Recently, heterozygous activating mutations in the genes forming the ATP-sensitive potassium 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 the parents gave written consent.
Table 1. Clinical and molecular study of the three children with early onset diabetes mellitus, as well as information about their sulfonylureas treatment.
| Case | 1 | 2 | 3 |
|---|---|---|---|
| Molecular study | R201L in KCNJ11 | R201H in KCNJ11 | Q211K in ABCC8 |
| Age DM was diagnosed (months) | 4 | 6 | 4 |
| Ketoacidosis at onset | + | + | + |
| Insulin dose before sulfonylurea treatment (U/Kg/day) | 0.6 | 0.7 | 0.3 |
| Type of insulin used | Glargine/lispro | NPH/lispro | Glargine/lispro |
| HbA1c before sulfonylurea treatment | 7.3 | 8.9 | 6.7 |
| Sulfonylureas treatment that allowed stopping insulin | |||
| Age sulfonylurea treatment was begun (yr) | 1.4 | 3.1 | 3 |
| Drug used for successful transfer | Glibenclamide | Glibenclamide | Glibenclamide |
| Dose (mg/kg/day) | 0.8 | 0.6 | 0.3 |
| Number of doses/day | 2 | 3 | 2 |
| Dose (mg/dose) | 3.75 - 3.75 | 2.5 - 3.0 -3.5 | 1.5 - 1.5 |
| Sulfonylureas treatment at the last medical visit | |||
| Drug used at the last medical visit | Glibenclamide | Glibenclamide | Tolbutamide |
| Duration of sulfonylureas treatment (months) | 26.0 | 5.0 | 4.5 |
| Dose (mg/kg/day) | 0.3 | 0.6 | 1.4 |
| Number of doses/day | 3 | 3 | 1 |
| Dose (mg/dose) | 0.75 -1.25 - 2.25 | 2.25 - 2.75 - 3.75 | 15.6 |
| HbA1c during sulfonylureas treatment | 5.0-6.5 | 5.8 | 6.8 |
| Medical problems observed during sulfonylureas treatment | |||
| Initial diarrhea Unexplained hyperglycemia Hyperglycemia associated with missed dose Hypoglycemia Sick day management |
Sick day management Unexplained occasional Hyperglycemia |
Hypoglycemia with low doses of glibenclamide Transitory diarrhea with glibenclamide |
Case 1
This girl was transferred from insulin to glibenclamide at 17 months (7), and has been on this treatment for two years. During this period blood glucose (BG) testing decreased from 5-6 to 2-3 tests/day. As BG levels were not affected by the ingestion of different amounts of carbohydrates, a free diet was initiated. Unexplained hyperglycemia episodes were occasionally observed and an appropriate decrease in the BG level was observed with the usual dose of glibenclamide, even in the face of hyperglycemia of 350 mg/dl, . When the parents missed one dose, BG 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 hypoglycaemia. One episode of rotavirus diarrhea was managed in hospital using insulin and stopping glibenclamide. Upon discharge, the sulfonylurea was restarted at the previous dose. Ketones were not detected on any of these acute illnesses.
Case 2
This 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, ketones were not detected and insulin was not required.
Case 3
This girl was treated with insulin until the confirmation of a novel mutation in ABCC8 when aged three years. Unexpectedly, a low dose of glibenclamide (0.1 mg/kg/day) 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, but as hyperglycemia recurred tolbutamide was begun resulting in good control without hypoglycaemia.
These cases show that the use of sulphonylureas in children with KATP mutations differ from adults with T2D. In 2 cases glibenclamide was best given three times a day. These children also required a higher night-time 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 so education in their prevention and treatment should be given. Hyperglycemia, even 350 mg/dl, responded to the usual dose of sulfonylureas, but if these patients consistently miss medication they risk ketoacidosis.
Acknowledgements
This work was supported in part by the Fondo Nacional de Desarrollo Científico y Tecnológico, Chile (FONDECYT) grant N° 1050452 to EC and by the Wellcome Trust. We are grateful to Dr. María Isabel Hernández and Mrs. 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.
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