The effects of gut microbiome-derived metabolites on glucose metabolism of hepatocytes

Type 2 diabetes (T2D) is the fourth leading cause of death in Israel and is considered a world-wide epidemic. The main manifestation of T2D is excessive blood glucose concentrations (hyperglycemia) with associated micro- and macrovascular complications. The liver plays a central role in regulating glycemia and excessive glucose production is a hallmark of T2D pathophysiology. Finding new therapeutics is critical to our ability to maintain normoglycemia in T2D patients. The gut microbiome has attracted much attention in recent years as a potential modulator of human physiology as well as pathophysiology. Gut-derived metabolites are potential mediators of these effects, however mechanistic understanding of how the microbiome regulates host’s physiology is missing. Recent studies suggest that indole derivatives, and specifically indole-3-propionic acid (IPA), which is exclusively produced by the microbiome, is associated with improved insulin resistance and whole-body glucose homeostasis. However, the exact mechanism is not clear. We hypothesize that indole derivatives, and specifically IPA, can act directly on hepatocytes and modulate their ability to metabolize glucose. Our preliminary data show that IPA significantly reduce glucose secretion from mouse primary hepatocytes and suppress the expression of gluconeogenic genes, pointing to a direct effect of IPA on hepatocytes. Our study provides a mechanistic understanding for the beneficial effects of a gut-derived metabolite.