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Monogenic diabetes

Nature Reviews Disease Primers volume 9, Article number: 12 (2023) Cite this article

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Abstract

Monogenic diabetes includes several clinical conditions generally characterized by early-onset diabetes, such as neonatal diabetes, maturity-onset diabetes of the young (MODY) and various diabetes-associated syndromes. However, patients with apparent type 2 diabetes mellitus may actually have monogenic diabetes. Indeed, the same monogenic diabetes gene can contribute to different forms of diabetes with early or late onset, depending on the functional impact of the variant, and the same pathogenic variant can produce variable diabetes phenotypes, even in the same family. Monogenic diabetes is mostly caused by impaired function or development of pancreatic islets, with defective insulin secretion in the absence of obesity. The most prevalent form of monogenic diabetes is MODY, which may account for 0.5–5% of patients diagnosed with non-autoimmune diabetes but is probably underdiagnosed owing to insufficient genetic testing. Most patients with neonatal diabetes or MODY have autosomal dominant diabetes. More than 40 subtypes of monogenic diabetes have been identified to date, the most prevalent being deficiencies of GCK and HNF1A. Precision medicine approaches (including specific treatments for hyperglycaemia, monitoring associated extra-pancreatic phenotypes and/or following up clinical trajectories, especially during pregnancy) are available for some forms of monogenic diabetes (including GCK- and HNF1A-diabetes) and increase patients’ quality of life. Next-generation sequencing has made genetic diagnosis affordable, enabling effective genomic medicine in monogenic diabetes.

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Fig. 1: Genes implicated in the pathogenesis of monogenic diabetes, T1DM and T2DM.
Fig. 2: Sites of function of monogenic diabetes gene products in pancreatic β-cells.
Fig. 3: Features used to differentiate between monogenic diabetes, T1DM and T2DM.

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Acknowledgements

A.B. is supported by the European Research Council (ERC OπO: 101043671). A.B., M.V. and P.F. are supported by the National Center for Precision Diabetic Medicine — PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL). V.M. and R.U. acknowledge the support of M/S Servier Laboratories to their work on monogenic diabetes as part of the PAN INDIA STUDY ON MODY (CTRI/2019/12/022394 & CTRI/2020/03/023968).

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Authors and Affiliations

  1. Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France

    Amélie Bonnefond, Martine Vaxillaire & Philippe Froguel

  2. Université de Lille, Lille, France

    Amélie Bonnefond, Martine Vaxillaire & Philippe Froguel

  3. Department of Metabolism, Imperial College London, London, UK

    Amélie Bonnefond & Philippe Froguel

  4. Department of Diabetology, Madras Diabetes Research Foundation, Indian Council of Medical Research Centre for Advanced Research on Diabetes and Dr Mohan’s Diabetes Specialities Centre, Chennai, India

    Ranjit Unnikrishnan & Viswanathan Mohan

  5. Research Division, Joslin Diabetes Center, Boston, MA, USA

    Alessandro Doria & Rohit N. Kulkarni

  6. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Alessandro Doria & Rohit N. Kulkarni

  7. Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy

    Vincenzo Trischitta

  8. Department of Experimental Medicine, Sapienza University, Rome, Italy

    Vincenzo Trischitta

Authors
  1. Amélie Bonnefond
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  2. Ranjit Unnikrishnan
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  3. Alessandro Doria
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  4. Martine Vaxillaire
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  5. Rohit N. Kulkarni
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  6. Viswanathan Mohan
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  7. Vincenzo Trischitta
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  8. Philippe Froguel
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Contributions

Introduction (A.B. and M.V.); Epidemiology (P.F.); Mechanisms/pathophysiology (A.B., A.D., M.V. and R.N.K.); Diagnosis, screening and prevention (A.B., R.U., V.M. and V.T.); Management (P.F., V.M. and V.T.); Quality of life (P.F. and A.B.); Outlook (P.F.); Overview of Primer (A.B. and P.F.).

Corresponding authors

Correspondence to Amélie Bonnefond or Philippe Froguel.

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The authors declare no competing interests.

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Nature Reviews Disease Primers thanks L. Billings, K. Owen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

ClinGen Monogenic Diabetes Variant Curation Expert Panel: https://clinicalgenome.org/affiliation/50016/

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Bonnefond, A., Unnikrishnan, R., Doria, A. et al. Monogenic diabetes. Nat Rev Dis Primers 9, 12 (2023). https://doi.org/10.1038/s41572-023-00421-w

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