Pancreatic β-cell KATP channels: Hypoglycaemia and hyperglycaemia

Bennett, Kate; James, Chela; Hussain, Khalid

doi:10.1007/s11154-010-9144-2

Cited by 52 publications

(44 citation statements)

References 69 publications

(96 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…KH tedavisinde temel amaç normogliseminin sağ-lanarak beyin hasarının önlenmesidir (16) . Tedavide ilk tercih edilen ilaç insülin salınımını engelleyen diazoksittir (17) .…”

Section: Discussionunclassified

A Neonatal Case of Congenital Hyperinsulinism Due to Homozygous KCNJ11 Gene Mutation

Demirol¹,

Olukman²,

Elmas³

et al. 2017

Terh

View full text Add to dashboard Cite

ÖZKonjenital hiperinsülinizm (KHİ), yenidoğan ve erken infantil dönemde yineleyici veya inatçı ağır hipogliseminin en sık nedenlerinden birisidir. Hastalığın görülme sıklığı toplumlar arasında farklılık göstermekle birlikte, genel populasyondaki sporadik oranlar yaklaşık 40000-50000 canlı doğumda birdir. Araplar, Ashkenazi Yahudileri ve Türkler gibi akraba evliliklerinin yaygın olduğu toplumlarda hastalığın ailesel formlarının görülme oranı 2500 canlı doğumda bire kadar yükselebilir. Etiyolojide sıklıkla pankreatik beta hücrelerinden insülin salınımında rol alan yolaklardaki genetik bozukluklar sorumlu tutulmaktadır. Ancak bugüne dek tanımlanabilen mutasyonların oranı hemen hemen %50 düzeyindedir. KHİ'de en yaygın rastlanan genetik defekt, K+ATP kanallarını oluşturan SUR1 ve Kir. 6,2'yi kodlayan, 11. kromozomda lokalize ABCC8 ve KCNJ11 gen mutasyonlarıdır. Bu makalede homozigot KCNJ11 gen mutasyonuna bağlı KHİ tanısı konulan bir yenidoğan olgusu, hastalığın inatçı ağır neonatal hipogliseminin ayırıcı tanısında önemini vurgulamak ve yüklü aile öyküsü varlığında ileri genetik çalışmaların gerekliliğine dikkat çekmek amacıyla sunulmuş-tur.Anahtar kelimeler: Konjenital hiperinsülinizm, KCNJ11 gen mutasyonu, olgu sunumu ABSTRACT Congenital hyperinsulinism (CHI) is one of the most common causes of recurrent or persistent severe hypoglycemia in the neonatal period and early infancy. Although the incidence may vary widely among different populations, the sporadic rates in the general population is approximately 1/40,000-50,000 live births. The incidence of the familial forms may be as high as 1/2,500 in certain communities like Arabs, Ashkenazi Jews and Turks, in which consanguineous marriages are common. Genetic disorders of the pathways of insulin release from pancreatic beta cells are frequently held responsible for the etiology. However the incidence rate of the identified mutations up to date is nearly 50 percent. The most common genetic defects found in CHI are mutations in the ABCCS and KCNJ11 genes, which are located on chromosome 11p and encode for the SUR1 and Kir 6.2 subunits of the KATP channels. Here we report a newborn infant diagnosed as CHI due to homozygous KCNJ11 gene mutation with the aim of emphasizing the importance of CHI in the differential diagnosis of persistent neonatal hypoglycemia and attracting attention to the necessity of further genetic studies in the presence of strong familial history.

show abstract

“…KH tedavisinde temel amaç normogliseminin sağ-lanarak beyin hasarının önlenmesidir (16) . Tedavide ilk tercih edilen ilaç insülin salınımını engelleyen diazoksittir (17) .…”

Section: Discussionunclassified

A Neonatal Case of Congenital Hyperinsulinism Due to Homozygous KCNJ11 Gene Mutation

Demirol¹,

Olukman²,

Elmas³

et al. 2017

Terh

View full text Add to dashboard Cite

show abstract

“…GSIS is a combination of glucose reception and insulin secretion functions. A number of studies have examined the genetic basis of diabetes and identified specific genes for insulin production (Melloul et al 2001), insulin reception (Kubota et al 2008;Guo et al 2009;Dobrzyn et al 2010), and GSIS (Pal 2009;Bennett et al 2010). It has been speculated that the genes for these various roles are functionally linked.…”

Section: Introductionmentioning

confidence: 99%

Development of novel cell lines of diabetic dysfunction model fit for cell-based screening tests of medicinal materials

et al. 2012

View full text Add to dashboard Cite

Pdx-1 and Irs-1, genes highly associated with diabetes onset, were knocked down in mouse embryonic stem (ES) cells in order to develop cell line models for diabetes. ES cells with different gene knockdown levels were induced to differentiate to the stage of insulin production. Among the cell lines that differentiated, we identified two in which the levels of expression of both genes were 20-40 % of that of control cells. These cell lines showed appreciable deficiencies in three characteristic malfunctions associated with diabetes, namely, insulin production, insulin reception signaling, and glucose-stimulated insulin secretion. These dysfunctions were consistent with results reported elsewhere from in vivo and in vitro studies. Both cell lines did not show any abnormal morphology such as size, shape, color, and surface roughness. No abnormal expression profiles for 17 genes relevant to diabetes were observed. Therefore, these cell lines fulfilled the criteria for a validated cell model for diabetes. The model cell lines developed here are promising biomaterials for cellbased screening tests of new medicines that may be effective in treating diabetes.

show abstract

“…5-5.5 u n c o r r e c t e d p r o o f mmol/L (1,2,3). K ATP channels are open at low glucose levels (1). Increased metabolism, resulting in an increased adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio, leads to closure of the K ATP channel, depolarisation of the beta cell membrane and subsequent calcium influx through voltage-gated calcium channels.…”

mentioning

confidence: 99%

“…In contrast diabetes occurs if K ATP channels remain open despite high blood glucose concentrations and increased metabolism in the beta cell (1,4). Recessive inactivating mutations of the K ATP channel genes (ABCC8 and KCNJ11) are the most common cause of severe diazoxide unresponsive diffuse CHI which usually requires pancreatectomy (1,10). Patients with dominant mutations of K ATP channel genes, ABCC8 and KCNJ11, may cause variable phenotype ranges from asymptomatic macrosomia, mild diazoxide responsive CHI to severe persistent HH as well as diabetes mellitus in later life (7,8,9,11).…”

mentioning

confidence: 99%

“…Patients with dominant mutations of K ATP channel genes, ABCC8 and KCNJ11, may cause variable phenotype ranges from asymptomatic macrosomia, mild diazoxide responsive CHI to severe persistent HH as well as diabetes mellitus in later life (7,8,9,11). CHI within the neonatal period and evolution to diabetes later in life has been reported in individuals with heterozygous inactivating mutations in the Hepatocyte nuclear factor 4A and 1A (HNF4A & HNF1A) (12,13,14) and dominant mutations in ABCC8 genes in very limited number of cases (1,7,11,13,15,16,17,18,19,20,21). To the best of our knowledge, CHI due to homozygous ABCC8 mutations and evolution to complete insulin deficient-diabetes later in life has not been reported.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Isik¹,

Demirbilek²,

Houghton³

et al. 2018

Jcrpe

Self Cite

View full text Add to dashboard Cite

What is already known on this topic?Homozygous ABCC8 mutations cause severe persistent diffuse hyperinsulinemic hypoglycaemia (HH) which is usually diazoxide unresponsive and requires surgical therapy. In medically managed patients with congenital hyperinsulinism (CHI), disease symptoms become milder overtime. Hyperinsulinemic hypoglycemia at neonatal period and later diabetes have been reported in heterozygous mutation of HNF4A and HNF1A as well as heterozygous ABCC8 mutations What this study adds? We describe the first homozygous ABCC8 mutation with HH at neonatal period and evolution to complete insulin deficient, sulphonylurea responsive diabetes mellitus. Findings from present work which show a broad range of clinical spectrum from asymptomatic, mild symptomatic hypoglycemia, severe hypoglycemia as well as insulin deficient diabetes mellitus in family members with identical mutation confirms the phenotypical variations in ABCC8 mutations Present case report emphasizes the need for long-term follow up of patients with HH at neonatal period due to ABCC8 mutations, particularly those managed with medical therapy for risk of developing diabetes in later life. Abstract:Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. Recessive inactivating mutations in the ABCC8 and KCNJ11 genes account for approximately 50 % of all CHI cases. Hyperinsulinaemic hypoglycaemia (HH) in infancy and diabetes in later life have been reported in subjects with HNF1A, HNF4A and ABCC8 mutations. Case report: Herein, we present a child who was diagnosed with CHI at birth, then developed diabetes mellitus at the age of 9 years due to a novel homozygous missense, p.L171F (c.511C>T) mutation in the exon 4 of ABCC8. The parents and one sibling were heterozygous carriers, whilst a younger sibling who had transient neonatal hypoglycemia was homozygous for the mutation. The mother and (maternal) uncle, who was also heterozygous for the mutation, developed diabetes within their third decade of life. The preliminary results of sulphonylurea (SU) treatment was suggestive for SU responsiveness. Patients with homozygous ABCC8 mutations can present with CHI in the newborn period, the hyperinsulinism can show variability in terms of clinical severity and age at presentation and can cause diabetes later in life. Patients with homozygous ABCC8 mutations who are managed medically should be followed as they may be at increased risk of developing diabetes.

show abstract

Pancreatic β-cell KATP channels: Hypoglycaemia and hyperglycaemia

Cited by 52 publications

References 69 publications

A Neonatal Case of Congenital Hyperinsulinism Due to Homozygous KCNJ11 Gene Mutation

A Neonatal Case of Congenital Hyperinsulinism Due to Homozygous KCNJ11 Gene Mutation

Development of novel cell lines of diabetic dysfunction model fit for cell-based screening tests of medicinal materials

Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation

Contact Info

Product

Resources

About