NR1H4 and Insulin resistance: To provide further evidence, human trials in insulin-resistant and non-insulin-resistant NAFLD patients found an inability for insulin-resistant patients to successfully transduce FGF19 binding into CYP7A1 repression.378 Collectively, decreases in incretin release by insulin resistance-induced 12α-OH BAs, ceramide-induced hepatocyte/adipocyte insulin resistance, and ceramide-induced overactivity of all four rate-limiting enzymes of gluconeogenesis create a strong connection between abnormal BA pool compositions, the gut-liver FXR-axis, and the T2DM phenotype.