Berberine signature and cardiometabolic diseases: a study leveraging randomized controlled trial, cohort study and Mendelian randomization

Background Statins are mainstay for treatment of hyperlipidemia, however, statins have the side effect of hyperglycemia. Berberine, lowering both lipids and glucose, is a promising candidate, but its effects on IHD and diabetes have not been examined. Methods Based on a randomized controlled trial of berberine in 80 men, and leveraging proteomics and sex hormones data, we built a signature reflecting the response to berberine (in short "berberine signature") using elastic net regression. We examined the associations of berberine signature with lipids and glucose in the trial and UK Biobank. We then assessed whether this signature was associated with IHD and diabetes in UK Biobank using logistic regression and for causal relationship, using bi-directional Mendelian randomization (MR), and examined the effect of each protein/hormone. Results The berberine signature includes 18 proteins and two sex hormones (testosterone and sex hormone binding globulin (SHBG)). It was related to lower lipids and glucose, lower risk of IHD and diabetes using observational study (odds ratio (OR) for IHD 0.87, 95% confidence interval (CI) 0.80 to 0.94; diabetes 0.66, 0.60 to 0.72) and MR (OR for IHD 0.82, 0.76 to 0.88; for diabetes 0.88, 0.80 to 0.96). SHBG, CCL5, PRSS2 and PLA2G7 may explain the effects on IHD, while testosterone, SHBG, CCL5, PRSS2, CNDP1, F11, LCN2, and THBS4 may explain the effects on diabetes. Conclusion Our study suggests beneficial effects of berberine on IHD and diabetes. The identified proteins and sex hormones underlying these effects might illustrate mechanisms for drug development.