OBJECTIVE: To report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient carrying the p.G53D (c.158G>A) mutation in KCNJ11 gene. SUBJECT AND METHOD: A 29-year-old male patient was diagnosed with diabetes in the third month of life and after identification of a heterozygous p.G53D mutation in the KCNJ11 gene, the therapy was switched from insulin to sulfonylurea. RESULTS: Long-term follow-up (30 months) showed that good metabolic control was maintained (HbA1c: 6.6%) and the glibenclamide dose could be reduced. CONCLUSION: Long-term therapy with sulfonylureas in patients with neonatal diabetes due to mutation in the KCNJ11 gene is safe and promotes sustained improvement of glycemic control.OBJETIVO: Reportar o efeito a longo prazo (30 meses) da substituição de insulina por sulfonilureia em um paciente com a mutação p.G53D (c.158G>A) no gene KCNJ11. SUJEITO E MÉTODO: Paciente do sexo masculino, atualmente com 29 anos de idade, foi diagnosticado com diabetes melito no terceiro mês de vida e, após identificação da mutação p.G53D (c.158G>A) em heterozigose no gene KCNJ11, a terapia foi substituída de insulina para sulfonilureia. RESULTADOS: Seguimento a longo prazo (30 meses) mostrou que o bom controle metabólico foi mantido (HbA1c: 6,6%) e a dose de glibenclamida pode ser reduzida. CONCLUSÃO: A terapia com sulfonilureia a longo prazo em pacientes com diabetes neonatal decorrente de mutações no gene KCNJ11 é segura e promove uma melhora persistente no controle metabólico.Universidade Federal de São Paulo (UNIFESP) Division of EndocrinologyUNIFESP, Division of EndocrinologySciEL

Gurgel, Lucimary Cavalcante

Moises, Regina Celia Mello Santiago

Vendramini, Marcio F.

Arquivos Brasileiros de Endocrinologia & Metabologia

OBJETIVO: Reportar o efeito a longo prazo (30 meses) da substituição de insulina por sulfonilureia em um paciente com a mutação p.G53D (c.158G>A) no gene KCNJ11. SUJEITO E MÉTODO: Paciente do sexo masculino, atualmente com 29 anos de idade, foi diagnosticado com diabetes melito no terceiro mês de vida e, após identificação da mutação p.G53D (c.158G>A) em heterozigose no gene KCNJ11, a terapia foi substituída de insulina para sulfonilureia. RESULTADOS: Seguimento a longo prazo (30 meses) mostrou que o bom controle metabólico foi mantido (HbA1c: 6,6%) e a dose de glibenclamida pode ser reduzida. CONCLUSÃO: A terapia com sulfonilureia a longo prazo em pacientes com diabetes neonatal decorrente de mutações no gene KCNJ11 é segura e promove uma melhora persistente no controle metabólico.OBJECTIVE: To report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient carrying the p.G53D (c.158G>A) mutation in KCNJ11 gene. SUBJECT AND METHOD: A 29-year-old male patient was diagnosed with diabetes in the third month of life and after identification of a heterozygous p.G53D mutation in the KCNJ11 gene, the therapy was switched from insulin to sulfonylurea. RESULTS: Long-term follow-up (30 months) showed that good metabolic control was maintained (HbA1c: 6.6%) and the glibenclamide dose could be reduced. CONCLUSION: Long-term therapy with sulfonylureas in patients with neonatal diabetes due to mutation in the KCNJ11 gene is safe and promotes sustained improvement of glycemic control.Universidade Federal de São Paulo (UNIFESP) Division of EndocrinologyUNIFESP, Division of EndocrinologySciEL

Vendramini, Marcio F. [UNIFESP]

Gurgel, Lucimary Cavalcante [UNIFESP]

Moises, Regina Celia Mello Santiago [UNIFESP]

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

Resposta a longo prazo com sulfonilureia em um paciente com diabetes associado à mutação no gene KCNJ11

OBJECTIVE: To report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient carrying the p.G53D (c.158G>A) mutation in KCNJ11 gene. SUBJECT AND METHOD: A 29-year-old male patient was diagnosed with diabetes in the third month of life and after identification of a heterozygous p.G53D mutation in the KCNJ11 gene, the therapy was switched from insulin to sulfonylurea. RESULTS: Long-term follow-up (30 months) showed that good metabolic control was maintained (HbA1c: 6.6%) and the glibenclamide dose could be reduced. CONCLUSION: Long-term therapy with sulfonylureas in patients with neonatal diabetes due to mutation in the KCNJ11 gene is safe and promotes sustained improvement of glycemic control

Vendramini,Marcio F.

Gurgel,Lucimary C.

Moisés,Regina S.

Long-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 gene

Repositório Institucional UNIFESP

Copyright© ABE&M todos os direitos reservados.Arq Bras Endocrinol Metab. 2010;54/8682original articleLong-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 geneResposta a longo prazo com sulfonilureia em um paciente com diabetes associado à mutação no gene KCNJ11Marcio F. Vendramini1, Lucimary C. Gurgel1, Regina S. Moisés1ABSTRACTObjective:  To report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient carrying the p.G53D (c.158G>A) mutation in KCNJ11 gene. Subject and method: A 29-year--old male patient was diagnosed with diabetes in the third month of life and after identification of a heterozygous p.G53D mutation in the KCNJ11 gene, the therapy was switched from insulin to sulfonylurea. Results: Long-term follow-up (30 months) showed that good metabolic control was maintained (HbA1c: 6.6%) and the glibenclamide dose could be reduced. Conclusion: Long-term therapy with sulfonylureas in patients with neonatal diabetes due to mutation in the KCNJ11 gene is safe and promotes sustained improvement of glycemic control. Arq Bras Endocrinol Metab. 2010;54(8):682-4 KeywordsNeonatal diabetes; KCNJ11 mutation; sulfonylurea therapy RESUMOObjetivo:  Reportar o efeito a longo prazo (30 meses) da substituição de insulina por sulfonilureia em um paciente com a mutação p.G53D (c.158G>A) no gene KCNJ11. Sujeito e método: Pacien-te do sexo masculino, atualmente com 29 anos de idade, foi diagnosticado com diabetes melito no terceiro mês de vida e, após identificação da mutação p.G53D (c.158G>A) em heterozigose no gene KCNJ11, a terapia foi substituída de insulina para sulfonilureia. Resultados: Seguimento a longo prazo (30 meses) mostrou que o bom controle metabólico foi mantido (HbA1c: 6,6%) e a dose de glibenclamida pode ser reduzida. Conclusão: A terapia com sulfonilureia a longo prazo em pacientes com diabetes neonatal decorrente de mutações no gene KCNJ11 é segura e promove uma melhora persistente no controle metabólico. Arq Bras Endocrinol Metab. 2010;54(8):682-4DescritoresDiabetes neonatal; mutação KCNJ11; terapia com sulfonilureia1 Division of Endocrinology, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil Correspondence to:Regina S. Moisés Universidade Federal de São Paulo,Escola Paulista de Medicina,Disciplina de Endocrinologia, Rua Botucatu, 740, 2º andar 04034-970 – São Paulo, SP, Brazil rmoises@unifesp.br Received on Apr/22/2010Accepted on Jul/7/2010InTRODUCTIOnNeonatal diabetes mellitus is a rare condition charac-terized by hyperglycemia within the first months of life, which may either be permanent or transient. Activat-ing mutations in the genes KCNJ11 and ABCC8, which encode the two subunits Kir6.2 and SUR1 of the pan-creatic ATP-sensitive potassium channel, are the most frequent cause of permanent neonatal diabetes (1-3). Approximately 30% of individuals with activating muta-tions in KCNJ11 have neurologic features in addition to neonatal diabetes (4). The main neurologic findings are developmental delay, muscle weakness and epilepsy and this has been proposed to be part of a syndrome referred as DEND (developmental delay, epilepsy and neonatal diabetes) syndrome (5). A less severe form without epi-lepsy is called intermediate DEND syndrome. Successful switch from insulin to sulfonylurea (SU) ther-apy has been reported in the majority of the patients with KCNJ11 mutations (6-8); however, there are few reports on the long-term efficacy and safety of this change (9-12).Here we report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient car-rying the p.G53D mutation in the KCNJ11 gene.Copyright© ABE&M todos os direitos reservados.683Arq Bras Endocrinol Metab. 2010;54/8Long-term use of sulfonylurea in KCNJ11 diabetesPATIEnT PRESEnTATIOnThe patient, who is currently 29 years of age, was di-agnosed with diabetes in the third month of life during a ketoacidosis episode. Insulin treatment was initiated at that time and even on intensive insulin therapy, his glucose control was erratic with marked hyperglycemia. His growth curve was consistently along the 10th per-centile for height. During follow-up a delay in motor milestones was observed: the proband started walking autonomously only at 28 months. No muscle weakness or lower limb hypotonia was present. Crisis of general-ized seizures started at age 5 during episodes of hy-poglycemia, mainly in nocturnal period. His EEG was normal. He also showed severe learning difficulties and very poor attention and despite receiving special educa-tion little improvement was achieved. At the age of 26 years, informed consent for ge-netic analysis was obtained from the proband’s parents. A blood sample was obtained and genomic DNA was extracted from peripheral blood leukocytes using a commercial kit (Puregene DNA Isolation Kit, Gentra System, Minneapolis, MN, USA). The single exon of KCNJ11 was amplified by PCR in three overlapping fragments. The PCR products were directly sequenced with the use of Big Dye Terminator Cycle Sequenc-ing Reaction Kit version 3.1 and analyzed on an ABI Prism 3100 Genetic Analyzer (Applied Biosystems, CA, USA). The proband was found to have a hetero-zygous change of guanine to adenine on nucleotide 158, which resulted in glycine to aspartic acid substi-tution at codon 53 (p.G53D, c.158G>A mutation). Both parents were negative for this mutation. On the basis of the genotype and clinical features consisting of neonatal diabetes with developmental delay but not epilepsy, the patient was given a diagnosis of intermedi-ate DEND syndrome. Following the identification of the mutation the patient was transferred from insulin to glibenclamide. The initial response to SU therapy was previously reported (13). After 4 weeks the patient was independent of insulin and using 0.8 mg/kg/day of glibenclamide divided into three doses. During the following 3 months, as the patient experienced mild hypoglycemic episodes, the glibenclamide dose was reduced to 0.68 mg/kg/day. A 72-hour continuous glucose monitoring system (CGMS, Medtronic Min-imed, Sylmar CA, USA) showed mean glucose of 108 mg/dL with 71% of glycemic values between 80 and 200 mg/dL and 1% values above 200 mg/dL (Fig-ure 1A). HbA1c levels reduced from 8.2% to 7.6% 3 months after the transfer. A weight loss of 3.8 kg was observed in the first 8 weeks of SU therapy with sub-sequent weight stabilization. Currently, 30 months af-ter the introduction of SU, good metabolic control is maintained (HbA1c: 6.6%) and the glibenclamide dose was reduced to 0.55 mg/kg/day. During the course of SU therapy no severe hypoglycemic episodes were reported. Another 72-hour continuous glucose moni-toring was performed and showed mean glucose of 107 mg/dL with 80% of glycemic values between 80 and 200 mg/dL and none above 200 mg/dL (Figura 1B). Incipient diabetic nephropathy was diagnosed 9 years ago and therapy with ACE-inhibitors was initiated at that time. Fourteen months after the introducing SU, microalbuminuria in nocturnal collection of urine de-creased from 77 ug/min to 32 ug/min and remained stable through the follow-up period.The investigation was approved by the Ethics Com-mitte of Escola Paulista de Medicina, Universidade Federal de São Paulo.Figure 1. Glucose levels captured by the 72-h continuous glucose monitoring system 3 months (A) and 30 months (B) after switching from insulin to glibenclamide therapy. Each line represents a 24-h period.79400300200Glucose – mg/dL200100003:00 06:00 09:00 12:00Time of day15:00 18:00 21:0079400300200Glucose – mg/dL200100003:00 06:00 09:00 12:00Time of day15:00 18:00 21:00A BCopyright© ABE&M todos os direitos reservados.684 Arq Bras Endocrinol Metab. 2010;54/8Long-term use of sulfonylurea in KCNJ11 diabetesDISCUSSIOnActivating mutations in the genes encoding the ATP-sensitive potassium channel causes failure of this chan-nel to close in response to increased intracellular ATP, thus inhibiting insulin secretion. However, sulfonyl-ureas bind to the SUR1 subunit and close the ATP-sensitive channel by an ATP-independent mechanism resulting in insulin release even in cells with activated mutations in KCNJ11 (14).We describe herein a 30-month experience of sul-fonylurea treatment in an adult patient with interme-diate DEND syndrome due to p.G53D mutation in KCNJ11. Following the transfer from insulin to SU we observed marked improvement in glycemic control that was maintained over the follow-up period, despite decreasing SU doses. No side effects were reported. The successful transfer to SU is consistent with the pre-vious report of a patient with permanent neonatal dia-betes carrying the same mutation (15). To examine the consequences of this mutation, Koster and cols. (15), coexpressed a mutant Kir6.2 subunit containing the p.G53D mutation with the wild-type SUR1 subunit. Channel activity in intact cells was screened by 86Rb+-efflux and ATP sensitivity was measured directly in ex-cised membrane patches (15). The authors have dem-onstrated an increased channel activity and reduced ATP sensitivity by approximately 20 fold in homomeric channels.There are few reports of chronic diabetes complica-tions in patients with neonatal diabetes and the role of SU treatment in their evolution. Klupa and cols. (10) re-ported progression of a pre-existing diabetic retinopathy in a patient whose treatment was transferred from insulin to SU (10). Despite no causal relationship between the retinal changes and SU treatment could be proven, the authors recommend special ophthalmological attention in subjects with pre-existing advanced diabetic retinopa-thy. Our patient had no diabetic retinopathy when sul-fonylurea was initiated and no evidence of this complica-tion was found during the follow-up period. Reduction in microalbuminuria was observed during SU therapy possibly related to the improvement of metabolic con-trol. Klupa and cols. (12) also observed some regression in the albumin/creatinine ratio in one patient.In summary, this case illustrates that switching from insulin to sulfonylurea is safe and promotes sustained im-provement of glycemic control on long-term follow-up. Disclosure: no potential conflict of interest relevant to this article was reported.REFEREnCES1. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slinger-land 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(18):1838-49.2. Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. Mu-tations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phe-notype determined by genotype. Diabetologia. 2006;49(6):1190-7.3. 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 res-ponse to sulfonylurea therapy. Diabetes. 2004;53(10):2713-8.4. Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM. Molecular basis of Kir6.2 mutations associated with neonatal dia-betes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA. 2004;101(50):17539-44.5. Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes. New Clinical Syndromes, New Scientific Insi-ghts, and New Therapy. Diabetes. 2005;54(9): 2503-13.6. 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(5):467-77.7. Tonini G, Bizzarri C, Bonfanti R, Vanelli M, Cerutti F, Faleschini E, et al. Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal dia-betes due to activating mutations of the KCNJ11 (Kir 6.2) gene. Diabetologia. 2006;49(9):2210-3.8. Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Janco-va E, et al. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab. 2007;92(4):1276-82.9. Wagner VM, Kremke B, Hiort O, Flanagan SE, Pearson ER. Transi-tion from insulin to sulfonylurea in a child with diabetes due to a mutation in KCNJ11 encoding Kir6.2 – initial and long-term res-ponse to sulfonylurea therapy. Eur J Pediatr. 2009;168(3):359-61.10. Klupa T, Skupien J, Mirkiewicz-Sieradzka B, Gach A, Noczynska A, Szalecki M, et al. Diabetic retinopathy in permanent neonatal diabetes due to Kir6.2 gene mutations: the results of a minimum 2-year follow-up after the transfer from insulin to sulphonylurea. Diabet Med. 2009;26(6):659-64.11. Begum-Hasan J, Polychronakos C, Brill H. Familial permanent ne-onatal diabetes with KCNJ11 mutation and the response to glybu-ride therapy-a three-year follow-up. J Pediatr Endocrinol Metab. 2008;21(9):895-903.12. Klupa T, Skupien J, Mirkiewicz-Sieradzka B, Gach A, Noczynska A, Zubkiewicz-Kucharska A, et al. Efficacy and safety of sulfonylurea use in permanent neonatal diabetes due to KCNJ11 gene mutations: 34-month median follow-up. Diabetes Technol Ther. 2010;12(5):387-91.13. Gurgel LC, Crispim F, Noffs MH, Belzunces E, Rahal MA, Moi-sés RS. Sulfonylurea treatment in permanent neonatal diabe-tes due to G53D mutation in the KCNJ11 gene: improvement in glycemic control and neurological function. Diabetes Care. 2007;30(11):e108.14. Koster JC, Remedi MS, Dao C, Nichols CG. ATP and sulfonylu-rea sensitivity of mutant ATP-sensitive K+ channels in neonatal diabetes: implications for pharmacogenomic therapy. Diabetes. 2005;54(9):2645-54.15. Koster JC, Cadario F, Peruzzi C, Colombo C, Nichols CG, Bar-betti F. The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. J Clin Endocrinol Metab. 2008;93(3):1054-61.

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Resposta a longo prazo com sulfonilureia em um paciente com diabetes associado à mutação no gene KCNJ11

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