Intestinal ghrelin impairs insulin signaling and increases liver glucose production via a gut-brain-liver pathway

Ghrelin is a multifaceted hormone known primarily for stimulating appetite, but its roles in other physiological processes are still being uncovered. While ghrelin's systemic effects on glucose metabolism are studied, the specific actions of intestinal ghrelin on hepatic glucose production (HGP) have remained unclear. Understanding this localized signaling is crucial because dysregulation of HGP is a key feature of metabolic diseases like type 2 diabetes. This research aims to fill that gap by investigating how ghrelin originating in the gut communicates with the liver to influence glucose homeostasis and insulin sensitivity, potentially revealing a novel neuro-hormonal circuit that could be a target for future metabolic therapies.

Researchers infused compounds directly into the duodenum of normal chow-diet rats to study the local effects of gut ghrelin. They used a pancreatic-euglycemic clamp procedure combined with a [3-3H] glucose tracer to precisely measure hepatic glucose production (HGP) and insulin sensitivity (glucose infusion rate, GIR). To dissect the mechanism, they co-infused ghrelin with various blockers: the ghrelin receptor antagonist [D-Lys3]-GHRP-6, an AMPK activator (AICAR), a local anesthetic (tetracaine), an NMDA receptor inhibitor (MK801), and used a viral vector (Ad-shNR1) to silence NMDA receptors in the brain's dorsal vagal complex. A final group underwent hepatic vagotomy to confirm the nerve's role.

Intraduodenal infusion of ghrelin significantly increased hepatic glucose production (HGP) and the expression of gluconeogenic enzymes in the liver. Concurrently, it decreased the glucose infusion rate (GIR) and impaired hepatic insulin signaling. The study identified that ghrelin first acted locally by inhibiting the duodenal AMP-dependent protein kinase (AMPK) signal pathway. The downstream effects on the liver were entirely dependent on a neural circuit. > Co-infusion of the ghrelin receptor antagonist [D-Lys3]-GHRP-6 or an AMPK agonist with ghrelin successfully diminished the ghrelin-induced increase in HGP and the decrease in GIR and hepatic insulin signaling. Furthermore, blocking neural transmission with tetracaine, performing a hepatic vagotomy, or inhibiting NMDA receptors within the brain's nucleus of the solitary tract (NTS) all completely negated the effects of gut ghrelin. When co-infused with lipids, ghrelin reversed the beneficial effects of lipids on GIR and HGP.