CoChat
Sign Up
Cited by 70Endoplasmic Reticulum Stress and DiseasePancreatic function and diabetesDiabetes and associated disorders

Impaired Cleavage of Preproinsulin Signal Peptide Linked to Autosomal-Dominant Diabetes

Open access
Liu, Ming, Lara-Lemus, Roberto, Shan, Shu-ou, Wright, Jordan, Haataja, Leena, Barbetti, Fabrizio, Guo, Huan, Larkin, Dennis +1 more·2012·Diabetes
DOI 10.2337/db11-0878PMC PMC3314357
Open this paper in CoChat — free account

Abstract

Recently, missense mutations upstream of preproinsulin’s signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER–oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.2337/db11-0878

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Heterozygous mutations can impair normal folding of insulin precursors, yielding abnormal molecules that act in a dominant-negative fashion to impair the exit of all proinsulin from the endoplasmic reticulum; this initially causes insulin deficiency, followed by severe beta cell endoplasmic reticulum stress and apoptosis.

    “Heterozygous mutations can also impair the normal folding of insulin precursors, yielding abnormal molecules that act in a dominant-negative fashion to impair the exit of all proinsulin from the endoplasmic reticulum100. This initially causes insulin deficiency, followed by severe beta cell endoplasmic reticulum stress and apoptosis100,101.”

    From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [101]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 41

  1. [2]Greeley SA Tucker SE Worrell HI Skowron KB Bell GI Philipson LH Update in neonatal diabetes. Curr Opin Endocrinol Diabetes Obes 2010; 17: 13– 19 19952737
  2. [3]Fajans SS Bell GI MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care 2011; 34: 1878– 1884 21788644 PMC3142024
  3. [4]Nishi M Nanjo K [The molecular mechanism of insulin biosynthesis and mutant insulin gene syndrome]. Nihon Rinsho 1994; 52: 2519– 2527 7983772
  4. [5]Garin I Edghill EL Akerman I; Neonatal Diabetes International Group Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci USA 2010; 107: 3105– 3110 20133622 PMC2840338
  5. [6]Støy J Edghill EL Flanagan SE; Neonatal Diabetes International Collaborative Group Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 2007; 104: 15040– 15044 17855560 PMC1986609
  6. [7]Polak M Dechaume A Cavé H; French ND (Neonatal Diabetes) Study Group Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group. Diabetes 2008; 57: 1115– 1119 18171712
  7. [8]Colombo C Porzio O Liu M; Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (SIEDP) Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest 2008; 118: 2148– 2156 18451997 PMC2350430
  8. [9]Ahamed A Unnikrishnan AG Pendsey SS Permanent neonatal diabetes mellitus due to a C96Y heterozygous mutation in the insulin gene. A case report. JOP 2008; 9: 715– 718 18981553
  9. [10]Edghill EL Flanagan SE Patch AM; Neonatal Diabetes International Collaborative Group Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 2008; 57: 1034– 1042 18162506 PMC7611804
  10. [11]Molven A Ringdal M Nordbø AM; Norwegian Childhood Diabetes Study Group Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 2008; 57: 1131– 1135 18192540
  11. [12]Bonfanti R Colombo C Nocerino V Insulin gene mutations as cause of diabetes in children negative for five type 1 diabetes autoantibodies. Diabetes Care 2009; 32: 123– 125 18840770 PMC2606844
  12. [13]Rubio-Cabezas O Edghill EL Argente J Hattersley AT Testing for monogenic diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes. Diabet Med 2009; 26: 1070– 1074 19900242
  13. [14]Boesgaard TW Pruhova S Andersson EA Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY). BMC Med Genet 2010; 11: 42 20226046 PMC2848224
  14. [15]Meur G Simon A Harun N Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes 2010; 59: 653– 661 20007936 PMC2828668
  15. [16]Liu M Ramos-Castañeda J Arvan P Role of the connecting peptide in insulin biosynthesis. J Biol Chem 2003; 278: 14798– 14805 12590147
  16. [17]Zhang BY Liu M Arvan P Behavior in the eukaryotic secretory pathway of insulin-containing fusion proteins and single-chain insulins bearing various B-chain mutations. J Biol Chem 2003; 278: 3687– 3693 12446709
  17. [18]Liu M Li Y Cavener D Arvan P Proinsulin disulfide maturation and misfolding in the endoplasmic reticulum. J Biol Chem 2005; 280: 13209– 13212 15705595 PMC2527538
  18. [19]Park SY Ye H Steiner DF Bell GI Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not efficiently secreted. Biochem Biophys Res Commun 2010; 391: 1449– 1454 20034470 PMC2817945
  19. [20]Liu M Hodish I Rhodes CJ Arvan P Proinsulin maturation, misfolding, and proteotoxicity. Proc Natl Acad Sci USA 2007; 104: 15841– 15846 17898179 PMC2000385
  20. [21]Liu M Haataja L Wright J Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport. PLoS ONE 2010; 5: e13333 20948967 PMC2952628
  21. [22]Gupta S McGrath B Cavener DR PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 2010; 59: 1937– 1947 20530744 PMC2911049
  22. [23]Hodish I Absood A Liu L In vivo misfolding of proinsulin below the threshold of frank diabetes. Diabetes 2011; 60: 2092– 2101 21677281 PMC3142084
  23. [24]Hodish I Liu M Rajpal G Misfolded proinsulin affects bystander proinsulin in neonatal diabetes. J Biol Chem 2010; 285: 685– 694 19880509 PMC2804216
  24. [25]Liu M Hodish I Haataja L Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. Trends Endocrinol Metab 2010; 21: 652– 659 20724178 PMC2967602
  25. [26]Sohma Y Hua QX Liu M Contribution of residue B5 to the folding and function of insulin and IGF-I: constraints and fine-tuning in the evolution of a protein family. J Biol Chem 2010; 285: 5040– 5055 19959476 PMC2836107
  26. [27]Rajan S Eames SC Park SY In vitro processing and secretion of mutant insulin proteins that cause permanent neonatal diabetes. Am J Physiol Endocrinol Metab 2010; 298: E403– E410 19952343 PMC2838531
  27. [28]Steiner DF Chan SJ Welsh JM Kwok SC Structure and evolution of the insulin gene. Annu Rev Genet 1985; 19: 463– 484 3909947
  28. [29]Oda N Nakai A Fujiwara K Polymorphisms of the insulin gene among Japanese subjects. Metabolism 2001; 50: 631– 634 11398136
  29. [30]Prehn S Tsamaloukas A Rapoport TA Demonstration of specific receptors of the rough endoplasmic membrane for the signal sequence of carp preproinsulin. Eur J Biochem 1980; 107: 185– 195 6249584
  30. [31]Miyamoto K Yamashita T Tsukiyama T Reversible membrane permeabilization of mammalian cells treated with digitonin and its use for inducing nuclear reprogramming by Xenopus egg extracts. Cloning Stem Cells 2008; 10: 535– 542 19049416
  31. [32]Eskridge EM Shields D The NH2 terminus of preproinsulin directs the translocation and glycosylation of a bacterial cytoplasmic protein by mammalian microsomal membranes. J Cell Biol 1986; 103: 2263– 2272 3023397 PMC2114610
  32. [33]Liu M Hua QX Hu SQ Deciphering the hidden informational content of protein sequences: foldability of proinsulin hinges on a flexible arm that is dispensable in the mature hormone. J Biol Chem 2010; 285: 30989– 31001 20663888 PMC2945590
  33. [34]Zito E Chin KT Blais J Harding HP Ron D ERO1-beta, a pancreas-specific disulfide oxidase, promotes insulin biogenesis and glucose homeostasis. J Cell Biol 2010; 188: 821– 832 20308425 PMC2845084
  34. [35]Khoo C Yang J Rajpal G Wang Y Liu J Arvan P Stoffers DA Endoplasmic reticulum oxidoreductase-1-like {beta} (ERO1l{beta}) regulates susceptibility to endoplasmic reticulum stress and is induced by insulin flux in {beta}-cells. Endocrinology 2011; 152: 2599– 2608 21540283 PMC3115612
  35. [36]Zhang L Lai E Teodoro T Volchuk A GRP78, but not protein-disulfide isomerase, partially reverses hyperglycemia-induced inhibition of insulin synthesis and secretion in pancreatic {beta}-cells. J Biol Chem 2009; 284: 5289– 5298 19103594
  36. [37]Nothwehr SF Gordon JI Structural features in the NH2-terminal region of a model eukaryotic signal peptide influence the site of its cleavage by signal peptidase. J Biol Chem 1990; 265: 17202– 17208 2120214
  37. [38]Racchi M Watzke HH High KA Lively MO Human coagulation factor X deficiency caused by a mutant signal peptide that blocks cleavage by signal peptidase but not targeting and translocation to the endoplasmic reticulum. J Biol Chem 1993; 268: 5735– 5740 8449937
  38. [39]Lyko F Martoglio B Jungnickel B Rapoport TA Dobberstein B Signal sequence processing in rough microsomes. J Biol Chem 1995; 270: 19873– 19878 7650000
  39. [40]Beuret N Rutishauser J Bider MD Spiess M Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus. J Biol Chem 1999; 274: 18965– 18972 10383395
  40. [41]Kang SW Rane NS Kim SJ Garrison JL Taunton J Hegde RS Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway. Cell 2006; 127: 999– 1013 17129784 PMC3656606
  41. [42]Eskridge EM Shields D Cell-free processing and segregation of insulin precursors. J Biol Chem 1983; 258: 11487– 11491 6352698

Cited by

Sorted by citations

Authors
Liu, M., Lara-Lemus, R., Shan, S.-O., Wright, J., Haataja, L., Barbetti, F., Guo, H., Larkin, D., & Arvan, P.
Affiliations
  • University of Michigan (US)
  • Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan
  • California Institute of Technology (US)
  • Bambino Gesù Children's Hospital (IT)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2012-03-14
Volume
61
Issue
4
Pages
828-837
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db11-0878
PMC
PMC3314357
OpenAlex
W2105713675
Cited by
70
References
1
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 4 · 2012: 1
FWCI
2.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-nd)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute of General Medical Sciences (R01GM078024, T32GM008322)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P60DK020572, R01DK48280, R01DK088856, P60 DK 20572, R01DK048280, P30DK020572)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
autosomal dominant diabetes, missense mutations, oxidative protein folding, endoplasmic reticulum retention, ER export, dominant negative effect, insulin biosynthesis, beta-cell failure, C-peptide
MeSH terms
Amino Acid Sequence, Animals, Cell Line, Diabetes Mellitus, Gene Expression Regulation, Genes, Dominant, Humans, Insulin, Mutation, Protein Precursors, Protein Sorting Signals, Mice, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review