title: Proinsulin entry and transit through the endoplasmic reticulum in pancreatic beta cells.
abstract: Insulin is an essential hormone for maintaining metabolic homeostasis in the body. To make fully bioactive insulin, pancreatic beta cells initiate synthesis of the insulin precursor, preproinsulin, at the cytosolic side of the endoplasmic reticulum (ER), whereupon it undergoes co- and post-translational translocation across the ER membrane. Preproinsulin is cleaved by signal peptidase to form proinsulin that folds on the luminal side of the ER, forming three evolutionarily conserved disulfide bonds. Properly folded proinsulin forms dimers and exits from the ER, trafficking through Golgi complex into immature secretory granules wherein C-peptide is endoproteolytically excised, allowing fully bioactive two-chain insulin to ultimately be stored in mature granules for insulin secretion. Although insulin biosynthesis has been intensely studied in recent decades, the earliest events, including proinsulin entry and exit from the ER, have been relatively understudied. However, over the past 5 years, more than 20 new insulin gene mutations have been reported to cause a new syndrome termed Mutant INS-gene-induced Diabetes of Youth (MIDY). Although these mutants have not been completely characterized, most of them affect proinsulin entry and exit from the ER. Here, we summarize our current knowledge about the early events of insulin biosynthesis and review recent advances in understanding how defects in these events may lead to pancreatic beta cell failure.
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, The University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Metabolism, Tianjin Medical University General Hospital, Tianjin, PR China. Electronic address: mingli@umich.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Wright
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, The University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address: parvan@umich.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D000818:Animals; D001692:Biological Transport; D003600:Cytosol / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D010179:Pancreas / Q000166:cytology / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D011384:Proinsulin / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D011498:Protein Precursors / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D021382:Protein Sorting Signals; D059748:Proteolysis
chemical_list: D007328:Insulin; D011498:Protein Precursors; D021382:Protein Sorting Signals; C013737:preproinsulin; D011384:Proinsulin
keywords: Diabetes; Endoplasmic reticulum; Pancreatic beta cells; Preproinsulin; Proinsulin; Protein folding; Protein translocation