N1-methylnicotinamide impairs gestational glucose tolerance in mice

Abstract

N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays anti-diabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with high fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired the glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, it reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. NAD+/Sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was deminished in placenta by MNAM. In addition, weight of placenta, fetus weight or litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of GTT by MNAM. Our data provide evidences for the careful usage of MNAM in treatment of GDM.