Incretin signaling suppresses high glucose-induced β-cell hypoxia through a cAMP/PKA-dependent mechanism.

Pancreatic β-cell dysfunction is a hallmark of diabetes, and hyperglycemia-induced β-cell hypoxia contributes to impaired β-cell function and viability. Incretin-based therapies have been shown to exert protective effects on pancreatic β-cells; however, it remains unclear whether incretin signaling regulates β-cell oxygen homeostasis. This study investigated the effects of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and the dual GLP-1/GIP receptor agonist tirzepatide (TZP) on β-cell hypoxia. Using isolated mouse islets and MIN6-derived pseudo-islets, we assessed hypoxia by pimonidazole adduct formation under high-glucose and experimentally induced hypoxic conditions, as well as in islets harvested from diabetic mice. We also examined the effects of TZP on oxygen consumption and the involvement of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling. Islet hypoxia was induced by high glucose in a dose- and time-dependent manner, while GLP-1, GIP, and TZP suppressed islet hypoxia in a concentration-dependent manner. The hypoxia-suppressive effect of TZP was reproduced in MIN6-derived pseudo-islets. TZP also attenuated hypoxia under experimentally induced hypoxic conditions and in islets from diabetic mice. Notably, TZP suppressed hypoxia despite increasing oxygen consumption, indicating that its effect was not due simply to reduced oxygen demand. Pharmacological analyses further revealed that the hypoxia-suppressive effect of TZP was mediated predominantly through the cAMP/PKA pathway. These findings identify incretin signaling as an important regulator of β-cell oxygen homeostasis and provide mechanistic insights into the β-cell-protective effects of incretin-based therapies.