Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells.
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 beta-cells, intracellular insulin stores in beta-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 beta-granules, apparently via crinophagy. However, this mechanism alone is not sufficient to maintain optimal insulin storage in beta-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 beta-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 beta-cells (P <or= 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 beta-cells was associated with a specific decrease in islet lysosomal-associated membrane protein 2 gene expression (P <or= 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 beta-cell's response to diminished insulin secretion during the pathogenesis of type 2 diabetes.
Marsh
Brad J
BJ
Institute for Molecular Bioscience, Queensland Bioscience Precinct, The University of Queensland, Brisbane, Queensland 4072, Australia.
Soden
Chad
C
Alarcón
Cristina
C
Wicksteed
Barton L
BL
Yaekura
Kazuro
K
Costin
Adam J
AJ
Morgan
Garry P
GP
Rhodes
Christopher J
CJ
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011384:Proinsulin / Q000096:biosynthesis; D020826:rab3A GTP-Binding Protein / Q000172:deficiency / Q000235:genetics
D007328:Insulin; D011384:Proinsulin; D020826:rab3A GTP-Binding Protein