Inside the Insulin Secretory Granule.

Mark Germanos,Matthew Taper,Belinda Yau,Melkam A Kebede,Andy Gao

doi:10.3390/metabo11080515

Abstract

The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.

Highlights

The study found that 99% of proinsulin entered immature SG (ISG) to lend itself for conversion, and that the resulting newly synthesized secretory granules (SGs) were preferentially secreted over older SGs when exposed to glucose
Insulin synthesis requires the entry of proinsulin and its processing enzymes into ISGs, followed by enzyme activation and the complete execution of enzymatic activity
Each of these steps are facilitated by ions that are supplied by channels and transporters, which exert influence on luminal proteins by altering their behavior

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The β-cell SG contains a cocktail of cargo proteins These proteins drive trafficking through the regulated secretory pathway and are released to affect systemic function [22,23,24,25]. It would follow that delayed MSG production could result in the increased release of ISGs and hyperproinsulinemia, and a failure of the β-cell to respond to glucose with the secretion of insulin [12,34,35]. The MSG holds at least 50 unique soluble and transmembrane proteins [38], and the biosynthesis of many are thought to be commonly regulated at the translational level following exposure of the β-cell to glucose [39] This enables their synchronized transit and congregation at the TGN, but from here, several proteins will traverse the ISG compartment on their way to other destinations. It is becoming more apparent that correctly forming this entity is crucial for systemic glucose homeostasis

Cargo Molecules

Luminal Enzymes and Chaperones

Sorting Receptors

Findings

Concluding Remarks