Mechanisms of Metabolicand GLP-1 receptor signaling on Islet hormone secretion

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Project Summary Diabetes is a prominent disease that affects people worldwide and is rapidly becoming more prevalent; it is estimated that 640 million people will be diagnosed with it by 2040. Defects in β-cell metabolism in pancreatic islets negatively impact insulin secretion and are associated with diabetes. β-cell metabolism is also controlled by another cell type in islets, the α-cell, which hypersecretes glucagon in diabetics. Current diabetes therapies, like glucagon-like peptide 1 receptor (Glp1r) agonists, have side effects like nausea, which prevents it from completely activating β-cells. Therefore, it is necessary to find an adjuvant therapy to fully treat type 2 diabetes. In this proposal, we identify pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate (PEP) to ATP and pyruvate in the final step of glycolysis, as a potential target for a new diabetes therapeutic. We have discovered that β-cell PK, by virtue of its ability to bind and inactivate KATP channels, is sufficient to initiate and amplify insulin secretion. Preliminary studies suggest that PK activators have the potential to improve the efficacy of Glp1r agonists. Overall, this proposal will reveal the mechanisms by which PK activation increases insulin secretion on the molecular level. Our hypothesis is that PK controls α- and β-cell hormone secretion by closing ATP-sensitive K+ channels. To study this hypothesis, we will: 1) Determine the direct effect of PK activation on α-cell metabolism and hormone secretion and 2) Determine the therapeutic potential of combining PK activators (PKa) with Glp1r agonists to enhance insulin secretion in obese mice and human islets. The effects of PK on α- and β-cell metabolism will be studied using fluorescent biosensor imaging, electrophysiology, and newly developed 3D light-sheet imaging. Achieving these aims will lead the characterization of PK’s role in α-cell metabolism and, ultimately, improvement in the treatment of type 2 diabetes.