Brief Communication | Published:

Precision medicine for a man presented with diabetes at 2-month old

European Journal of Human Genetics (2019) | Download Citation


A 22-year-old man was referred for continuation of diabetes mellitus treatment. He was first diagnosed with diabetes mellitus 2 months after birth, when he failed to thrive and showed symptoms of diabetic ketoacidosis. There was no family history of diabetes mellitus. The patient did not exhibit the full set of features to be qualified for any developmental delay, epilepsy and neonatal diabetes mellitus (DEND) syndrome. Insulin replacement therapy was initiated; however, management was challenged by wide glycemic excursion, hypoglycemic unawareness and insulin-associated cutaneous lipo-hypertrophy. Re-evaluation, including genetic testing, revealed a heterozygous missense p.Arg201Cys variation in the KCNJ11 gene encoding the potassium channel subunit Kir6.2. Successful treatment conversion from insulin to glibenclamide was achieved over an extended period of 2 months (up-titrating to a dose of 1.0 mg/kg) in this patient despite his long diabetes duration of 27 years with elimination of hypoglycemia unawareness and achievement of excellent glycemic control sustained over more than 5 years. This case highlights the importance of after having secured a firm genetic diagnosis, to undertake conversion to sulphonylurea with careful dose titration and perseverance over months. Confirmation of variants with functional implications by genetic testing in patients suspected of neonatal diabetes is important for accurate molecular diagnosis and precision-treatment strategy with optimal outcome.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Iafusco D, Stazi MA, Cotichini R, Cotellessa M, Martinucci ME, Mazzella M, et al. Permanent diabetes mellitus in the first year of life. Diabetologia. 2002;45:798–804.

  2. 2.

    Edghill EL, Dix RJ, Flanagan SE, Bingley PJ, Hattersley AT, Ellard S, et al. HLA genotyping supports a nonautoimmune etiology in patients diagnosed with diabetes under the age of 6 months. Diabetes. 2006;55:1895–8.

  3. 3.

    Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–49.

  4. 4.

    Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456–66.

  5. 5.

    Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, et al. 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;57:1034–42.

  6. 6.

    Stoy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA. 2007;104:15040–4.

  7. 7.

    Colombo C, Porzio O, Liu M, Massa O, Vasta M, Salardi S, et al. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest. 2008;118:2148–56.

  8. 8.

    Edghill EL, Flanagan SE, Ellard S. Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. Rev Endocr Metab Disord. 2010;11:193–8.

  9. 9.

    Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, et al. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab. 2004;89:3932–5.

  10. 10.

    Edghill EL, Gloyn AL, Goriely A, Harries LW, Flanagan SE, Rankin J, et al. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J Clin Endocrinol Metab. 2007;92:1773–7.

  11. 11.

    Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA. 2004;101:17539–44.

  12. 12.

    Proks P, Girard C, Ashcroft FM. Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol Genet. 2005;14:2717–26.

  13. 13.

    Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes. 2004;53:2713–8.

  14. 14.

    Zung A, Glaser B, Nimri R, Zadik Z. Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab. 2004;89:5504–7.

  15. 15.

    Klupa T, Edghill EL, Nazim J, Sieradzki J, Ellard S, Hattersley AT, et al. The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of beta cell function among carriers of the R201H mutation. Diabetologia. 2005;48:1029–31.

  16. 16.

    Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355:467–77.

  17. 17.

    Bowman P, Sulen Å, Barbetti F, Beltrand J, Svalastoga P, Codner E, et al. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study. The Lancet Diabetes &. Endocrinology. 2018;6:637–46.

  18. 18.

    Kumaraguru J, Flanagan SE, Greeley SAW, Nuboer R, Støy J, Philipson LH, et al. Tooth discoloration in patients with neonatal diabetes after transfer onto glibenclamide. Diabetes Care. 2009;32:1428.

  19. 19.

    Babiker T, Vedovato N, Patel K, Thomas N, Finn R, Mannikko R, et al. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes. Diabetologia. 2016;59:1162–6.

Download references


This study is funded by National Healthcare Group (NHG)-Khoo Teck Puat Hospital (KTPH) Small Innovative Grants: SIGI/13038, SIGII/14001 and STAR17201. We would also like to thank the patient for giving consent to share his case for the benefit of improving diabetes care.

Author information


  1. Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore, Singapore

    • Su Fen Ang
    • , Clara Si Hua Tan
    • , Jessie Choi Wan Fong
    •  & Su Chi Lim
  2. Diabetes Centre, , Khoo Teck Puat Hospital (KTPH), Singapore, Singapore

    • Su Chi Lim
  3. Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore

    • Su Chi Lim


  1. Search for Su Fen Ang in:

  2. Search for Clara Si Hua Tan in:

  3. Search for Jessie Choi Wan Fong in:

  4. Search for Su Chi Lim in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Su Chi Lim.

About this article

Publication history