Hepatic stearoyl-CoA desaturase deficiency ameliorates hyperglycemia through bile acid signaling in an insulin-independent manner.

Hyperglycemia in Type 1 Diabetes (T1D) is managed almost exclusively via exogenous insulin therapy, an approach restricted by significant glycemic fluctuations, long-term side effects such as weight gain, and high economic burden. Identifying physiological pathways capable of clearing blood glucose independent of insulin is therefore of paramount clinical importance. Here, we demonstrate that liver-specific stearoyl-CoA desaturase-1 (SCD1) deficiency protects against diabetic hyperglycemia and hepatic steatosis in an insulin-independent manner. SCD1 ablation decreases cellular oleate availability, altering lipid flux and redirecting excess cholesterol into alternative biosynthetic pathways. This redirection drives a 2-fold elevation in hepatic bile acids and a striking 10-fold increase in plasma bile acids, predominantly characterized by the accumulation of taurocholic acid. This shifted bile acid pool stimulates the expression of glucose transporter 1 (Glut1) in the liver via activation of the nuclear hormone receptor FXR, facilitating basal glucose clearance in the absence of insulin. Genetic deletion models show that while the hepatokine FGF21 serves as a partial mediator of this phenotype, the local bile acid-FXR axis remains a sufficient driver of systemic glucose clearance. Finally, we show that dietary oleate supplementation completely reverses this protective phenotype, turning down Glut1 expression and restoring overt diabetes. Together, our findings uncover a novel bile acid-FXR-Glut1 signaling axis triggered by SCD1 inhibition, offering a framework for insulin-independent glycemic control.