Gut-Derived GLP-1 Released by Rare Sugar d-Allulose Cooperates With Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity.

Ohbayashi, Kento; Tanida, Mamoru; Abe, Chikara; Ishihara, Hirotaka; Omi, Wataru; Kubota, Naoto; Drucker, Daniel J; Yada, Toshihiko et al. · Diabetes · 2026

basic_science · Level V

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Abstract

Compared with glucagon-like peptide 1 (GLP-1) receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. We used the rare sugar d-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. d-allulose-induced intestinal GLP-1 release cooperates with insulin to activate left-side vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. Because this acute mechanism improved hyperglycemia in type 2 diabetes to an extent comparable to that observed with GLP-1 receptor agonists, targeting GLP-1/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for type 2 diabetes.