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Review
. 2020 Oct;63(10):1981-1989.
doi: 10.1007/s00125-020-05192-7. Epub 2020 Sep 7.

The making of insulin in health and disease

Jovana Vasiljević  1   2   3 , Juha M Torkko  1   2   3 , Klaus-Peter Knoch  1   2   3 , Michele Solimena  4   5   6   7
Affiliations
Review

The making of insulin in health and disease

Jovana Vasiljević et al. Diabetologia. 2020 Oct.

Abstract

The discovery of insulin in 1921 has been one of greatest scientific achievements of the 20th century. Since then, the availability of insulin has shifted the focus of diabetes treatment from trying to keep patients alive to saving and improving the life of millions. Throughout this time, basic and clinical research has advanced our understanding of insulin synthesis and action, both in healthy and pathological conditions. Yet, multiple aspects of insulin production remain unknown. In this review, we focus on the most recent findings on insulin synthesis, highlighting their relevance in diabetes. Graphical abstract.

Keywords: Beta cell; Insulin biosynthesis; Insulin maturation; Post-transcriptional regulation; Proinsulin conversion; Review; Type 1 diabetes; Type 2 diabetes.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
The insulin peptide. Insulin is synthesised as a 110 amino-acid-long preproinsulin including a signal peptide (orange), a B chain (blue), a connecting peptide (C-peptide, yellow) and an A chain (red). The signal peptide targets the preproinsulin to the ER, where it is cleaved by the signal peptidase and converted into proinsulin. In the ER, three disulfide bonds are formed between cysteine residues with the help of PDIs. Proinsulin is trafficked from the ER, through the Golgi and the trans-Golgi network to secretory granules (SGs), where PC1/3 and CPE process the dibasic residues (grey) to form mature insulin. Zn2+ non-covalently binds to the HisB10 to form the insulin hexamer. Amino acids mentioned in the text are shown in a darker colour. This figure is available as part of a downloadable slideset
Fig. 2
Fig. 2
Schematic of insulin production and secretion, from mRNA to the mature hormone. The preproinsulin mRNA is stabilised by its binding to various hnRNPs in the cytosol. Preproinsulin translation and its translocation to the ER starts after the formation and activation of the ribosomal complex. Following proinsulin folding in the ER and the removal of the C-peptide, mature insulin is formed in secretory granules (SGs). Environmental changes, such as metabolic stress or inflammation, that can hamper this highly regulated process are shown in red for type 2 diabetes (T2D) and in orange for type 1 diabetes (T1D); genetic changes resulting in different types of diabetes are labelled in blue (T2D and gestational diabetes mellitus [GDM]) and in green (neonatal diabetes). ATF6, activating transcription factor 6; miR, microRNA; SRP, signal recognition particle; TGN, trans-Golgi network. This figure is available as part of a downloadable slideset
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References

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