The making of insulin in health and disease
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REVIEW
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 1,2,3,4
Received: 2 March 2020 / Accepted: 28 April 2020 / Published online: 31 August 2020 # The Author(s) 2020
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.
Keywords Beta cell . Insulin biosynthesis . Insulin maturation . Post-transcriptional regulation . Proinsulin conversion . Review . Type 1 diabetes . Type 2 diabetes Abbreviations CPE Carboxypeptidase E/H DDX1 DEAD-box helicase 1 eIF Eukaryotic initiation factor ER Endoplasmic reticulum ERO1α/β Endoplasmic reticulum oxidoreductin 1α/β GLP-1 Glucagon-like peptide 1 hnRNP Heterogeneous nuclear ribonucleoprotein IRE1α Inositol-requiring enzyme 1α mTOR Mammalian target of rapamycin PC1/3 Proprotein convertase 1/3 PDI Protein disulfide isomerase
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-020-05192-7) contains a slideset of the figures for download, which is available to authorised users. * Michele Solimena [email protected] 1
Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
2
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
3
Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Tatzberg 47/49, 01307 Dresden, Germany
4
Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Dresden, Germany
PERK PTBP1 RBP tRNA UPR UTR
Protein kinase RNA-like endoplasmic reticulum kinase Polypyrimidine tract-binding protein 1 RNA-binding protein Transfer RNA Unfolded protein response Untranslated region
Introduction Discovered first by Frederik Banting and Charles Best in 1921, insulin is a 51-amino-acid long peptide hormone, which is key for control of glucose homeostasis, metabolism and cell growth [1]. Insulin is thought to be only produced and secreted by the beta cells of the pancreatic islets, although controversial findings have suggested that minute amounts may also be expressed in a subset of neurons in the central nervous s y s t e m [2]. Within 1–10 min following a me al, hyperglycaemia prompts beta cells to secrete a small fraction (3 × 103 new insulin molecules per second per beta cell [11], each step for insulin production must have been optimised during evolution.
Glucose regulates insulin mRNA transc
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