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Review
. 2021 Mar;78(5):1957-1970.
doi: 10.1007/s00018-020-03688-4. Epub 2020 Nov 4.

Insulin granule biogenesis and exocytosis

Muhmmad Omar-Hmeadi  1 , Olof Idevall-Hagren  2
Affiliations
Review

Insulin granule biogenesis and exocytosis

Muhmmad Omar-Hmeadi et al. Cell Mol Life Sci. 2021 Mar.

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.

Keywords: Diabetes; Insulin; Lipids; β-Cell.

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Figures

Fig. 1
Fig. 1
Insulin granule formation at the trans-Golgi network. Proinsulin is sequestered to the secretory granule budding site through interactions with proteins like Chromogranin A/B (CgA/B) and VGF, and together these form large aggregates. Additional sorting is provided by membrane-bound proteins like Phogrin and Secretogranin 3 (SgIII), and this occurs in parallel with sorting of proinsulin-processing proteins (PC1/3, PC2 and CPE). Insulin granule budding depends on the action of Arf1 and the membrane bud is stabilized by clathrin, the clathrin-adaptor AP-1, and BAR-domain proteins (PICK1 and ICA69) and is facilitated by high concentrations of the phospholipid PI4P
Fig. 2
Fig. 2
Insulin granule maturation. Proinsulin processing to insulin occurs inside the granule. The proteolytic conversion of insulin requires granule acidification by the H+-transporting V-ATPase, which in turn activates the prohormone-processing enzymes (PC1/3, PC2 and CPE). Insulin is stored as a hexamer in complex with Zn2+, and at least some of the Zn2+ accumulation occurs via ZnT8-mediated transport. Granule-localized cholesterol transporters (ABCG/A) and phosphoinoside-transporting (STARD10) and modulating (PI4K, Sac2) proteins are responsible for changes in the lipid composition of the granule. During maturation, the granule shrinks due to clathrin-dependent retrieval of membrane and cargo for sorting or degradation. Maturation also involves removal of the clathrin coat, which likely depends on the action of Auxilin and Hsc70, and acquisition of factors required for granule transport and docking, such as Rab27a and Rab3 and their corresponding effector proteins (Granuphilin and Rabphilin)
Fig. 3
Fig. 3
Insulin granule transportation. Long-range transport of insulin granules occurs along microtubules and depend on the anterograde motor protein Kinesin-1. Short-range transport close to the plasma membrane instead occurs along F-actin tracks and depends on interactions between mature insulin granule proteins and the motor proteins Myosin Va and Myosin VIII
Fig. 4
Fig. 4
Insulin granule exocytosis. The three main stages of insulin granule exocytosis at the plasma membrane, docking, priming, and fusion are regulated by interactions between specific sets of proteins and lipids (see text for details)
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