A New Biomarker To Predict Impaired Glucose Metabolism And New Pathway To Improve Glycometabolism

AimsAlthough total bile acid（TBA）has been known to correlate with insulin resistance and the development of diabetes,the relationship between TBA level and the risk of gestational diabetes mellitus（GDM）remains unclear.Thus,the aim of the present study was to clarify whether first trimester TBA could be a potential biomarker discriminating women at high risk for GDM.In addition to biomarker,we also investigated the hypoglycemic effect of mitochondrial complex I inhibition and whether AMP-activated protein kinase（AMPK）activation was indispensable,so as to explore a new pathway to improve glucose metabolism.MethodsThe biochemical profiles were obtained from 742 pregnant women at 12 weeks of gestation.Diagnostic 75-g oral glucose tolerance test（OGTT）was performed at24–28th weeks of gestation to diagnose GDM.In basic research,introperitoneal glucose tolerance test（IPGTT）and insulin tolerance test（ITT）were performed to assessed the change of glucose homeostasis in diabetic db/db mice treated with rotenone.The effects of complex I inhibition on glycolysis and gluconeogenesis were tested.The effect of rotenone on AMPK activity was assessed by western blot.DN-AMPK adenovirus was administrated to block the activity of AMPK in the cells.Under these circumstances,the hypoglycemic effect of rotenone was assessed.ResultsSerum levels of TBA at first trimester pregnancy elevated in GDM women（n=268）compared to healthy pregnant women（n=474）（2.3±1.4μmol/L vs.1.9±1.0μmol/L,P<0.001）.Binary logistic regression analysis revealed TBA was an independent risk factor for GDM after adjustment for age and other confounders（OR,1.383;95%CI,1.183-1.616,P<0.001）.TBA levels were analyzed in five categories.When considering TBA category 1 as reference,women in the third and the fifth categories had significantly higher risk for GDM（OR,2.53;95%CI,1.29-4.99,P=0.007;OR,7.72;95%CI,3.22-18.50,P<0.001）after controlling for other confounders.In basic research,we found that rotenone ameliorated hyperglycemia and insulin resistance in db/db mice（P<0.05）.Rotenone,amobarbital,or gene silence of GRIM-19 induced glycolysis in HepG2 cells and C2C12 cells,and reduced hepatic glucose output in primary hepatocytes（P<0.05）.Rotenone activated phosphorylation of AMPK(Thr₁₇₂)and its downstream target protein ACC(Ser₇₉).Furthermore,it remained effective in the condition of AMPK inactivation.ConclusionsFirst-trimester TBA level was independently associated with GDM.TBA level can be a potential biomarker distinguishing women at high risk for GDM at early pregnancy.Futhermore,mitochondrial complex I emerges as a key target of glycometabolism regulation.Inhibition of complex I with rotenone improves glucose homeostasis independent of AMPK pathway.