RESUMEN
AIMS/HYPOTHESIS: The release of podocyte-derived microparticles into the urine may reflect early kidney injury in diabetes. We measured the urinary excretion of podocyte-derived microparticles in youth with type 1 and type 2 diabetes, and related the values to blood pressure, renal function and blood glucose levels. METHODS: Cross-sectional, exploratory analysis of urine samples and clinical data from youth with type 1 (n = 53) and type 2 (n = 50) diabetes was carried out. Urinary podocyte-derived microparticle numbers, measured by flow cytometry, were assessed in relation to measures of blood glucose levels and renal function. RESULTS: Podocyte-derived microparticle excretion (MPE) normalised to urinary creatinine (MP/UCr) was higher in type 1 vs type 2 diabetes (median [IQR] MP/UCr: 7.88 [8.97] vs 1.84 [8.62]; p < 0.0001), despite the type 2 diabetes group having higher blood pressure (systolic blood pressure, median [range]: 124 [110-154] vs 114 [94-143] mmHg) and higher proportions of microalbuminuria (44.0% vs 13.2%), but shorter time since diabetes diagnosis (median [range]: 1.2 [0.0-7.0] vs 6.4 [2.0-13.9] years), than the type 1 diabetes cohort. MPE in youth with type 1 diabetes was associated with blood glucose (p = 0.01) and eGFR (p = 0.03) but not HbA1c, systolic or diastolic blood pressure or urine albumin/creatinine ratio. After adjustment for age at baseline, duration of diabetes, sex and BMI, the association with eGFR remained significant (p = 0.04). No associations were found between MPE and these clinical variables in youth with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Significant associations between podocyte MPE, blood glucose levels and eGFR were observed in youth with type 1 diabetes but not in those with type 2 diabetes, notwithstanding increased renal pathology in the type 2 diabetes cohort. These findings suggest that podocyte injury differs in the two diabetes cohorts. Graphical abstract.
Asunto(s)
Lesión Renal Aguda/orina , Glucemia/metabolismo , Micropartículas Derivadas de Células/metabolismo , Diabetes Mellitus Tipo 1/orina , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/orina , Podocitos/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Adolescente , Presión Sanguínea , Creatinina/orina , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Femenino , Citometría de Flujo , Tasa de Filtración Glomerular , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Orina/química , Orina/citologíaRESUMEN
11ß-Hydroxysteroid dehydrogenase type-1 (11ß-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11ß-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11ß-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11ß-HSD1 inhibitor or crossed with 11ß-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11ß-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11ß-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11ß-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11ß-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/deficiencia , Aterosclerosis/metabolismo , Médula Ósea/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Aterosclerosis/genética , Médula Ósea/efectos de los fármacos , Glucocorticoides/metabolismo , Ratones , Ratones Noqueados , Factores de Riesgo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
OBJECTIVE: Glycated haemoglobin (A1C) has been recommended for the diagnosis of type 2 diabetes mellitus. Chronic kidney disease (CKD) is reported to increase A1C. The prevalence of CKD and its association with A1C as a diagnostic test for type 2 diabetes screening in a community population was studied. RESEARCH DESIGN AND METHODS: Age, gender, ethnicity (white/South Asian), haemoglobin, A1C, fasting glucose and fructosamine were compared in participants with estimated glomerular filtration rate (eGFR) 30-59 (CKD 3) and ≥60 ml/min/1.73 m(2) using chi-squared or t-tests. Multivariable linear regression analyses were performed with A1C as the dependent variable; remaining variables were forced into a model to identify correlates with A1C. Data were parametric and expressed as means. RESULTS: Of 949 participants 83.7% had eGFR ≥60, 16.3% had CKD 3 and only 2 had eGFR <30 (CKD ≥4). Compared with eGFR ≥60, patients with CKD 3 were older [p<0.001], had higher A1C [6.0% vs. 5.8%, p<0.001], fasting glucose [5.4 vs. 5.2m mol/L, p=0.003] and fructosamine [233.7 vs. 225.8µ mol/L, p<0.001] but lower haemoglobin [p=0.006]. After adjustment, gender and CKD stage were not associated with A1C. A1C was associated (p<0.05) positively with age, South Asian ethnicity, fasting glucose and fructosamine and inversely with haemoglobin levels. CONCLUSIONS: Severe CKD (stage ≥4) is rare in primary care patients being screened for type 2 diabetes and its impact on A1C could not be evaluated. Although A1C is higher among patients with CKD stage 3 compared to those with eGFR ≥60, this appeared to be due to the confounding effect of other variables rather than the presence of CKD.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada/análisis , Insuficiencia Renal Crónica/sangre , Adulto , Anciano , Pueblo Asiatico , Biomarcadores/sangre , Distribución de Chi-Cuadrado , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiología , Inglaterra/epidemiología , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón/fisiopatología , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/etnología , Insuficiencia Renal Crónica/fisiopatología , Reproducibilidad de los Resultados , Factores de Riesgo , Índice de Severidad de la Enfermedad , Población BlancaRESUMEN
Glucocorticoid overexposure during pregnancy programmes offspring physiology and predisposes to later disease. However, any impact of ethologically relevant maternal stress is less clear, yet of physiological importance. Here, we investigated in rats the short- and long-term effects in adult offspring of repeated social stress (exposure to an aggressive lactating female) during late pregnancy on glucose regulation following stress, glucose-insulin homoeostasis and peripheral expression of genes important in regulating glucose and lipid metabolism and glucocorticoid action. Prenatal stress (PNS) was associated with reduced birth weight in female, but not male, offspring. The increase in blood glucose with restraint was exaggerated in adult PNS males compared with controls, but not in females. Oral glucose tolerance testing showed no effects on plasma glucose or insulin concentrations in either sex at 3 months; however, at 6 months, PNS females were hyperinsulinaemic following an oral glucose load. In PNS males, plasma triglyceride concentrations were increased, with reduced hepatic mRNA expression of 5α-reductase and peroxisome proliferator-activated receptor α (Pparα (Ppara)) and a strong trend towards reduced peroxisome proliferator-activated receptor gamma coactivator 1α (Pgc1α (Ppargc1a)) and Pparγ (Pparg) expression, whereas only Pgc1α mRNA was affected in PNS females. Conversely, in subcutaneous fat, PNS reduced mRNA expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ßhsd1), phosphoenolpyruvate carboxykinase (Pepck (Pck1)), adipose triglyceride lipase (Atgl) and diglyceride acyltransferase 2 (Dgat2) in females, but only Pepck mRNA expression was reduced in PNS males. Thus, prenatal social stress differentially programmes glucose homoeostasis and peripheral metabolism in male and female offspring. These long-term alterations in physiology may increase susceptibility to metabolic disease.