Neonatal diabetes with response to very low doses of sulfonylureas after 47 years of diagnosis

Moreno Tirado, Antonio; del Val Zaballos, Florentino

doi:10.1016/j.medcle.2022.11.014

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It should be suspected in the presence of hyperglycaemia in the first 6 months of life. In these cases, a genetic study should be carried out, as a monogenic underlying cause is present in up to 80%–85% of the cases.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>The mutation in the KCNJ11 gene encoding the Kir 6.2 subunit of adenosine triphosphate-sensitive potassium channel (KATP) of cells β has been described as the most frequent cause of permanent neonatal diabetes.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Genetic diagnosis is very important as it may have an impact on treatment. Cases secondary to KATP mutations can be treated with sulfonylurea drugs, thereby obtaining good glycaemic control without the need for insulin. This occurs because sulfonylureas bind to the sulfonylurea receptor SUR1 subunit and close the KATP channel, allowing the membrane to depolarise and cell functionality to be restored β promoting insulin production in response to glucose.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a>Neonatal diabetes associated with KCNJ11 gene mutation is also associated with a possible delay in maturation and seizures (in 20%–30% of individuals), constituting the DEND syndrome, since the KATP channels are also present in the brain.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>We present the case of a 46-year-old male patient weighing 65kg, with a personal history of psychomotor retardation attributed to childhood cerebral palsy secondary to cerebral anoxia, spastic tetraparesis and epileptic seizures, who was diagnosed with type 1 diabetes mellitus at 3 months of age, receiving treatment with insulin ever since. He was currently undergoing treatment with basal bolus insulin (degludec 24 units) and a correction regimen (insulin aspart), with acceptable glycaemic control (times in range: 64% on target, 0% low and very low, 33% high and 3% very high).He was referred to endocrinology outpatients to resume follow-up, which until then had been taken care of by his GP. Due to the history of psychomotor retardation and early diagnosis of diabetes mellitus, a genetic study was requested, and the results showed a heterozygous pathogenic variant in exon 1 of the KCNJ11 p.Glu179Ala gene. This established the diagnosis of permanent neonatal diabetes, which due to the association with epilepsy and psychomotor retardation constituted the DEND syndrome.After the diagnosis, it was decided to withdraw the insulin and gradually introduce glibenclamide treatment. Due to hypoglycaemic episodes, the dose had to be reduced until currently he is receiving 1875mg of glibenclamide per day divided into 2 doses, one of 1.25mg at breakfast and the other of 0.625mg at dinner, which is a dose of less than 0.0375mg/kg/day. This has obtained good glycaemic control and is an improvement on the previous treatment with insulin (as can be seen in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, where the times in range during treatment with insulin and glibenclamide can be compared).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>There are multiple mutations in the KCNJ11 gene; in our case our attention has been drawn to the excellent glycaemic control maintained with very low doses of sulfonylurea and after a long period of treatment with insulin, which could be secondary to the pathogenic variant found in heterozygosity in exon 1 of the KCNJ11 p.Glu179Ala gene. Therefore, we can conclude that the duration of diabetes should not be a contraindication for the transition from insulin to sulfonylurea and that the dose will depend on the mutation subtype, since usually the required dose is between 0.5−1mg/kg/day and in the case of our patient it is much lower.After the presentation of this clinical case, we consider that it is necessary to reconsider the classification of diabetes when a patient is first referred to our clinics, investigating the family history and the form and age of onset of diabetes. This is because changes in the diagnosis can make us change the treatment, obtaining benefits for the patient.Ethical considerationsThe authors declare that they have followed the protocols established by their respective health centres to access the data from the medical records in order to be able to carry out this type of study to aid research/dissemination in the scientific community. However, no patient data appears in this article.Fundingwe have not received funding in relation to this article.Conflict of interestsThe authors have no conflict of interest to declare in relation to this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interests" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1389 "Ancho" => 3167 "Tamanyo" => 455232 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0040" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Comparison between AGP reports during insulin (left) and glibenclamide (right) treatment." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Standards of Medical Care in Diabetes—2021" ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.2337/dc21-Sint" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care." "fecha" => "2020" "volumen" => "44" "paginaInicial" => "S1" "paginaFinal" => "S2" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33298409" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.2337/dc21-Sint" "WWW" => array:1 [ "link" => "ADA-Standards-of-Medical-Care-Diabetes-Care-2021.pdf" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neonatal diabetes due to potassium channel mutation: response to sulfonylurea according to the genotype" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L. Garcin" 1 => "V. Mericq" 2 => "A.-L. Fauret-Amsellem" 3 => "H. Cave" 4 => "M. Polak" 5 => "J. Beltrand" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/pedi.13041" "Revista" => array:7 [ "tituloSerie" => "Pediatr Diabetes." 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