geometric mean (95% CI)]: control subjects 74 (52-104) (pg/mmol creatinine), normoalbuminuric 146 (97-221), microalbuminuric 222 (158-312) and macroalbuminuric group 261 (175-390). Urine-NGAL increased significantly from the normo- to the micro- and further to the macroalbuminuric group (P<0.05). Urine-NGAL was higher in normoalbuminuric vs. control subjects (P<0.01). Plasma-NGAL was significantly higher in the normoalbuminuric and macroalbuminuric groups than in the control group. Urine-KIM1 was higher in all diabetic groups than in the control group (P<0.001), with no difference between diabetic groups. During lisinopril treatment, urine-NGAL was reduced (95% CI) 17% (11-50) (not significant). CONCLUSIONS: Urine-NGAL and urine-KIM1 (u-KIM1) are elevated in Type1 diabetic patients, with or without albuminuria, indicating tubular damage at an early stage. Urine-NGAL increases significantly with increasing albuminuria. The ACE inhibitor lisinopril reduced urine-NGAL, but this was not statistically significant.


Asunto(s)
Proteínas de Fase Aguda/orina , Albuminuria/orina , Diabetes Mellitus Tipo 1/orina , Nefropatías Diabéticas/orina , Lipocalinas/orina , Lisinopril/uso terapéutico , Glicoproteínas de Membrana/orina , Proteínas Proto-Oncogénicas/orina , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Lipocalina 2 , Masculino , Glicoproteínas de Membrana/efectos de los fármacos , Persona de Mediana Edad , Receptores Virales/efectos de los fármacos
13.
Diabetologia ; 52(12): 2590-3, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19834686

RESUMEN

AIMS/HYPOTHESIS: Hyperglycaemia increases oxidative stress and may thereby increase the risk of diabetic complications, including diabetic nephropathy. Cells are protected from oxidative damage by, for example, the manganese superoxide dismutase enzyme (MnSOD), but the functional polymorphism V16A affects the localisation of MnSOD and therefore its ability to scavenge superoxide radicals. In a Danish cohort of type 1 diabetes patients, we sought to confirm previous findings of association between the V allele and the risk of diabetic nephropathy and to investigate the influence of this polymorphism on the development of cardiovascular disease. METHODS: Type 1 diabetes patients attending the Steno Diabetes Center, Gentofte, Denmark, between 1993 and 2001 were enrolled in this study. A total of 441 cases with diabetic nephropathy (albumin excretion > or =300 mg/24 h) and 314 controls with persistent normoalbuminuria (<30 mg/24 h), despite diabetes of duration > or =20 years, were identified. The median duration of diabetes was 35 years (range 12-73 years). RESULTS: We confirmed the significant association between carrier status of the V allele and diabetic nephropathy. The association was independent of age at diabetes onset, HbA(1c), sex, smoking and diabetes duration (OR 1.7, 95% CI 1.2-2.4). The VV and AV genotypes considered together also predicted the risk of cardiovascular disease, independently of age at follow-up, HbA(1c), sex, smoking, systolic blood pressure, cholesterol and nephropathy status. The hazard ratio was 1.6 (95% CI 1.0-2.5). CONCLUSIONS/INTERPRETATION: The MnSOD V16A polymorphism is involved in the development of nephropathy caused by type 1 diabetes and seems to predict cardiovascular disease during follow-up.


Asunto(s)
Enfermedades Cardiovasculares/genética , Diabetes Mellitus Tipo 1/genética , Angiopatías Diabéticas/genética , Nefropatías Diabéticas/genética , Polimorfismo de Nucleótido Simple , Superóxido Dismutasa/genética , Adulto , Albuminuria/sangre , Presión Sanguínea , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/epidemiología , Puente de Arteria Coronaria/estadística & datos numéricos , Complicaciones de la Diabetes/enzimología , Complicaciones de la Diabetes/genética , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/enzimología , Angiopatías Diabéticas/enzimología , Angiopatías Diabéticas/epidemiología , Nefropatías Diabéticas/enzimología , Nefropatías Diabéticas/epidemiología , Estudios de Seguimiento , Hemoglobina Glucada/metabolismo , Humanos , Fallo Renal Crónico/enzimología , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/genética , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/genética , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética
14.
Mol Genet Metab ; 94(3): 347-51, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18467141

RESUMEN

UNLABELLED: The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma 2 gene is suggested to associate with diabetic nephropathy and cardiovascular disease in type 2 diabetes. The aim of this study was to investigate the polymorphism in relation to diabetic nephropathy, end-stage renal disease (ESRD), mortality and cardiovascular (CVD) events in type 1 diabetic patients. This prospective observational follow-up study included 415 type 1 diabetic patients with overt diabetic nephropathy (252 men; age 42.2+/-10.4 years [mean+/-SD], duration of diabetes 28.3+/-8.8 years, GFR 66+/-8.8 ml/min) and 428 patients with longstanding type 1 diabetes and persistent normoalbuminuria (230 men; age 45.4+/-11.6 years, duration of diabetes 27.8+/-10.1 years). FOLLOW-UP: 8.1 (0.0-12.8) years (median [range]). There where no significant differences between cases and controls in genotype (p=0.51) or allele frequencies (p=0.25). Cox regression analysis revealed a covariate-adjusted hazard ratio (HR) for all-cause mortality in patients with the Ala/Ala genotype of 2.44 (1.23-4.84). The Pro12Ala polymorphism did not predict CVD events. However, the Ala/Ala genotype predicts ESRD (covariate-adjusted HR 2.60 (1.11-6.07)). Furthermore, Carriers of the Ala-allele had a higher rate of decline in GFR (p=0.040). In conclusion, the Pro12Ala polymorphism is not associated with type 1 diabetic nephropathy. The Ala-allele is associated with enhanced decline in GFR and predicts ESRD and all-cause mortality in patients with nephropathy.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/mortalidad , Nefropatías Diabéticas/diagnóstico , Fallo Renal Crónico/genética , PPAR gamma/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/mortalidad , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Tasa de Filtración Glomerular/genética , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , PPAR gamma/fisiología , Polimorfismo de Nucleótido Simple/fisiología , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia
15.
Clin Physiol Funct Imaging ; 37(1): 30-36, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26147681

RESUMEN

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.


Asunto(s)
Artropatía Neurógena/diagnóstico por imagen , Pie Diabético/diagnóstico por imagen , Huesos del Pie/irrigación sanguínea , Huesos del Pie/diagnóstico por imagen , Imagen de Perfusión/métodos , Cintigrafía , Radiofármacos/administración & dosificación , Medronato de Tecnecio Tc 99m/administración & dosificación , Anciano , Área Bajo la Curva , Artropatía Neurógena/fisiopatología , Pie Diabético/fisiopatología , Femenino , Cámaras gamma , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Imagen de Perfusión/instrumentación , Valor Predictivo de las Pruebas , Curva ROC , Cintigrafía/instrumentación , Flujo Sanguíneo Regional , Reproducibilidad de los Resultados , Estudios Retrospectivos
19.
Scand J Clin Lab Invest ; 66(3): 173-80, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16714246

RESUMEN

OBJECTIVE: It has been suggested that an aldosterone synthase gene polymorphism (CYP11B2 -344T/C) is predictive of the blood pressure lowering effect of angiotensin II receptor blockers in essential hypertension. We investigated whether this polymorphism is predictive of reductions in blood pressure and albuminuria and preservation of glomerular filtration rate (GFR) during short-term and long-term treatment with losartan in 57 hypertensive type-1 diabetic patients with diabetic nephropathy. MATERIAL AND METHODS: After a 4-week washout period, patients received losartan (100 mg o.d.) and were followed for a mean follow-up of 36 months. At baseline, after 2 and 4 months, and every 6 months thereafter, GFR (51Cr-EDTA-clearance), albuminuria and 24-h blood pressure were determined. The CYP11B2 -344T/C polymorphism was determined by standard polymerase chain reaction (PCR). RESULTS: The TT, CT and CC genotypes were found in 28 %, 58 % and 14 % of patients, respectively. At baseline albuminuria and blood pressure did not differ between genotype groups. Plasma aldosterone levels (geometric mean (95 % CI)) were similar at baseline: 87 (60-125), 77 (53-112), and 89 (49-161) pg mL(-1) and during follow-up (not significant). After initiation of losartan treatment, comparable mean (SE) reductions in blood pressure and albuminuria were seen in patients with TT, CT and CC genotypes (p >0.6 between groups). After long-term follow-up, there was a tendency towards a difference in systolic blood pressure reduction (p = 0.07, one-way ANOVA), suggesting a poorer response in patients with the CC genotype. No significant difference in rate of decline in GFR (median (range)) was seen between groups (TT, CT, CC): 4.2 (-1.0 to 16.0), 3.2 (-1.6 to 13.8) and 2.6 (-0.1 to 11.0) mL min(-1)year(-1), respectively (p = 0.5). CONCLUSIONS: Compared to a previous smaller study of angiotensin II receptor blockade in essential hypertension, we could not confirm that CYP11B2 -344T/C genotypes contribute towards explaining the observed variability in response to treatment with angiotensin II receptor blockers, which could be due to lack of power.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Citocromo P-450 CYP11B2/genética , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/enzimología , Losartán/uso terapéutico , Adulto , Albuminuria/tratamiento farmacológico , Albuminuria/enzimología , Albuminuria/genética , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/enzimología , Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/fisiopatología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/enzimología , Hipertensión/genética , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Sistema Renina-Angiotensina/efectos de los fármacos , Factores de Tiempo
20.
Diabet Med ; 23(6): 675-80, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16759311

RESUMEN

AIMS: Aldosterone is one of the main effectors of the renin-angiotensin-aldosterone system regulating blood pressure. Previous studies have shown that the aldosterone synthase promoter polymorphism -344T/C influences aldosterone levels and is associated with hypertension, a risk factor for the initiation and progression of diabetic nephropathy. Therefore, we investigated whether the -344T/C polymorphism is associated with the development and progression of diabetic nephropathy in Type 1 diabetes mellitus. METHODS: The -344T/C polymorphism was determined using standard PCR techniques in 422 Type 1 diabetic patients with overt diabetic nephropathy [mean age 43 years (SD 11)], and in 479 patients with persistent normoalbuminuria and long-standing Type 1 diabetes [age 47 years (SD 12), duration of diabetes 27 years (SD 10)]. Furthermore, we genotyped 163 Type 1 diabetic patients with overt diabetic nephropathy treated with angiotensis-converting enzyme inhibitors (ACE-I). These patients were followed for a median of 6 years (range 3-14), with nine measurements (range 3-29) of glomerular filtration rate (GFR), and had a decline in GFR of 3.1 (-3.2; 23.7) ml/min per year. RESULTS: There was no significant difference between cases and controls in either genotype distributions (cases TT 0.33, TC 0.48, CC 0.19; controls TT 0.32, TC 0.48, CC 0.20) or allele frequencies (cases T/C 0.57/0.43; controls T/C 0.56/0.44). Furthermore, a genotype-phenotype interaction analysis in the normoalbuminuric patients revealed no differences in sex distribution, age, duration of diabetes, blood pressure, HbA(1c,) or urinary albumin excretion rate across genotypes. In the observational follow-up study, the rate of decline in GFR did not differ between groups of patients with different -344T/C genotype (P = 0.41). However, the T-allele made a statistically significant contribution to both systolic and diastolic pressure during follow-up (P = 0.006 and 0.032, respectively). CONCLUSIONS: The -344T/C polymorphism of the aldosterone synthase gene is not associated with initiation or progression of diabetic nephropathy in Caucasian Type 1 diabetic patients, but modulates blood pressure variation.


Asunto(s)
Citocromo P-450 CYP11B2/genética , Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Hipertensión/genética , Polimorfismo Genético , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/etnología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/etnología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Población Blanca
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