Circulating bilirubin, a natural antioxidant, is associated with decreased risk of type 2 diabetes (T2D), but the nature of the relationship remains unknown. We performed Mendelian randomization in a prospective cohort of 3,381 participants free of diabetes at baseline (age 28-75 years; women 52.6%). We used rs6742078 located in the uridine diphosphateglucuronosyltransferase locus as an instrumental variable (IV) to study a potential causal effect of serum total bilirubin level on T2D risk. T2D developed in a total of 210 participants (6.2%) during a median follow-up period of 7.8 years. In adjusted analyses, rs6742078, which explained 19.5% of bilirubin variation, was strongly associated with total bilirubin (a 0.68-SD increase in bilirubin levels per T allele; P < 1 3 10 2122 ) and was also associated with T2D risk (odds ratio [OR] 0.69 [95% CI 0.54-0.90]; P = 0.006). Per 1-SD increase in log-transformed bilirubin levels, we observed a 25% ; P = 0.004) lower risk of T2D. In Mendelian randomization analysis, the causal risk reduction for T2D was estimated to be 42% (causal OR for IV estimation per 1-SD increase in log-transformed bilirubin 0.58 [95% CI 0.39-0.84]; P = 0.005), which was comparable to the observational estimate (Durbin-Wu-Hausman x 2 test,

Our results indicate that low UKV is associated with a higher risk of graft failure and mortality in RTRs. Specific attention for adequate potassium intake after transplantation seems warranted. This trial was registered at clinicaltrials.gov as NCT02811835.

Bilirubin, a potent endogenous antioxidant, was found to protect against the development of diabetic nephropathy (DN) in rodents. In humans, cross-sectional studies found an inverse relation between bilirubin and DN. We prospectively investigated whether bilirubin is associated with progression of DN toward end-stage renal disease (ESRD). To this end, we performed a post hoc analysis in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial with independent replication in the Irbesartan Diabetic Nephropathy Trial (IDNT). Subjects with type 2 diabetes and nephropathy with alanine aminotransferase, aspartate aminotransferase (AST), and bilirubin levels &lt;1.5 times the upper limit of normal were included. The renal end point was defined as the composite of confirmed doubling of serum creatinine or ESRD. Bilirubin was inversely associated with the renal end point in RENAAL independent of age, sex, race, BMI, smoking, total cholesterol, diastolic blood pressure, HbA1c, treatment, estimated glomerular filtration rate, albumin-to-creatinine ratio, and AST. These results were confirmed in IDNT. This study indicates an independent inverse association of bilirubin with progression of nephropathy in RENAAL and IDNT. These data suggest a protective effect of bilirubin against progression of nephropathy in type 2 diabetes. The well-established role of bilirubin as an antioxidant is a potential explanation for the findings.