Insulin secretion from pancreatic beta-cells is critical for glucose homeostasis. When insulin secretion is impaired, when beta-cell mass declines or when resistance to insulin occurs, diabetes results in one or more complex forms. Curiously, zinc deficiency is also a hallmark of all diabetic states. We hypothesize that zinc signaling and recycling may be impaired in beta-cells during diabetes. We postulate that autocrine extracellular zinc and ATP signaling may occur within islet microenvironments and support pancreatic beta-cell homeostasis. Preliminary work in beta-cells and islets supports these hypotheses. Taken together, we pose the central hypothesis that: Zinc and ATP are secreted by pancreatic beta-cells and have essential extracellular autocrine influence and intracellular effects on beta-cell homeostasis and function. We propose two specific aims. #1: Define the secretion or co-secretion of ATP and zinc with insulin in response to glucose and other stimuli. #2: Examine autocrine supportive effects of zinc and ATP for beta-cells via membrane receptors and transporters. Lay Summary: Diabetes in its multiple forms is caused by loss of function of the blood glucose-storing hormone, insulin. Zinc deficiency has also been linked to all forms of diabetes. Maneuvers or therapeutic targets that support, protect and/or augment pancreatic beta-cell function with zinc and/or ATP are sought to understand cytoprotective roles of zinc for beta-cells and islet. ? ? ?
