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Published online March 2, 2007
Diabetes Care 30:e28-e29, 2007
DOI: 10.2337/dc06-2134
© 2007 by the American Diabetes Association
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Online Letters: Observations

Sulfonylurea Treatment in Young Children With Neonatal Diabetes

Dealing with hyperglycemia, hypoglycemia, and sick days

Ethel Codner, MD1, Sarah E. Flanagan, BSC2, Francisca Ugarte, MD3, Hernán García, MD4, Teresa Vidal, MD5, Sian Ellard, PHD, MRCPATH2 and Andrew T. Hattersley, DM, FRCP2

1 Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile
2 Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.
3 Hospital Exequiel González Cortés, Santiago, Chile
4 Clínica Santa María, Santiago, Chile
5 Hospital Dr. Hernán Henríquez, Temuco, Chile

Address correspondence to Prof. Andrew T. Hattersley, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, U.K. E-mail: a.t.hattersley{at}ex.ac.uk

Recently, heterozygous activating mutations in the genes forming the ATP-sensitive K+ channel (KATP channel), KCNJ11 and ABCC8, have been shown to cause neonatal diabetes (1–4). Sulfonylurea treatment restores insulin secretion in these patients (3,5,6), but information on the practical management of children with mutated KATP channels taking this medication is limited.

We report clinical aspects of the successful transfer to oral treatment in three cases of young children with KCNJ11 and ABCC8 mutations (Table 1). All parents gave written consent.


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  		Table 1— Clinical and molecular study of the three children with early-onset diabetes and information about their sulfonylureas treatment

 
In case 1, a girl was transferred from insulin to glibenclamide at 17 months (7) and had been on this treatment for 2 years. During this period, blood glucose testing decreased from 5–6 to 2–3 tests/day. As blood glucose levels were not affected by the ingestion of different amounts of carbohydrates, a free diet was initiated. Unexplained episodes of hyperglycemia were occasionally observed, and an appropriate decrease in the blood glucose level was observed with the usual dose of glibenclamide, even in cases of hyperglycemia (blood glucose 350 mg/dl). When the parents missed one dose, blood glucose was 455 mg/dl without ketosis, which was treated at home with lispro insulin dose and administration of the missed sulfonylurea dose. Only one episode of symptomatic hypoglycemia (30 mg/dl) occurred and was successfully treated with fruit juice and a temporary decrease in glibenclamide.

Minor episodes of viral respiratory disease were managed by decreasing the sulfonylurea dose to avoid hypoglycemia. One episode of rotavirus diarrhea was managed in a hospital using insulin and by stopping glibenclamide. Upon discharge, the sulfonylurea was restarted at the previous dose. Ketones were not detected on any of these acute illnesses.

In case 2, a boy with a KCNJ11 mutation was successfully transferred from insulin to glibenclamide at 38 months. This patient also had some episodes of unexpected hyperglycemia, which responded to taking the normal glibenclamide dose. An episode of a febrile upper respiratory tract viral illness was managed with a decrease of the glibenclamide dose, and ketones were not detected and insulin was not required.

In case 3, a girl was treated with insulin until the confirmation of a novel mutation in ABCC8 when aged 3 years. Unexpectedly, a low dose of glibenclamide (0.1 mg · kg–1 · day–1) not only allowed the stopping of insulin but also resulted in episodes of asymptomatic hypoglycemia. The dose was reduced and then discontinued completely for 12 days. However, as hyperglycemia recurred tolbutamide was started, which resulted in good control without hypoglycemia.

These cases show that the use of sulfonylureas in children with KATP mutations differ from adults with type 2 diabetes. In two cases, glibenclamide was best given three times a day. These children also required a higher nighttime dose to lower morning glucose, possibly as sulfonylureas act through facilitating the response to incretins in this type of diabetes (5). Sulfonylurea treatment was well tolerated; however, the risk of hypo- and hyperglycemia persists, and education in their prevention and treatment should be given. Hyperglycemia, even at blood glucose level 350 mg/dl, responded to the usual dose of sulfonylureas, but if these patients consistently miss medications they risk ketoacidosis.

Acknowledgments

This work was supported, in part, by the Fondo Nacional de Desarrollo Científico y Tecnológico, Chile (FONDECYT) Grant 1050452 (to E.C.) and by Wellcome Trust.

We are grateful to Dr. María Isabel Hernández and Alejandra Ávila, BSc, from the Institute of Maternal and Child Research, University of Chile, Santiago, Chile, for their help in the care of these patients.

References

  1. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JMCL, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JPH, Sumnik Z, van Rhijn A, Wales JKH, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849, 2004[Abstract/Free Full Text]
  2. Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S: A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 15:1793–800, 2006[Abstract/Free Full Text]
  3. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P: Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355:456–466, 2006[Abstract/Free Full Text]
  4. Hattersley AT, Ashcroft FM: Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54:2503–2513, 2005[Abstract/Free Full Text]
  5. Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert J-J, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT, the Neonatal Diabetes International Collaborative Group: Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355:467–477, 2006[Abstract/Free Full Text]
  6. Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR: Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713–2718, 2004[Abstract/Free Full Text]
  7. Codner E, Flanagan S, Ellard S, Garcia H, Hattersley AT: High-dose glibenclamide can replace insulin therapy despite transitory diarrhea in early-onset diabetes caused by a novel R201L Kir6.2 mutation. Diabetes Care 28:758–759, 2005[Free Full Text]

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