Gut-derived GLP-1 Released by Rare Sugar D-allulose Cooperates with Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear, largely because of its limited access to pancreatic b-cells. Here, we used D-allulose, a non-metabolizable zero-calorie rare sugar, as a GLP-1 secretagogue. We show that D-allulose–induced intestinal GLP-1 secretion (AIGS) cooperates with insulin to reduce blood glucose levels by enhancing insulin action, rather than insulin secretion, in male mice. This cooperation and remote signaling require left–sided vagal afferents forming the common hepatic branch, but not right–sided afferents. AIGS–enhanced insulin action required both GLP-1 receptors and insulin receptor substrate 2 in these neurons. Remarkably, in db/db mice exhibiting severe insulin resistance, AIGS improved insulin resistance and hyperglycemia more rapidly and potently than the GLP-1RA exendin-4. These findings reveal that a subclass of vagal afferent neurons synergistically activated by endogenous intestinal GLP-1 and insulin does not stimulate insulin secretion but augments insulin action to improve glucose tolerance. This novel extra-pancreatic GLP-1 action mediated by vagal afferents provides a promising basis for innovative type 2 diabetes therapies.