Abstract
Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. It is generally defined as glucose intolerance with onset or first recognition during pregnancy. The pathogenesis of GDM has long been attributed to inadequate pancreatic β-cell compensation for the physiological insulin resistance of pregnancy. This defect is thought to resolve after pregnancy but become manifest in later life as an increased risk of diabetes. Examination of mechanisms underlying GDM does not support this commonly held picture. In this Perspective, we present evidence that, like diabetes outside of pregnancy, GDM has no single etiology. It results from multiple causes of a common physiological manifestation, inadequate β-cell function, which leads to a common clinical manifestation, elevated glucose levels. We provide evidence that GDM often represents detection of chronic and progressive β-cell dysfunction that is temporally but not mechanistically related to pregnancy. We provide detailed characterization of the β-cell defect in one high-risk group, Hispanic Americans. Finally, we address some of the clinical and research implications of these findings. ARTICLE HIGHLIGHTS: Gestational diabetes mellitus (GDM) is not one disease but many that share inadequate β-cell function as a common cause for elevated glucose levels. Inadequate β-cell function may result from factors that occur outside of pregnancy, such as autoimmunity, monogenic disorders, obesity, and insulin resistance. Pregnancy-specific causes may exist as well but remain to be defined. Detailed physiological studies in women with obesity reveal that inadequate β-cell function is likely a chronic condition that is detected by routine glucose screening in pregnancy and that worsens over time, leading to diabetes in later life. The authors' studies in Hispanic patients identify obesity and insulin resistance as important causes of β-cell dysfunction, providing a rationale for treating both to prevent diabetes after GDM. Additional work is needed to define the full breadth of underlying causes of GDM as the basis for precision management during and, especially, after pregnancy.