Gut Ghrelin Controls Liver Glucose and Insulin Through Brain Connection

The liver's release of glucose, known as hepatic glucose production (HGP), is a primary contributor to elevated blood sugar levels in metabolic conditions like type 2 diabetes. Understanding the intricate mechanisms that regulate HGP and insulin signaling is crucial for developing effective therapeutic strategies. This study specifically investigates how gut-derived ghrelin influences HGP and hepatic insulin sensitivity through a potential gut-brain-liver axis.

The study revealed that ghrelin-deficient mice exhibited reduced hepatic glucose production (HGP) and improved hepatic insulin sensitivity, suggesting that endogenous ghrelin typically promotes HGP. Conversely, gut-specific ghrelin overexpression in wild-type mice led to a significant increase in HGP and impaired hepatic insulin sensitivity, with the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamps decreasing by ~25% compared to control mice. This observed effect was completely abolished in ghrelin receptor-deficient mice, unequivocally confirming the mediation by the GHSR1a receptor. Intriguingly, vagal denervation entirely blocked the gut ghrelin-induced increase in HGP and insulin resistance, underscoring the vagus nerve's critical role. Moreover, central ghrelin administration (ICV) also increased HGP and impaired insulin signaling, mirroring the effects of gut-derived ghrelin. The study found that gut ghrelin activates the vagus nerve, which then signals to the brain, leading to increased sympathetic nervous system activity and subsequent promotion of hepatic glucose production.