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Regulated Autophagy Controls Hormone Content in Secretory-Deficient Pancreatic Endocrine ß-Cells

Institute for Molecular Bioscience (B.J.M., A.J.C., G.P.M.), Queensland Bioscience Precinct, The University of Queensland, Brisbane, Queensland 4072, Australia; The Kovler Diabetes Center (C.S., C.A., B.L.W., K.Y., C.J.R.), Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Christopher J. Rhodes, Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, 5841 South Maryland Avenue, MC 1027, Room N138, Chicago, Illinois 60637. E-mail: cjrhodes{at}uchicago.edu.

Endocrine cells are continually regulating the balance between hormone biosynthesis, secretion, and intracellular degradation to ensure that cellular hormone stores are maintained at optimal levels. In pancreatic ß-cells, intracellular insulin stores in ß-granules are mostly upheld by efficiently up-regulating proinsulin biosynthesis at the translational level to rapidly replenish the insulin lost via exocytosis. Under normal circumstances, intracellular degradation of insulin plays a relatively minor janitorial role in retiring aged ß-granules, apparently via crinophagy. However, this mechanism alone is not sufficient to maintain optimal insulin storage in ß-cells when insulin secretion is dysfunctional. Here, we show that despite an abnormal imbalance of glucose/glucagon-like peptide 1 regulated insulin production over secretion in Rab3A^–/– mice compared with control animals, insulin storage levels were maintained due to increased intracellular ß-granule degradation. Electron microscopy analysis indicated that this was mediated by a significant 12-fold up-regulation of multigranular degradation vacuoles in Rab3A^–/– mouse islet ß-cells (P 0.001), which by further electron microscopy-tomography analysis was found to be mostly contributed by microautophagic activity. This increased autophagic activity in Rab3A^–/– mouse islet ß-cells was associated with a specific decrease in islet lysosomal-associated membrane protein 2 gene expression (P 0.05), at both the mRNA and protein expression levels. Lysosomal-associated membrane protein 2 is a documented negative regulator of autophagy. These findings indicate that the up-regulation of degradative pathways provides secretory-deficient endocrine cells with a compensatory mechanism for regulating their intracellular hormone content in vivo. These data may also have implications for the ß-cell’s response to diminished insulin secretion during the pathogenesis of type 2 diabetes.

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