197-OR: Dynorphin, a Novel Paracrine Factor That Regulates Insulin Secretion

Abstract

Within the pancreatic islet, the crosstalk between different islet cells through paracrine signals orchestrates a hormonal response that controls glucose levels. The dysregulation of these signals contributes to impaired glucose homeostasis and diabetes. Therefore, understanding intra-islet communication is imperative for developing new strategies for diabetes management. Here, we show that intra-islet dynorphin (Dyn) stimulates somatostatin (SST) secretion and is a novel factor regulating islet function and insulin secretion in human and mouse islets. Dyn, an opioid peptide involved in stress response, pain, and addiction is synthesized in human and mouse β-cells and secreted in response to glucose. Dyn acts mainly through the k-opioid receptor (KOR) expressed in all islet cells with the highest expression in δ-cells. Using perifusion and static incubation studies, we show that Dyn induces SST secretion and decreases insulin secretion in mouse and human islets and that Dyn fails to induce SST secretion in islets from mice with KOR deletion in δ-cells, thereby providing a mechanism for feedback control of insulin secretion (β- to δ-cell Dyn/KOR negative feedback loop). Our data also show that Dyn is increased in islets from HFD-fed mice (8-fold) and in human β-cells from T2D donors. Remarkably, dynorphin mRNA is one of the top ten most upregulated genes in islets from HFD-fed mice, higher than several critical β-cell genes, including pdx1 or ucn3. We demonstrate that the β- to δ-cell Dyn/KOR negative feedback loop is upregulated in diabetes and pharmacological inhibition or genetic deletion of KOR in δ-cells improves glucose homeostasis in high-fat diet (HFD)-fed mice, demonstrating the therapeutic potential of this system. The novel role of the Dyn/KOR axis in islet function in healthy and diabetogenic conditions can have profound implications for glucose homeostasis and serve to develop potential targets for T2D. Disclosure M.Blandino-rosano: None. J.Panzer: None. E.Bernal-mizrachi: None.