Altered G i signaling in enteroendocrine K cells in vivo causes pronounced changes in glucose homeostasis
2026-07-29
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that promotes postprandial insulin release and euglycemia. Although GIP is the dominant incretin in humans, the precise mechanisms regulating GIP release from enteroendocrine K cells in vivo remain to be elucidated. Heterotrimeric G proteins of the G i family regulate numerous key physiological functions. To explore the potential role of these proteins in modulating K cell function in vivo, we analyzed mutant mice that allowed us to selectively stimulate G i signaling in K cells or studied mice lacking functional G i in K cells only. Stimulation of K cell G i signaling in vivo and in vitro led to reduced GIP release via an exchange protein directly activated by 3ʹ-5ʹ-cyclic adenosine monophosphate 2–dependent pathway and various metabolic deficits. In contrast, inactivation of this class of G proteins in K cells caused elevated plasma GIP levels and pronounced improvements in glucose homeostasis in lean and obese mice. These data provide important insights into the mechanisms of GIP release.