Introduction: Gestational diabetes mellitus (GDM) is associated with significant maternal and perinatal complications. Although GDM affects 11% of all pregnancies on average, the incidence has reached epidemic proportions within Asian (>16%) and Indian (>20%) populations. Sirtuin 1 (SIRT1), a ‘‘reverse thrifty gene’’ that protects against metabolic diseases by directing the organism to limit energy consumption and expenditure, is a nutrient sensing protein deacetylase involved in glucose and insulin metabolism and nutrient transport. We aimed to characterize and determine the role of SIRT1 in human placenta and to investigate whether circulating concentrations can be used as an early marker for GDM.
Methods: Human term placentas were obtained from women whose pregnancies were normal or complicated by GDM and controlled by diet. SIRT1 activity was inhibited in primary syncytiotrophoblasts with the selective SIRT1 inhibitor Ex-527 in vitro. Gene and protein expressions were examined by real-time PCR and western blotting, respectively. Serum samples from GDM cases and controls who participated in the SCOPE study in Auckland, New Zealand were obtained at 15 and 20 weeks’ gestation. SIRT1 levels in serum were analysed by ELISA.
Results: SIRT1 mRNA and protein expressions were down-regulated in term placentas from pregnancies complicated with GDM. Hyperglycaemia resulted in reduced SIRT1 protein expression in primary syncytiotrophoblasts in vitro. Whereas, SIRT1 inhibition resulted in up-regulation of fatty acid transporter proteins FATP2, FATP4 and GLUT4 after 24 hours and down-regulation of FATP6, amino acid transporters SNAT2 and ASCT1 gene expressions after 48 hours. SIRT1 levels were significantly lower at 15 weeks’ in women who developed GDM compared to control women.
Conclusion: Our data implicate a role for SIRT1 in the pathogenesis of GDM and in the regulation of nutrient transporter proteins in human placenta. Manipulation of SIRT1 may constitute a novel future approach for the treatment of GDM.