Unfavorable cytokine and adhesion molecule profiles during and after pregnancy, in women with gestational diabetes mellitus

Abstract

Background

Gestational diabetes mellitus is a significant risk factor for metabolic syndrome and cardiovascular disease.

Aims

To assess the relationships between components of the metabolic syndrome and cytokine and adhesion molecule levels in women with GDM during pregnancy and after delivery.

Patients and methods

A prospective case–control study on a sample of 126 pregnant women (63 with and 63 without gestational diabetes mellitus). In an intra-subject analysis, 41 women with history of gestational diabetes mellitus and 21 controls were re-assessed in the postpartum period. Clinical data and levels of cytokines and adhesion molecules were recorded during weeks 24–29 of pregnancy and 12 months after delivery.

Results

In the postpartum period, there were significantly higher levels of tumor necrosis factor alpha in both cases and controls, and of adiponectin in controls. Cases showed higher leptin levels, with no significant differences during and after pregnancy. No significant differences were seen in adhesion molecules and interleukin-6 between cases and controls during pregnancy and in the postpartum period, but levels of both were higher in cases. During pregnancy and after delivery, adiponectin decreased in cases and increased in controls. Significant positive correlations were seen between adiponectin and fasting blood glucose levels and vascular cell adhesion molecule-1, and also between leptin and tumor necrosis factor alpha levels.

Conclusions

The results suggest that increased inflammation and transient hyperglycemia during pregnancy would represent a latent form of metabolic syndrome, with an increased risk for type 2 diabetes mellitus and future cardiovascular disease.

Resumen

Antecedentes

La diabetes mellitus gestacional es un factor de riesgo importante para el síndrome metabólico y la enfermedad cardiovascular.

Objetivos

Se evaluaron las relaciones entre los componentes del síndrome metabólico, los niveles de citocinas y moléculas de adhesión en mujeres con diabetes gestacional durante el embarazo y en el posparto.

Pacientes y métodos

Estudio prospectivo de casos y controles. Se analizaron 126 mujeres gestantes (63 con diabetes mellitus gestacional y 63 controles). En el periodo posparto, se reevaluaron 41 casos y 21 controles. Se analizaron variables clínicas, niveles de citocinas y moléculas de adhesión durante las semanas 24-29 de la gestación y 12 meses después del parto.

Resultados

En el periodo posparto, el factor de necrosis tumoral alfa en casos y controles, y la adiponectina en controles fueron significativamente más altos. Los casos mostraron mayores niveles de leptina, sin diferencias significativas durante el embarazo y después del parto. No se observaron diferencias significativas en las moléculas de adhesión y la interleucina 6 entre casos y controles durante el periodo de embarazo y el posparto, pero ambos fueron mayores en los casos. Durante el embarazo y posparto, la adiponectina disminuyó en los casos y aumentó en los controles. Observamos correlaciones positivas significativas entre adiponectina con glucemia en ayunas y moléculas de adhesión celular vascular-1, y entre leptina y factor de necrosis tumoral alfa.

Conclusiones

Los resultados indican que el aumento de la inflamación y la hiperglucemia transitoria durante el embarazo representarían una forma latente de síndrome metabólico, con un mayor riesgo de diabetes mellitus tipo 2 y de enfermedad cardiovascular en el futuro.

Introduction

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance that begins, or is first recognized, during pregnancy. It complicates about 1–14% of all pregnancies worldwide. GDM mothers and their offspring are at increased risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, the mechanisms underlying these processes are unclear.¹

Metabolic syndrome (MetS) is the clustering of central-trunk obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, hypertension and dysglycemia. However, there is no consensus as to what defines MetS. Insulin resistance (IR) is proposed as the common link between the different manifestations of MetS and, as well, the cause of most of the associated abnormalities.²

Adipokines regulate glucose metabolism, insulin secretion and its activity, and fetal development. A high correlation between adiposity and IR with interleukin 6 (IL-6) concentrations has been described. High IL-6 secretion may aggravate IR in pregnancy and participate in the pathogenesis of GDM. Tumor necrosis factor alpha (TNF-α) has been used to predict GDM and its prognosis.³ TNF-α and IL-6 are involved in mechanisms that contribute to endothelial damage, including inhibition of endothelial nitric oxide synthase, vascular smooth muscle proliferation, and elevated concentrations of adhesion molecules.⁴ Pregnancy, such as obesity, associates a hypothalamic leptin resistance and, therefore, a rise in plasma leptin levels. However, the role of leptin in GDM is unclear.⁵ Adiponectin is a protein secreted exclusively by adipose tissue, with an inverse statistical correlation with MetS, together with a predictive role in the development of T2DM and atherosclerosis.⁶ Higher leptin, IL-6 and TNF-α with lower adiponectin levels in women with GDM compared with controls have been reported, together with low leptin, adiponectin, TNF-α and IL6 levels in offspring with macrosomia.⁶

Several cell adhesion molecules (AMs) are implicated in early stages of atherosclerosis development through the adhesion of monocytes to the endothelium cells. Among the AMs are: intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and cellular molecule (E-selectin) all of which correlate with the concentrations of pro-inflammatory cytokines.⁷ Elevated E-selectin and VCAM-1 serum concentrations have been reported in women at risk of developing T2DM.⁸ This could be related to the degree of glycemic control that influences E-selectin concentrations through its effect on oxidative stress.⁹ Other markers of endothelial dysfunction include fibrinogen, microalbuminuria¹⁰ and hyperuricemia.¹¹

Hence, the aim of the present study was to evaluate the levels of cytokines and AMs and CVD risk markers in women with GDM during and after pregnancy. The results could provide an insight into the pathogenesis of GDM as well as MetS.