In celebration of a century with insulin - Update of insulin gene mutations in diabetes

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperReviewResearchpeer-review

  • Julie Støy
  • Elisa De Franco, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
  • ,
  • Honggang Ye, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
  • ,
  • Soo-Young Park, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
  • ,
  • Graeme I Bell, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
  • ,
  • Andrew T Hattersley, NIHR Exeter Clinical Research Facility, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.

BACKGROUND: While insulin has been central to the pathophysiology and treatment of patients with diabetes for the last 100 years it has only been since 2007 that genetic variation in the INS gene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INS gene are now recognised as important causes of neonatal diabetes and offer important insights both into the structure and function of insulin. It is also recognised that in rare cases, mutations in the INS gene can present in patients with diabetes diagnosed outside the first year of life.

SCOPE OF REVIEW: This review examines the genetics and clinical features of monogenic diabetes resulting from INS gene mutations from the first description in 2007 and includes information from 389 patients from 292 families diagnosed in Exeter with INS gene mutations. We discuss the implications for diagnosing and treating this subtype of monogenic diabetes.

MAJOR CONCLUSIONS: The dominant mutations in the INS gene typically affect the secondary structure of the insulin protein usually by disrupting the 3 disulfide bonds in mature insulin. The resulting misfolded protein results in ER stress and beta-cell destruction. In contrast recessive INS gene mutations typically result in no functional protein being produced as a result of reduced insulin biosynthesis or loss-of-function mutations of the insulin protein. There are clinical differences between the two genetic aetiologies, between the specific mutations, and finally variation within patients with identical mutations.

Original languageEnglish
Article number101280
JournalMolecular Metabolism
ISSN2212-8778
DOIs
Publication statusE-pub ahead of print - 23 Jun 2021

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Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

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