1756-P: Dynorphin Expression in Beta-Cells—Insights into Regulation

The expression of dynorphin within beta-cells, an endogenous opioid peptide predominantly expressed in the CNS and involved in stress response, pain, and addiction, has intrigued researchers for over two decades. Yet, its functional implications in islet physiology remain incompletely elucidated. Genetically, the Pdyn gene is prominently upregulated in beta-cells under high-fat diet conditions and in human beta-cells affected by Type 2 Diabetes, emphasizing its potential relevance in metabolic disorders. This comprehensive investigation elucidates the regulatory mechanisms and developmental dynamics of dynorphin within this specific subset of beta-cells. Our investigation revealed a developmental progression in dynorphin expression, with undetectable levels at birth gradually escalating with advancing age. Notably, dynorphin expression was heterogeneous within beta-cells, manifesting in approximately 15% of beta-cells at two months. In vitro studies show that an increase in glucose levels notably correlates with increased dynorphin expression specifically in beta-cells already expressing dynorphin, unveiling a critical interplay where cAMP, Ca²⁺ and Creb signaling cascades emerge as pivotal regulators governing dynorphin expression within this subset of beta-cells. Furthermore, our findings show the synergistic effect of palmitate in conjunction with high glucose, amplifying dynorphin levels in these specific beta-cells expressing dynorphin. This selective interaction underscores the complex interrelationship between nutrient exposure and dynorphin expression, offering intriguing insights into the responses of a subset of beta-cells to diverse dietary components.