A Preliminary Study On The Correlation Between AME And Novel Biomarkers Caused By HSD11B2 New Mutation Site And DKD Progression In Type 2 Diabetes

Objective: Apparent Mineralocorticoid Excess(AME)is a rare disorder with hypokalemic hypertension caused by the mutation in 11β-hydroxysteroid dehydrogenase 2(HSD11B2)gene.This study was to characterize an AME patient with a novel HSD11B2 mutation,and to establish the effect of the mutation in vitro.Methods: Herein we present a case of a boy affected by severe hypertension and hypokalemia.Urine cortisol-to-cortisone ratio(F/E)was measured as a surrogate marker of 11β-HSD2 activity in vivo.Peripheral blood DNA was used for gene sequencing.Wild-type or mutant 11β-HSD2 plasmids were transfected into human embryonic kidney 293 FT cells to evaluate the enzyme activity in vitro.Molecular docking study was carried out by Modeller 9.15 and Autodock Vina 1.1.2 software.Result: The proband displayed typical AME features such as hypertension,hypokalemia,hypoaldosteronemia,low renin levels and high F/E in urine.A novel missense homozygous substitution C1088 T in exon 5 of HSD11B2 was discovered by DNA sequencing of the proband,resulting in an amino acid change from leucine to proline at position 363(L363P).A monoallelic mutation was found in his parents.In vitro,the activity of the mutant enzyme was significantly inhibited compared with wild-type.The docking study indicated that the loss of enzymatic function was due to L363 P substitution reducing the affinity between 11β-HSD2 and cortisol.Conclusions: Here,we report a novel mutation of HSD11B2 causing AME syndrome.This mutation significantly restrains the enzymatic activity of 11β-HSD2,probably through crippling its binding ability to cortisol.Objective: Based on a prospective cohort study,we aimed to explore the relationship between new biological markers(s TNFR1,s TNFR2,RBP)and renal function in diabetic kidney disease.Method: A total of 160 diabetic patients with microalbuminuria were recruited as subjects in this study.Clinical and biochemical data(including renal function,s TNFR1,s TNFR2,RBP etc.)was collected at baseline and after 6 months.Pearson Correlation and Multiple linear regression analysis were used to analyze the above index with renal related indicators urine albumin to creatinine ratio(UACR),urine albumin excretion(UAE)and estimated glomerular filtration rate(e GFRcr-cys).Results: At baseline,RBP、s TNFR1、s TNFR2 were all negatively correlated with e GFRcr-cys with R value-0.523,-0.334,-0.392 respectively.The relationships still existed after multiple linear regression adjustment.RBP、s TNFR1、s TNFR2 at baseline were all negatively correlated with e GFRcr-cys at 6 months with R value-0.254,-0.323,-0.401 respectively.After 6 months,only the change of RBP(△ RBP)was significantly correlated with △e GFRcr-cys(R=-0.699,P<0.001)even after adjustment by multiple linear regression.Conclusion: s TNFR1 、 s TNFR2 、 RBP levels at baseline could independently predict renal function at 6 months.The increment of RBP was significantly correlated with the decrease of e GFR.