Insulin granule biogenesis and exocytosis

Abstract

Insulin is produced by pancreatic β-cells, and once released to the blood, the hormone stimulates glucose uptake and suppresses glucose production. Defects in both the availability and action of insulin lead to elevated plasma glucose levels and are major hallmarks of type-2 diabetes. Insulin is stored in secretory granules that form at the trans-Golgi network. The granules undergo extensive modifications en route to their release sites at the plasma membrane, including changes in both protein and lipid composition of the granule membrane and lumen. In parallel, the insulin molecules also undergo extensive modifications that render the hormone biologically active. In this review, we summarize current understanding of insulin secretory granule biogenesis, maturation, transport, docking, priming and eventual fusion with the plasma membrane. We discuss how different pools of granules form and how these pools contribute to insulin secretion under different conditions. We also highlight the role of the β-cell in the development of type-2 diabetes and discuss how dysregulation of one or several steps in the insulin granule life cycle may contribute to disease development or progression.

Regulatory effects of protein S-acylation on insulin secretion and insulin action

“…Insulin is stored in a Zn 2+ -stabilized hexameric state in secretory granules that form at the Golgi. These granules undergo fusion with the plasma membrane (or ‘exocytosis’) primarily in response to a rise in the level of glucose in the blood [ 24 , 25 ] (summarized in figure 1 ). Glucose-stimulated insulin secretion occurs as a result of changes in metabolism and ion fluxes in the β-cells.…”

“…Decreased efflux of K + from the β-cells contributes to membrane depolarization and the opening of voltage-gated Ca 2+ channels, the activity of which is also controlled by other ion fluxes controlling membrane potential. The resulting Ca 2+ influx stimulates SNARE protein-dependent fusion of insulin granules with the plasma membrane and secretion of insulin from the β-cell [ 25 ]. Insulin secretion occurs in two phases: the first phase has been proposed to occur due to the rapid exocytosis of a ‘readily-releasable’ pool of granules, whereas the second-phase insulin secretion may reflect the recruitment of ‘newcomer’ granules to the membrane and their subsequent exocytosis [ 25 ].…”

“…The resulting Ca 2+ influx stimulates SNARE protein-dependent fusion of insulin granules with the plasma membrane and secretion of insulin from the β-cell [ 25 ]. Insulin secretion occurs in two phases: the first phase has been proposed to occur due to the rapid exocytosis of a ‘readily-releasable’ pool of granules, whereas the second-phase insulin secretion may reflect the recruitment of ‘newcomer’ granules to the membrane and their subsequent exocytosis [ 25 ]. Several SNARE proteins are involved in insulin granule exocytosis including syntaxin 1 and SNAP25 (plasma membrane SNAREs), and vesicle-associated membrane protein-2 (VAMP-2) on the insulin granule membrane [ 25 ].…”

“…Insulin secretion occurs in two phases: the first phase has been proposed to occur due to the rapid exocytosis of a ‘readily-releasable’ pool of granules, whereas the second-phase insulin secretion may reflect the recruitment of ‘newcomer’ granules to the membrane and their subsequent exocytosis [ 25 ]. Several SNARE proteins are involved in insulin granule exocytosis including syntaxin 1 and SNAP25 (plasma membrane SNAREs), and vesicle-associated membrane protein-2 (VAMP-2) on the insulin granule membrane [ 25 ]. Additional SNAREs appear to function in granule exocytosis that contributes to second-phase insulin secretion, including syntaxin-3/-4 and VAMP8 [ 25 ].…”

“…Several SNARE proteins are involved in insulin granule exocytosis including syntaxin 1 and SNAP25 (plasma membrane SNAREs), and vesicle-associated membrane protein-2 (VAMP-2) on the insulin granule membrane [ 25 ]. Additional SNAREs appear to function in granule exocytosis that contributes to second-phase insulin secretion, including syntaxin-3/-4 and VAMP8 [ 25 ]. Calcium-secretion coupling involves members of the synaptotagmin protein family, in particular synaptotagmin-7 [ 26 ] and synaptotagmin-9 [ 25 , 27 , 28 ].…”