A mutation in KCNJ11 causing human hyperinsulinism (Y12X) results in a glucose-intolerant phenotype in the mouse.
A mutation in KCNJ11 causing human hyperinsulinism (Y12X) results in a glucose-intolerant phenotype in the mouse.
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DOI：
10.1007/s00125-010-1866-x
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发表时间：
2010-11
期刊：
影响因子：
8.2
通讯作者：
Cox RD
中科院分区：
文献类型：
--
作者：
Hugill A;Shimomura K;Ashcroft FM;Cox RD
我们鉴定了一只在KATP通道的KCNJ11亚基中具有点突变（Y12STOP）的小鼠，该突变与在婴儿期先天性高胰岛素血症（HI）患者中发现的突变相同。我们的目的是表征这种功能丧失突变引起的表型，并将其与其他小鼠模型和HI患者的表型进行比较。通过测量葡萄糖和胰岛素血浆浓度的腹腔葡萄糖耐量试验，研究了n -乙基-n -亚硝基脲（ENU）诱导的C3H/HeH背景突变（Kcnj11Y12STOP）的表型。在离体胰岛上测量胰岛素分泌和对肠促胰岛素的反应。纯合子雄性和雌性成年Kcnj11Y12STOP小鼠在体内和体外均表现出糖耐量受损和胰岛素分泌缺陷。胰岛的肠促胰岛素反应受损，胰岛素含量降低。纯合子Kcnj11Y12STOP小鼠的表型与其他Kcnj11敲除小鼠模型一致。与纯合携带该突变的患者相反，我们没有观察到高胰岛素血症或低血糖。据报道，HI患者可能发展为糖尿病，我们的小鼠模型可能反映了这一临床特征。因此，Kcnj11Y12STOP模型可能有助于进一步研究各种细胞类型中的KATP通道功能，并研究HI患者高血糖的发生。
We identified a mouse with a point mutation (Y12STOP) in the KCNJ11 subunit of the KATP channel that is identical to that found in a patient with congenital hyperinsulinism of infancy (HI). We aimed to characterise the phenotype arising from this loss-of-function mutation and to compare it to that of other mouse models and patients with HI. An N-ethyl-N-nitrosourea (ENU) induced mutation on a C3H/HeH background (Kcnj11Y12STOP) was phenotyped using intraperitoneal glucose tolerance testing measuring both glucose and insulin plasma concentrations. Insulin secretion and response to incretins was measured on isolated islets. Homozygous male and female adult Kcnj11Y12STOP mice exhibit impaired glucose tolerance and a defect in insulin secretion measured both in vivo and in vitro. Islets had an impaired incretin response and reduced insulin content. The phenotype of homozygous Kcnj11Y12STOP mice is consistent with that of other Kcnj11 knockout mouse models. In contrast to the patient carrying this mutation homozygously, we did not observe hyperinsulinaemia or hypoglycaemia. It has been reported that HI patients may develop diabetes and our mouse model may reflect this clinical feature. The Kcnj11Y12STOP model may thus be useful in further studies of KATP channel function in various cell types and in the investigation of the development of hyperglycaemia in HI patients.
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