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 -cells, intracellular insulin stores in -granules are mostly upheld by efficiently upregulating 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 -granules, apparently via crinophagy. However, this mechanism alone is not sufficient to maintain optimal insulin storage in -cells when insulin secretion is dysfunctional. Here, we show that despite an abnormal imbalance of glucose/GLP-1² regulated insulin production over secretion in Rab3A^-/- mice compared to control animals, insulin storage levels were maintained due to increased intracellular -granule degradation. Electron microscopy (EM) analysis indicated that this was mediated by a significant 12-fold upregulation of multigranular degradation vacuoles in Rab3A^-/- mouse islet -cells (p 0.001), which by further EM-tomography analysis was found to be mostly contributed by microautophagic activity. This increased autophagic activity in Rab3A^-/- mouse islet -cells was associated with a specific decrease in islet LAMP-2 gene expression (p 0.05), at both the mRNA and protein expression levels. LAMP-2 is a documented negative-regulator of autophagy. These findings indicate that the upregulation 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 -cell's response to diminished insulin secretion during the pathogenesis of type 2 diabetes.