Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells

Mol Endocrinol. 2007 Sep;21(9):2255-69. doi: 10.1210/me.2007-0077. Epub 2007 Jun 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proinsulin / biosynthesis
  • rab3A GTP-Binding Protein / deficiency
  • rab3A GTP-Binding Protein / genetics

Substances

  • Insulin
  • Proinsulin
  • rab3A GTP-Binding Protein