A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults.
A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults.
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作者：
Tarasov AI;Nicolson TJ;Riveline JP;Taneja TK;Baldwin SA;Baldwin JM;Charpentier G;Gautier JF;Froguel P;Vaxillaire M;Rutter GA
ATP 敏感 K+ (KATP) 通道将葡萄糖代谢与胰腺 β 细胞的电活动联系起来，从而调节胰岛素分泌。此前已证明该通道的 Kir6.2 或 SUR1 亚基突变会导致新生儿糖尿病。我们在此描述了编码 SUR1 的 ABCC8 基因的激活突变，该突变仅与成人 2 型糖尿病的发展相关。使用基于 pIRES2 的载体在 HEK293 或 INS1(832/13) 细胞中表达重组 KATP 通道亚基，并通过共聚焦显微镜分析 c-myc 标记的 SUR1 通道的亚细胞分布。在由内而外的斑块中测量 KATP 通道活性，并在穿孔的全细胞斑块中测量质膜电位。使用 Fura-red 对细胞质 [Ca2+] 进行成像。在一名 39 岁时诊断出高血糖的患者和两名胰岛素分泌受损的成年后代中观察到 ABCC8/SUR1 的突变，导致第七跨膜 α 螺旋中的 Y356C 取代。整合 Y356C-SUR1 的单个 KATP 通道对 MgATP 表现出较低的敏感性（野生型和突变型通道的 IC50 分别为 24μmol/l 和 95μmol/l）。在不存在 Mg2+ 的情况下观察到类似的效应，表明通过相关的 Kir6.2 通道产生变构效应。 Y356C-SUR1 在 INS1(832/13) 细胞中的过度表达会损害葡萄糖诱导的细胞去极化并增加细胞内游离 Ca2+ 浓度，尽管比新生儿糖尿病相关的 SUR1 突变体更弱。 ABCC8/SUR1 突变对 KATP 通道活性和 β 细胞葡萄糖感应影响相对较小，可导致成年糖尿病。这些数据表明 SUR1 特性改变与临床表型之间存在密切相关性。
ATP-sensitive K+ (KATP) channels link glucose metabolism to the electrical activity of the pancreatic β-cell to regulate insulin secretion. Mutations in either the Kir6.2 or SUR1 subunit of the channel have previously been shown to cause neonatal diabetes. We describe here an activating mutation in the ABCC8 gene, encoding SUR1, that is associated with the development of type 2 diabetes mellitus only in adults. Recombinant KATP channel subunits were expressed using pIRES2-based vectors in HEK293 or INS1(832/13) cells and the subcellular distribution of c-myc-tagged SUR1 channels analysed by confocal microscopy. KATP channel activity was measured in inside-out patches, and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca2+] was imaged using Fura-red. A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning α-helix, was observed in a patient diagnosed with hyperglycemia at age 39, and in two adult offspring with impaired insulin secretion. Single KATP channels incorporating Y356C-SUR1 displayed lower sensitivity to MgATP (IC50=24μmol/l and 95μmol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg2+, suggesting an allosteric effect via associated Kir6.2 channels. Over-expression of Y356C-SUR1 in INS1(832/13) cells impaired glucose-induced cell depolarisation and increases in intracellular free Ca2+ concentration, albeit more weakly than neonatal diabetes-associated SUR1 mutants. An ABCC8/SUR1 mutation with relatively minor effects on KATP channel activity and β-cell glucose sensing causes diabetes in adulthood. These data suggest a close correlation between altered SUR1 properties and clinical phenotype.
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