Targeting Adrenomedullin to Improve Lipid Homeostasis in Diabetic Pregnancies

Abstract Context Gestational diabetes mellitus (GDM) is associated with disturbances in maternal lipid metabolism. Hypertriacylglycerolemia in GDM is associated with an increased risk of large for gestational age neonates, but the pathogenesis of disrupted lipid homeostasis remains unclear. Objectives To determine the role of adrenomedullin (AM), a multifunctional peptide, in lipid metabolism in GDM. Design Omental adipose biopsies were collected in term pregnancy from women with normal glucose tolerance (NGT, n = 10) and GDM (n = 10). Results AM and its receptor components, calcitonin receptor-like receptor, receptor activity-modifying protein 2, and receptor activity-modifying protein 3, were higher in adipose tissues from GDM compared with NGT pregnancies, and these expressions in normal adipose tissues were enhanced by glucose and tumor necrosis factor–α in vitro. AM dose- and time-dependently stimulated lipolysis in human adipocytes, and this effect was reversed by AM antagonist AM22-52. Furthermore, AM inhibited phosphorylation of insulin receptor–β and insulin receptor substrate–1 and enhanced the protein expression of leptin and resistin in adipose tissue from NGT women. The increased messenger RNA expression of leptin and resistin in adipose tissue from GDM was reduced by AM22-52 treatment. Conclusions GDM pregnancies are associated with increased AM and its receptor expression in adipose tissues. AM stimulates lipolysis and leptin and resistin expression, and these effects can be reversed by AM antagonist. To our knowledge, manipulation of AM and its receptors in adipocytes might represent an approach in reducing the risk of GDM and fetal overgrowth. Adrenomedullin and its receptors are elevated in adipose tissue from women with gestational diabetes mellitus; adrenomedullin increases lipolysis, leptin, and resistin and decreases insulin’s action.