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Diabetes-Associated Mutations in Proinsulin Provide a “Molecular Rheostat” of Nascent Foldability

  • Pediatric Type 2 and Monogenic Diabetes (O Pinhas-Hamiel, Section Editor)
  • Published:
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Abstract

Purpose of Review

Diabetes mellitus (DM) due to toxic misfolding of proinsulin variants provides a monogenic model of endoplasmic reticulum (ER) stress. The mutant proinsulin syndrome (also designated MIDY; Mutant INS-gene-induced Diabetes of Youth or Maturity-onset diabetes of the young 10 (MODY10)) ordinarily presents as permanent neonatal-onset DM, but specific amino-acid substitutions may also present later in childhood or adolescence. This review highlights structural mechanisms of proinsulin folding as inferred from phenotype-genotype relationships.

Recent Findings

MIDY mutations most commonly add or remove a cysteine, leading to a variant polypeptide containing an odd number of thiol groups. Such variants are associated with aberrant intermolecular disulfide pairing, ER stress, and neonatal β-cell dysfunction. Non-cysteine-related (NCR) mutations (occurring in both the B and A domains of proinsulin) define distinct determinants of foldability and vary in severity. The range of ages of onset, therefore, reflects a “molecular rheostat” connecting protein biophysics to quality-control ER checkpoints. Because in most mammalian cell lines even wild-type proinsulin exhibits limited folding efficiency, molecular barriers to folding uncovered by NCR MIDY mutations may pertain to β-cell dysfunction in non-syndromic type 2 DM due to INS-gene overexpression in the face of peripheral insulin resistance.

Summary

Recent studies of MIDY mutations and related NCR variants, combining molecular and cell-based approaches, suggest that proinsulin has evolved at the edge of non-foldability. Chemical protein synthesis promises to enable comparative studies of “non-foldable” proinsulin variants to define key steps in wild-type biosynthesis. Such studies may create opportunities for novel therapeutic approaches to non-syndromic type 2 DM.

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Notes

  1. Abbreviations. DM, diabetes mellitus; ER, endoplasmic reticulum; MIDY, mutant INS-gene-induced Diabetes of Youth; MODY, maturity-onset diabetes of the young; NCR, non-cysteine-related; PND, permanent neonatal-onset DM; and UPR, unfolded-protein response. Residues are designated by standard three-letter code. Residue positions in insulin are shown in superscript (chain and residue number); Leu at position 15 of the B chain, for example, is denoted LeuB15. Cystine pairings are identified by brackets; the disulfide pairing between CysB19 and CysA20, for example, is [B19-A20]. Gene names are italicized.

  2. Although insulin chain combination is in general robust to mutations in the A1-A8 α-helix [91, 92], MODY variant GluA4Lys lies on the surface of this helix. Its effect on the foldability of proinsulin may be due to disruption of a salt bridge with Arg89 (in the dibasic CA junction) in a proinsulin folding intermediate; in the solution structure of a proinsulin monomer this salt bridge appears to provide an N-cap of A1-A8 α-helix [48]. LysA4 could introduce electrostatic repulsion within this element and so attenuate nascent helix formation. A structural puzzle is posed by neonatal-onset MIDY mutation ThrA8Ser [50], also on the surface of insulin.

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Acknowledgements

The authors thank P. Arvan, T.L. Blundell, D. Chatterjee, Y.S. Chan, M. Jarosinski, S.B. Kent, F. Ismail-Beigi, M. Liu, N.B. Phillips, J. Racca, and Y. Yang for helpful discussion. We thank L. Liu, P. Arvan, G.I. Bell, L. Philipson, and E. De Franco for communication of results prior to publication. M.A.W. is grateful to the late G.G. Dodson, P.G. Katsoyannis, and D.F. Steiner for their encouragement in the early years of this research program.

Funding

This work was supported in part by a grant from the National Institutes of Health (R01 DK040949). BD is supported in part by a grant from the Diabetes Research Connection.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Balamurugan Dhayalan & Michael A. Weiss

  2. Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA

    Michael A. Weiss

  3. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA

    Michael A. Weiss

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  1. Balamurugan Dhayalan
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  2. Michael A. Weiss
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Correspondence to Michael A. Weiss.

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This article is part of the Topical Collection on Pediatric Type 2 and Monogenic Diabetes

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Dhayalan, B., Weiss, M.A. Diabetes-Associated Mutations in Proinsulin Provide a “Molecular Rheostat” of Nascent Foldability. Curr Diab Rep 22, 85–94 (2022). https://doi.org/10.1007/s11892-022-01447-2

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