Dynorphin, a novel paracrine factor that regulates insulin secretion

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Dynorphin, a novel paracrine factor that regulates insulin secretion The inability to maintain glucose homeostasis leads to diabetes, a life-threatening disease of epidemic proportions. The adaptation of pancreatic islets to insulin resistance is a significant determinant of developing type 2 diabetes (T2D). Within the pancreatic islet, the crosstalk between different islet cells through paracrine signals orchestrates a hormonal response that controls glucose levels. Dysregulation of these signals contributes to impaired glucose homeostasis and diabetes. The long-term goal of my research program is to understand how paracrine interactions within islet cells regulate hormone secretion and glucose homeostasis in physiological and pathological conditions. The objective of this proposal is to assess the β- to δ-cell Dynorphin (Dyn)/Kappa opioid receptor (KOR) negative feedback loop during physiology and pathological states. The central hypothesis is that insulin secretion is regulated by a novel β- to δ-cell Dyn/KOR negative feedback loop, and this feedback loop regulates glucose homeostasis and contributes to hyperglycemia in diabetes. The rationale underlying this proposal is that completion will identify key targets for improving insulin secretion in conditions of insulin resistance and diabetes. The central hypothesis will be tested by pursuing two specific aims: 1) Characterize the Dyn secretion in mouse and human β-cells and determine the contribution to islet function and glucose homeostasis (First component of the feedback loop). 2) Determine the role of δ-cell KOR and examine the potential of the Dyn/KOR axis as a therapeutic target in diabetes (Second component of the feedback loop). We will pursue these aims using an innovative combination of newly generated mice models with specific deletion of KOR in δ-cells and overexpression and deletion of Dyn in β-cells. The proposed research is significant because it will identify that the endogenous opioid peptide Dyn, is a key intra-islet paracrine molecule that regulates insulin secretion and glucose homeostasis. It is also significant because it will reveal how the regulation of KOR impacts islet secretion in diabetogenic conditions. This work will develop foundational knowledge of how Dyn and its function in islet cells impact glucose metabolism and insulin resistance. The proximate expected outcome of this work is understanding the mechanism of how the Dyn/KOR axis participates in the adaptation of β-cells to insulin resistance and β-cell injury. The results will have an important positive impact immediately. After all, we will uncover the role of the Dyn/KOR axis in islet function. Resolving the in vivo mechanisms of β- to δ-cell Dyn/KOR negative feedback loop will have profound implications for glucose homeostasis and serve to develop potential targets for T2D.