TY - JOUR
T1 - Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine β-cells
AU - Marsh, Brad J.
AU - Soden, Chad
AU - Alarcón, Cristia
AU - Wicksteed, Barton L.
AU - Yaekura, Kazuro
AU - Costin, Adam J.
AU - Morgan, Garry P.
AU - Rhodes, Christopher J.
PY - 2007/9
Y1 - 2007/9
N2 - 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 β-cells, intracellular insulin stores in β-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 β-granules, apparently via crinophagy. However, this mechanism alone is not sufficient to maintain optimal insulin storage in β-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 β-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 β-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 β-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 β-cell's response to diminished insulin secretion during the pathogenesis of type 2 diabetes.
AB - 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 β-cells, intracellular insulin stores in β-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 β-granules, apparently via crinophagy. However, this mechanism alone is not sufficient to maintain optimal insulin storage in β-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 β-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 β-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 β-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 β-cell's response to diminished insulin secretion during the pathogenesis of type 2 diabetes.
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U2 - 10.1210/me.2007-0077
DO - 10.1210/me.2007-0077
M3 - Article
C2 - 17579214
AN - SCOPUS:34548368589
SN - 0888-8809
VL - 21
SP - 2255
EP - 2269
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 9
ER -
