286-OR: JNK3-A Key Downstream Target of Incretin Responses in ß-Cells

• Published in: Diabetes (New York, N.Y.) Vol. 73; p. 1
• Main Authors: Neto, Ruy Andrade Louzada, Gonzalez, Marel, Pita-Grisanti, Valentina, Blandino-Rosano, Manuel, Bernal-Mizrachi, Ernesto
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2024
• Subjects: Beta cells; c-Jun protein; Cell signaling; Cell survival; Clonal deletion; Cyclic AMP response element-binding protein; Glucose tolerance; Insulin resistance; Insulin secretion; JNK protein; JNK3 protein; Pancreas; Phosphorylation; Physiology; Transcription factors
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db24-286-OR

The c-Jun N-terminal Kinases (JNKs) regulate crucial physiological processes. JNK1 and JNK2 exhibit broad tissue distribution and are implicated in insulin resistance, inflammation, and cell signaling. Conversely, JNK3 (MAPK10) is predominantly found in CNS neurons and pancreatic β- cells and the physiological function of this JNK member is less understood. To explore JNK3's role in pancreatic β-cells, we generated mice with JNK3 deletion in beta-cells (βJNK3KO). βJNK3KO exhibited glucose intolerance and insulin secretion only after oral, suggesting a role for JNK3 in incretin responses. Assessment of incretin responses demonstrated impaired insulin secretion induced by Exendin 4 (Ex4) in βJNK3KO and this was associated with reduced GLP1R expression. These findings were validated in human islets treated with a specific JNK3 inhibitor (iJNK3). Downstream of GLP1-R, CREB phosphorylation upon Ex4 was decreased in βJNK3KO islets suggesting a crosstalk between JNK3 and GLP1-R signaling on regulation of acute insulin secretion by incretins. Notably, GLP1R/cAMP/CREB axis induction of IRS2 expression, a master regulator of β-cell survival and growth, was also downregulated in βJNK3KO mice and human islets treated with iJNK3. As a result of decreased IRS2 expression, the protective effect of Ex4 was lost in βJNK3KO islets exposed to proinflammatory cytokines and human islets treated with iJNK3. Finally, the beneficial protective effect of Ex4 treatment was partially attenuated in βJNK3KO in a model of multiple low doses of STZ.