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Pancreatic ß-Cells Secrete Insulin in Fast- and Slow-Release Forms

¹ Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California
² Department of Endocrinology, University of Heidelberg, Heidelberg, Germany
³ Department of Endocrinology, Larry Hillblom Islet Research Center, University of California, Los Angeles, California

Address correspondence and reprint requests to Robert H. Chow, University of Southern California, Department of Physiology and Biophysics, 1501 San Pablo St., ZNI 323, Los Angeles, CA 90089. E-mail: rchow{at}usc.edu

Abbreviations: GFP, green fluorescent protein; TIRF, total internal reflection fluorescence

Insulin vesicles contain a chemically rich mixture of cargo that includes ions, small molecules, and proteins. At present, it is unclear if all components of this cargo escape from the vesicle at the same rate or to the same extent during exocytosis. Here, we demonstrate through real-time imaging that individual rat and human pancreatic ß-cells secrete insulin in heterogeneous forms that disperse either rapidly or slowly. In healthy pancreatic ß-cells maintained in culture, most vesicles discharge insulin in its fast-release form, a form that leaves individual vesicles in a few hundred milliseconds. The fast-release form of insulin leaves vesicles as rapidly as C-peptide leaves vesicles. Healthy ß-cells also secrete a slow-release form of insulin that leaves vesicles more slowly than C-peptide, over times ranging from seconds to minutes. Individual ß-cells make vesicles with both forms of insulin, though not all vesicles contain both forms of insulin. In addition, we confirm that insulin vesicles store their cargo in two functionally distinct compartments: an acidic solution, or halo, and a condensed core. Thus, our results suggest two important features of the condensed core: 1) It exists in different states among the vesicles undergoing exocytosis and 2) its dissolution determines the availability of insulin during exocytosis.

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