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Pancreatic islet dysfunction is central to type 2 diabetes mellitus (T2DM) pathogenesis and consists of both α-cell and β-cell dysfunction. The regulation of α-cell and β-cell health is determined by a complex network of paracrine regulators that are incompletely defined. To improve the treatment and prevention of T2DM, it is critical to have a complete picture of α-cell and β-cell regulation. We have identified the signaling protein, 14-3-3ζ, as an important regulator of β-cell function and crosstalk between α-cells and β-cells. Specifically, recent work from our lab demonstrates that β-cell 14-3-3ζ inhibition increases glucose-stimulated insulin secretion (GSIS) and activates α-cell active glucagon-like peptide-1 (GLP-1) production and secretion in mouse and human islets. It is increasingly evident that α-cells play an important role in the potentiation of GSIS, thereby expanding their function beyond that of the traditional counterregulatory role. Efforts to understand the role of the α-cell in the regulation of islet function have revealed both transcriptional and functional heterogeneity. Further analysis of this heterogeneity suggests that functionally distinct α-cell subpopulations display alterations in their hormone profile, with some α-cells producing active GLP-1 from the proglucagon precursor. While GLP-1 and glucagon are both able to potentiate GSIS via local actions mediated by GLP-1R and glucagon receptor expressed by β-cells, only glucagon stimulates hepatic glucose production (HGP). In effect then by switching their endocrine output from glucagon to GLP-1, α-cells favor GSIS over the stimulation of HGP. How plasticity in α-cell endocrine profile is regulated and how it impacts overall islet function is unknown. Therefore, we will test the hypothesis that β-cell 14-3-3ζ regulates GSIS by enhancing α-cell to β-cell crosstalk. Aim 1 will determine the role of α-cell GLP-1 in 14-3-3ζ regulation of islet function. To this end, we will assess GSIS in response to β-cell 14-3-3ζ inhibition in islets from wild-type mice and mice with α-cell-specific inability to produce GLP-1. Aim 2 will define the regulation of plasticity in α-cell hormone production by β-cell 14-3-3ζ. To this end, we will define the regulation of GLP-1+ α-cells induced by β-cell 14-3-3ζ ablation and determine the receptor class responsible for activation of α-cell GLP-1 production.