Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

Slingerland, Annabelle S.; Nuboer, Roos; Hadders‐Algra, Mijna; Hattersley, Andrew T.; Bruining, G. J.

doi:10.1007/s00125-006-0407-0

Cited by 116 publications

(94 citation statements)

References 22 publications

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“…The effectiveness of oral sulfonylurea in improving glycemic control of diabetic patients due to KCNJ11 mutations after transfer from insulin therapy has been confi rmed by many reports, with doses ranging from 0.05 to 1.5 mg/kg/d (12)(13)(14)(15)(16)(17); however data concerning the use of sulfonylurea in the treatment of PNDM with DEND syndrome have shown variable results. Several mutations related to severe DEND syndrome (Q52R, G53R, V59G, I296L, G334D) are insensitive to glibenclamide (4,12,19,20); nevertheless in some forms of intermediate DEND syndrome (I167L, G53D, H46L, V59M), characterized by less severe developmental delay and without epilepsy, glibenclamide therapy has improved metabolic control, neuromuscular symptoms (17,(21)(22)(23)(24) and even cognition (V59M) (25).…”

Section: Discussionmentioning

confidence: 99%

“…Several mutations related to severe DEND syndrome (Q52R, G53R, V59G, I296L, G334D) are insensitive to glibenclamide (4,12,19,20); nevertheless in some forms of intermediate DEND syndrome (I167L, G53D, H46L, V59M), characterized by less severe developmental delay and without epilepsy, glibenclamide therapy has improved metabolic control, neuromuscular symptoms (17,(21)(22)(23)(24) and even cognition (V59M) (25). Evidence that sulfonylurea could change CNS blood fl ow and function was provided by the use of Figure 1.…”

Section: Discussionmentioning

confidence: 99%

“…So the identifi cation of a KCNJ11 mutation has implications for clinical management since many patients have been treated successfully with oral sulphonylureas rather than insulin (12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Manna

Battistim

Radonsky

et al. 2008

Arq Bras Endocrinol Metab

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Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (PNDM) and several cases have been successfully treated with oral sulfonylureas. We report on the attempted transfer of insulin therapy to glibenclamide in a 4-year old child with PNDM and DEND syndrome, bearing a C166Y mutation in KCNJ11. An inpatient transition from subcutaneous NPH insulin (0.2 units/kg/d) to oral glibenclamide (1 mg/ kg/d and 1.5 mg/kg/d) was performed. Glucose and C-peptide responses stimulated by oral glucose tolerance test (OGTT), hemoglobin A1c levels, the 8-point self-measured blood glucose (SMBG) profi le and the frequency of hypoglycemia episodes were analyzed, before and during treatment with glibenclamide. Neither diabetes control nor neurological improvements were observed. We concluded that C166Y mutation was associated with a form of PNDM insensitive to glibenclamide. RESUMO Falha de resposta à Glibenclamida em Criança Brasileira com Diabetes MelitoNeonatal Permanente e Síndrome DEND Devido a Mutação C166Y no Gene KCNJ11 (Kir6.2). As mutações ativadoras, heterozigóticas do gene KCNJ11 (Kir6.2) são a causa mais freqüente de diabetes melito neonatal permanente (DMNP) e a terapêu-tica oral com sulfoniluréias tem sido bem sucedida em muitos destes casos. Relatamos o processo de substituição da insulinoterapia convencional para o tratamento oral com glibenclamida em uma paciente de 4 anos, portadora de DMNP e síndrome DEND devido a uma mutação C166Y no gene KCNJ11. A insulina NPH (0,2 U/kg/dia) foi substituída pela glibenclamida (1 mg/kg/dia e 1,5 mg/kg/dia) durante internação hospitalar. As respostas de glicose e peptídeo-C no teste de tolerância oral à glicose (OGTT), os níveis de hemoglobina glicada, o perfi l de glicemias capilares de 8 pontos e a freqüência de hipoglicemias foram comparados antes e durante o tratamento com glibenclamida. Não houve melhora no controle glicêmico, nem no quadro neurológico. Concluímos que a mutação C166Y associa-se a uma forma de DMNP insensível à glibenclamida.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Manna

Battistim

Radonsky

et al. 2008

Arq Bras Endocrinol Metab

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“…In contrast, insulin secretion from β-V59M islets was stimulated by tolbutamide; this is expected because the drug bypasses the metabolic steps and blocks K ATP channels directly (31), thereby triggering membrane depolarization and insulin secretion. Although V59M K ATP channels are blocked less potently by sulfonylureas, this is still sufficient to elicit secretion in β-V59M mice and in human patients (32). In vivo, the lower insulin content and reduced β cell number of β-V59M islets are also expected to contribute to the hypoinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes

Girard¹,

Wunderlich²,

Shimomura³

et al. 2008

J. Clin. Invest.

145

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Neonatal diabetes is a rare monogenic form of diabetes that usually presents within the first six months of life. It is commonly caused by gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of the plasmalemmal ATP-sensitive K + (K ATP ) channel. To better understand this disease, we generated a mouse expressing a Kir6.2 mutation (V59M) that causes neonatal diabetes in humans and we used Cre-lox technology to express the mutation specifically in pancreatic β cells. These β-V59M mice developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Islets isolated from β-V59M mice secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose. This was due to a reduced sensitivity of K ATP channels in pancreatic β cells to inhibition by ATP or glucose. In contrast, the sulfonylurea tolbutamide, a specific blocker of K ATP channels, closed K ATP channels, elevated intracellular calcium levels, and stimulated insulin release in β-V59M β cells, indicating that events downstream of K ATP channel closure remained intact. Expression of the V59M Kir6.2 mutation in pancreatic β cells alone is thus sufficient to recapitulate the neonatal diabetes observed in humans. β-V59M islets also displayed a reduced percentage of β cells, abnormal morphology, lower insulin content, and decreased expression of Kir6.2, SUR1, and insulin mRNA. All these changes are expected to contribute to the diabetes of β-V59M mice. Their cause requires further investigation.

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“…In case of the CNS symptoms, this would depend on the ability of sulphonylureas to cross the blood-brain barrier (BBB). Although it is not clear to what extent sulphonylureas can cross BBB, early studies of iDEND patients treated with sulphonylureas suggested that sulphonylurea drugs can indeed treat CNS symptoms [57,62,63].…”

Section: Implications For Therapymentioning

confidence: 99%

The KATP Channel and Neonatal Diabetes

Shimomura

2009

Endocr J

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Abstract. ATP-sensitive potassium (K ATP ) channels play a key role in glucose-dependent insulin secretion in pancreatic β-cells. Recently, activating mutations in β-cell K ATP channels were found to be an important cause of neonatal diabetes. In some patients, these mutations may also affect K ATP channel function in muscles, nerves and brain which can result in a severe disease termed DEND syndrome (Developmental delay, Epilepsy and Neonatal Diabetes). This review focuses on mutations in the pore-forming K ATP channel subunit (Kir6.2) that cause neonatal diabetes and discusses recent advances in our understanding of clinical features of neonatal diabetes, its underlying molecular mechanisms and their impact on treatment.

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Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

Cited by 116 publications

References 22 publications

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes

The KATP Channel and Neonatal Diabetes

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