The pathogenesis and pathophysiology of gestational diabetes mellitus: Deductions from a three-part longitudinal metabolomics study in China

Abstract

Gestational diabetes mellitus (GDM) is a form of diabetes that is first recognised during pregnancy, with no evidence of pre-existing type 1 or type 2 diabetes. The prevalence of GDM has been rising steadily over the past few decades, coinciding with the ongoing epidemic of obesity and type 2 diabetes. Although GDM normally disappears after delivery, women who have been previously diagnosed with GDM are at a greater risk of developing gestational diabetes in subsequent pregnancies, and type 2 diabetes later in life. Infants born to mothers with GDM also have a higher risk of developing type 2 diabetes in their teens or early adulthood. There are many possible causes of insulin resistance, and multiple metabolic aberrants are known to be involved in the development of different forms of diabetes. Increasing evidence suggests that different forms of diabetes share common pathogenesis and pathophysiological dysregulation resulting from a progressive β-cell demise or dysfunction. The outcome manifests clinically as hyperglycaemia. The development of GDM may represent a very early stage of the progression to type 2 diabetes that is being manifested under the stresses of pregnancy. However, the exact mechanisms of GDM development are not clearly understood. Based on the results of a three-part longitudinal metabolomics study of Chinese pregnant women, in combination with the current literature, a new model of GDM development is proposed to outline the biomolecular mechanisms underpinning GDM. A possible cause of GDM is obesity, which is an important clinical risk factor for the development of diabetes. Women who develop GDM generally have higher body mass indices when compared with healthy pregnant women, and obesity can induce low-grade inflammation. Chronic low-grade inflammation induces the synthesis of xanthurenic acid, which is known to be associated with the development of type 2 diabetes, pre-diabetes and GDM. Hyperglycaemia accelerates purine nucleotide synthesis, which in turn stimulates nucleotide breakdown and increases the concentration of nucleotide degradation products, including superoxide molecules and uric acid. Reactive oxygen species and excessive intracellular uric acid may also have direct effects on the development of the disease or further deterioration of the condition.

Keywords: Diabetes; Gestational diabetes mellitus; Lipotoxicity; Meta-inflammation; Metabolomics; Purine metabolism; Tryptophan metabolism.