Pathogenesis of Gestational Diabetes

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Gestational diabetes is a common pregnancy complication. Although the precise underlying mechanism has yet to be identified, insulin resistance and inadequate insulin secretion to compensate for it play a central role in the pathophysiology of GDM. Excess adiposity is an important modifiable risk factor for the development of the condition. Mechanisms linking excess adiposity to elevated risk of GDM are not completely understood, but recent evidence points to the crucial role of specific hormones and cytokines (adipokines) secreted by the adipose tissue. The general goal of this project is for research on the pathogenesis of GDM. Under this research theme, the specific aim of this project is to prospectively investigate novel biochemical markers, for instance, biomarkers involved in adipocyte cytokine secretion and metabolism in association with subsequent risk of GDM and fetal overgrowth. This project utilizes bio-specimens collected 4 times throughout pregnancy from GDM cases and matched controls within the NICHD Fetal Growth Studies. In the past year multiple advances have been made to our understanding of the pathogenesis of GDM. Research on plasma fatty acids provides novel evidence for distinct associations of individual and subclasses of saturated fatty acids (SFAs) and poly-unsaturated fatty acids (PUFAs) varying by chain length, in relation to subsequent risk of GDM. For instance, it was demonstrated that primarily endogenously metabolized n-6 PUFAs including GLA, DGLA, and DTA in early to mid-pregnancy in the development of GDM. Several plasma acylcarnitine species are differentially associated with GDM risk by chain length. Carnitine plays a pivotal role in transporting fatty acids into the mitochondria for subsequent fatty acid oxidation (FAO). This process results in the esterification of carnitine to form acylcarnitine derivatives. Dysregulation of acylcarnitine derivatives may be indicative of impaired FAO and mitochondrial dysfunction, which in turn contributes to the pathogenesis of insulin resistance. In addition, based on non-targeted lipidomics profile of 420 metabolites, we observed that plasma lipid metabolites in early pregnancy both individually and interactively in distinct networks were associated with subsequent GDM risk. Taken together, these new findings shed light on the biological mechanisms that underlie prior findings on dietary fat and GDM risk and support the concept of precision nutrition for GDM prevention. Additionally, maternal vitamin D deficiency as early as the first trimester of pregnancy was associated with an elevated risk of GDM. The association was stronger for women who were persistently deficient through the second trimester. Assessment of vitamin D status in early pregnancy may be clinically important and valuable for improving risk stratification and developing effective interventions for the primary prevention of GDM. Furthermore, sex hormone binding protein, prolactin, and understudied adipokines including FABP4, chemerin, and sOB-R have been associated with GDM risk and may be involved in the pathophysiology of GDM, long before the diagnosis of GDM in the second half of pregnancy. Further research is needed to further elucidate the mechanisms in which these biomarkers are involved in GDM development.