JNK3 regulates β cell responses to incretins in human islets and mouse models

The c-Jun N-terminal kinases (JNKs) regulate diverse physiological processes. Whereas JNK1 and JNK2 are broadly expressed and associated with insulin resistance, inflammation, and stress responses, JNK3 is largely restricted to central nervous system neurons and pancreatic β cells, and its physiological role in β cells remains poorly defined. To investigate its function, we generated mice lacking JNK3 specifically in β cells (βJNK3-KO). These mice displayed glucose intolerance and defective insulin secretion, particularly after oral glucose challenge, indicating impaired incretin responses. Consistently, Exendin-4-stimulated (Ex4-stimulated) insulin secretion was blunted in βJNK3-KO islets, accompanied by reduced GLP-1R expression. Similar findings were observed in human islets treated with a selective JNK3 inhibitor (iJNK3). Downstream of GLP-1R, Ex4-induced CREB phosphorylation was diminished in βJNK3-KO islets, indicating impaired canonical signaling. Moreover, activation of the GLP-1R/CREB/IRS2 pathway, a key regulator of β cell survival, was reduced in βJNK3-KO islets and iJNK3-treated human islets. As a consequence, the protective effects of Ex4 were lost in cytokine-treated βJNK3-KO and human islets, and Ex4-mediated protection was partially attenuated in βJNK3-KO mice exposed to multiple low-dose streptozotocin. These findings identify JNK3 as a regulator of β cell function and survival and suggest that targeting this pathway may enhance incretin-based therapies.