Normal and defective pathways in biogenesis and maintenance of the insulin storage pool
Ming Liu, Yumeng Huang, Xiaoxi Xu, Xin Li, Maroof Alam, Anoop Arunagiri, Leena Haataja, Li Ding, Shusen Wang, Pamela Itkin-Ansari, Randal J. Kaufman, Billy Tsai, Ling Qi, Peter Arvan
Ming Liu, Yumeng Huang, Xiaoxi Xu, Xin Li, Maroof Alam, Anoop Arunagiri, Leena Haataja, Li Ding, Shusen Wang, Pamela Itkin-Ansari, Randal J. Kaufman, Billy Tsai, Ling Qi, Peter Arvan
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Review Series

Normal and defective pathways in biogenesis and maintenance of the insulin storage pool

Abstract

Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes.

Authors

Ming Liu, Yumeng Huang, Xiaoxi Xu, Xin Li, Maroof Alam, Anoop Arunagiri, Leena Haataja, Li Ding, Shusen Wang, Pamela Itkin-Ansari, Randal J. Kaufman, Billy Tsai, Ling Qi, Peter Arvan

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Figure 1

An overview of insulin biosynthesis in β cells.

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An overview of insulin biosynthesis in β cells. (i) Expression of INS ge...
(i) Expression of INS gene is controlled quantitatively and qualitatively by transcriptional networks including PDX1, NGN3, NEUROD1, NKX2.2, FOXA2, and MAFA. (ii) Newly synthesized preproinsulin (PPI) undergoes cotranslational (SRP- and Sec61-dependent) and posttranslational (Sec62/63-dependent) translocation across the ER membrane, in which TRAP plays an important yet poorly defined role. (iii) Upon delivery to the ER lumen, the preproinsulin signal peptide is rapidly excised, forming proinsulin (PI) that undergoes rapid oxidative folding — ultimately forming three highly conserved disulfide bonds. ER folding machinery (BiP, ERO1, PDI, ERp46, GRP94, etc.) acts in concert to promote folding, and may recognize unfolded/misfolded proinsulin for degradation through ERAD and ER-phagy. Misfolded proinsulin can also activate the unfolded protein response (UPR; including three classic arms involving PERK, IRE1, and ATF6). (iv) Well-folded proinsulin is exported from the ER via COPII vesicles for delivery to the Golgi complex, where proinsulin forms hexamers in the presence of Zn2+. Upon proinsulin delivery to (more acidic, Ca2+-rich) immature secretory granules (ISGs), PC1/3, PC2, and CPE act to convert proinsulin to insulin, which is ultimately stored in mature granules (MGs).