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Clinical implications of a molecular genetic classification of monogenic β-cell diabetes

Abstract

Monogenic diabetes resulting from mutations that primarily reduce β-cell function accounts for 1–2% of diabetes cases, although it is often misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more-appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. We propose that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications. Firstly, diabetes diagnosed before 6 months of age frequently results from mutation of genes that encode Kir6.2 (ATP-sensitive inward rectifier potassium channel) or sulfonylurea receptor 1 subunits of an ATP-sensitive potassium channel, and improved glycemic control can be achieved by treatment with high-dose sulfonylureas rather than insulin. Secondly, patients with stable, mild fasting hyperglycemia detected particularly when they are young could have a glucokinase mutation and might not require specific treatment. Thirdly, individuals with familial, young-onset diabetes that does not fit with either type 1 or type 2 diabetes might have mutations in the transcription factors HNF-1α (hepatocyte nuclear factor 1-α) or HNF-4α, and can be treated with low-dose sulfonylureas. Finally, extrapancreatic features, such as renal disease (caused by mutations in HNF-1β) or deafness (caused by a mitochondrial m.3243A>G mutation), usually require early treatment with insulin.

Key Points

  • The old clinical classifications of maturity-onset diabetes of the young (MODY) and neonatal diabetes should now be replaced with a molecular genetic diagnosis, as this offers a more useful guide to clinical management

  • Monogenic β-cell diabetes is often misdiagnosed as type 1 or type 2 diabetes and a correct diagnosis can improve treatment

  • Diabetes diagnosed before 6 months of age will be monogenic diabetes and the underlying gene mutations can be identified in 75% of cases

  • Most neonatal patients with mutations in the potassium-sensitive ATP channel subunits Kir6.2 and sulfonylurea receptor 1 will be best treated with high-dose sulfonylureas rather than insulin injections, despite seeming insulin dependent

  • Patients with glucokinase mutations have stable, mild, regulated hyperglycemia throughout life and do not need pharmacological treatment except possibly during pregnancy

  • Patients with mutations in HNF1A have hyperglycemia that deteriorates with age and that can be severe; these patients, like patients with mutations in HNF4A, are sensitive to the hypoglycemic effects of sulfonylureas

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Figure 1: Clinical subtypes and management of monogenic β-cell diabetes that does not have extrapancreatic features.
Figure 2: Clinical subtypes and management of monogenic β-cell diabetes that has extrapancreatic features.
Figure 3: Phenotypes seen in diabetes with extra-pancreatic features.

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Acknowledgements

We thank all our colleagues in Exeter (past and present) for their contributions to the literature reviewed here. The assistance of K Colclough during the preparation of the manuscript is appreciated. Our research is supported by the Wellcome Trust (AT Hattersley is a Wellcome Trust Clinical Research Leave Fellow) and the Research and Development Directorate at the Royal Devon and Exeter NHS Foundation Trust (S Ellard). Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Murphy, R., Ellard, S. & Hattersley, A. Clinical implications of a molecular genetic classification of monogenic β-cell diabetes. Nat Rev Endocrinol 4, 200–213 (2008). https://doi.org/10.1038/ncpendmet0778

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