Permanent neonatal diabetes (PND) is a rare disease characterized by hyperglycemia diagnosed within the first 6 months of life (1). Activating mutation of the KCNJ11 gene encoding Kir6.2 subunit of the ATP-potassium (KATP) channel has been described as the most frequent cause of PND. Under physiologic circumstances, KATP channel closure plays a central role in glucose-stimulated insulin secretion from pancreatic β-cells. Sulfonylureas (SUs) stimulate insulin secretion by closing KATP channels via an ATP-independent mechanism. Since 2004, SUs are best choice of treatment in PND with such mutations and allow better glycemic control in children and adults than insulin (2).

Some authors report that adult patients are unable to switch successfully from insulin to SU and that the doses required to get the insulin independence are higher (3,4). We present our experience in switching the treatment from insulin to SU and the usefulness of adding sitagliptin.

We describe an 18-year-old Spanish girl with PND due to the previously reported H46Y mutation in the KNCJ11 gene. No history of epilepsy or developmental delay was present. Clinical characteristics are shown in Table 1.

Table 1

Clinical characteristics of patient

Clinical characteristics of patient
Clinical characteristics of patient

After discovering the etiology of the diabetes, switching from insulin to SU was attempted. Informed consent was obtained from the patient. We started glibenclamide (GB) therapy according to a standardized protocol at initial dose of 0.2 mg/kg/day and then gradually increased it until she reached a dose of 1 mg/kg/day. Insulin was progressively reduced. Four weeks after the beginning of the transition, the glycemic control was poor, so we decided to continue with insulin and SU at high doses. Six months after initiating GB, she was receiving basal insulin (20 units/day) and GB (0.8 mg/kg/day) with little improvement of glycemic control, but, in agreement with the patient, we decided to continue with this compound treatment. Twelve months after the start of SU treatment, her HbA1c was high and we decided to add sitagliptin (100 mg/day). After 3 months with GB (0.6 mg/kg/day) plus sitagliptin and glargine (16 units/day), HbA1c was 7% (53 mmol/mol) and insulin was discontinued. After 3 years of insulin independence, the patient has good glycemic control and has reduced the dose of GB to 0.3 mg/kg/day. She continues with sitagliptin combined with SU.

To our knowledge, this is the first report of sitagliptin as a possible therapeutic tool in PND with mutations in the KCNJ11 gene. Today, we know that patients with KCNJ11 mutations who are receiving SU have marked insulin secretion in response to oral glucose (2). This finding is consistent with the hypothesis that improved glycemic control in PND treated with SU could be, in part, mediated by incretin effects. SUs close the KATP channel and depolarize the membrane of β-cells, so that they are able to respond to glucagon-like peptide 1 and other secretagogues (3). Glucagon, like glucagon-like peptide 1, does not stimulate insulin secretion in PND unless SUs are present. In adult patients with PND with KCNJ11 mutations unable to switch from insulin to SU or with long transitions, dipeptidyl peptidase 4 inhibitors could be an option of treatment.

Acknowledgments. The authors thank L. Castaño (Hospital Universitario de Cruces, Spain), who provided sequence analysis of the KCNJ11 gene.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. J.S. took care of the patient, researched data, and wrote the manuscript. A.L. and F.d.V. took care of the patient, researched data, and contributed to the writing of the manuscript. A.A. took care of the patient since diagnosis to adult age, contributed to discussion, and reviewed the manuscript. J.L. contributed to discussion and reviewed the manuscript. J.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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