An IP₃R3-independent glucose-specific taste signaling pathway triggers an unconditioned cephalic insulin response in...

The cephalic-phase insulin response (CPIR) is elicited by oral stimulation with sapid substances. It produces a rapid rise in plasma insulin that promotes glucose disposal during and after meals. Although some taste and food-related cues require conditioning to evoke a CPIR, oral stimulation with D-glucose elicits this response without prior conditioning in mice. Here, we investigated how D-glucose activates this unconditioned CPIR. First, we measured chorda tympani (CT) taste nerve responses in wild-type C57Bl/6 (B6) mice and a strain lacking the type 3 inositol 1,4,5-trisphosphate receptor (IP₃R3), a principal mediator of sweet-, bitter-, and umami-evoked taste signaling. Unexpectedly, the IP₃R3 KO mice retained CT nerve responses to D-glucose while responses to all other sweeteners were abolished. Second, we tested whether this IP₃R3-independent taste signaling pathway mediates the unconditioned CPIR by determining whether oral stimulation with D-glucose still evoked a CPIR in IP₃R3 KO mice. Licking D-glucose elicited a normal CPIR, consistent with this hypothesis. Third, we found that selective stimulation of the taste system with D-glucose, but not fructose, was sufficient to trigger a CPIR in wild-type B6 mice. Finally, the unconditioned CPIR exhibited remarkable stimulus specificity in wild-type B6 mice: it was elicited by D-glucose but not by L-glucose, monosodium glutamate, soybean oil, saccharin, or isomaltulose, and was unaffected by olfactory loss. These findings provide evidence for a D-glucose-selective taste signaling pathway that initiates the unconditioned CPIR independently of canonical sweet taste transduction.