Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes

Abstract

The incidence of gestational diabetes mellitus (GDM) has doubled over the last 6–8 years and is paralleling the obesity epidemic. GDM carries long-term implications for the subsequent development of type 2 diabetes in the mother and increased risk for obesity and glucose intolerance in the offspring. Insulin resistance exists before pregnancy in women with a history of GDM but worsens during gestation. Insulin secretion is inadequate to compensate for the insulin resistance, leading to hyperglycemia that is detected by routine glucose screening in pregnancy. Thus, chronic insulin resistance is a central component of the pathophysiology of GDM. Human pregnancy is characterized by a series of metabolic changes that promote adipose tissue accretion in early gestation, followed by insulin resistance and facilitated lipolysis in late pregnancy. In early pregnancy, insulin secretion increases, while insulin sensitivity is unchanged, decreased, or may even increase (1,2). However, in late gestation, maternal adipose tissue depots decline, while postprandial free fatty acid (FFA) levels increase and insulin-mediated glucose disposal worsens by 40–60% compared with prepregnancy (2). The ability of insulin to suppress whole-body lipolysis is also reduced during late pregnancy (3), and this is further reduced in GDM subjects (4), contributing to greater postprandial increases in FFAs, increased hepatic glucose production, and severe insulin resistance (2,5–7). Although various placental hormones have been suggested to reprogram maternal physiology to meet fetal needs, the cellular mechanisms for this complex transition remain obscure (8). Further, the critical molecular mechanisms involved in increasing maternal lipid flux in obese women throughout pregnancy that may underlie skeletal muscle insulin resistance and increased fetal fuels are just beginning to be investigated. Skeletal muscle is the principal site of whole-body glucose disposal, and along with adipose tissue, becomes severely insulin resistant during the latter half of pregnancy. Normal …