RESUMEN
OBJECTIVE: Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. DESIGN: Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. SETTING: Antenatal clinics. POPULATION: Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). METHODS: Maternal serum levels of sRAGE (total circulating pool), N(ε)-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. MAIN OUTCOME MEASURES: Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-). RESULTS: In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. CONCLUSIONS: In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Productos Finales de Glicación Avanzada/sangre , Preeclampsia/sangre , Embarazo en Diabéticas/sangre , Receptores Inmunológicos/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Imidazoles/sangre , Modelos Lineales , Lisina/análogos & derivados , Lisina/sangre , Preeclampsia/diagnóstico , Embarazo , Estudios Prospectivos , Receptor para Productos Finales de Glicación AvanzadaRESUMEN
AIMS/HYPOTHESIS: Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFbeta1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia. METHODS: Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term. RESULTS: Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n = 26) vs those without hypertensive complications (diabetic normotensive, n = 95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p < 0.05) and the normal rise of PlGF during pregnancy was blunted (p < 0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r(2) = 42%, p < 0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p < 0.0001). CONCLUSIONS/INTERPRETATION: Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.
Asunto(s)
Inhibidores de la Angiogénesis/sangre , Diabetes Mellitus Tipo 1/complicaciones , Preeclampsia/sangre , Adulto , Antígenos CD/sangre , Diabetes Mellitus Tipo 1/sangre , Endoglina , Proteínas del Ojo/sangre , Femenino , Hemoglobina Glucada/análisis , Hormona del Crecimiento/sangre , Humanos , Proteínas de la Membrana/sangre , Factores de Crecimiento Nervioso/sangre , Embarazo , Complicaciones del Embarazo/sangre , Receptores de Superficie Celular/sangre , Serpinas/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
The aim of the present study was to identify in young, diabetes-prone subjects the early abnormalities which may predispose to the development of type 2 diabetes. We studied 10 full-blood Australian Aborigines all of whom had a family history of diabetes and who were from an urbanised community with a high prevalence of this disorder. They were compared to 10 age- and body-mass-index-matched Caucasian controls with no family history of diabetes. Glucose kinetics were measured basally and following an oral glucose load. Fasting plasma glucose was equal in the two groups, but 2 h following the 75 g glucose load, the Aboriginal subjects had higher glycaemia than the controls (P less than 0.01). Insulinaemia was higher in the Aborigines both basally and following the glucose drink (P less than 0.05). Despite the hyperinsulinaemia, hepatic glucose production was higher in the Aboriginal subjects (P less than 0.01), while metabolic clearance rate was lower. It is concluded that in young Australian Aborigines with a strong family history of type 2 diabetes, both hepatic and peripheral insulin resistance are early abnormalities.
Asunto(s)
Diabetes Mellitus/epidemiología , Glucosa/metabolismo , Enfermedades Metabólicas/diagnóstico , Nativos de Hawái y Otras Islas del Pacífico/genética , Administración Oral , Adulto , Australia/epidemiología , Índice de Masa Corporal , Diabetes Mellitus/genética , Femenino , Glucosa/administración & dosificación , Glucosa/farmacología , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina/fisiología , Masculino , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Prevalencia , Factores de RiesgoRESUMEN
Based on oral glucose tolerance testing, the prevalence of diabetes in Australian adults has ranged from 2.3% in Europids in 1966 to 20% in small surveys of Aborigines. We have surveyed Aborigines and Europids simultaneously for further comparison of diabetes prevalence between these population groups. The samples were drawn from two adjacent country towns in south-eastern Australia, where Aborigines and Europids have been in contact for 150 years. By the 2-h (post-75 g oral glucose load) criterion (venous plasma glucose greater than or equal to 11.1 mmol/l), the crude prevalence of diabetes among 306 Aborigines was 7.8%, significantly higher than the 3.4% among 553 Europids (P less than 0.01). The prevalence of impaired glucose tolerance was similar in both groups (6.9% in Aborigines, 6.0% in Europids, no significant difference). Adjustment for the marked differences in age distribution between Aborigines and Europids by direct standardization to the 1980 world population increased the apparent differences, with the finding of a four-fold greater prevalence among Aborigines (8.1% compared with 1.9%). The greater frequency of glucose intolerance among Aborigines appears to persist despite the higher proportion of Europid genetic mix with these urbanized south-eastern groups than with Aborigines from remote settings.