Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel.
Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel.
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作者：
Hamming KS;Soliman D;Matemisz LC;Niazi O;Lang Y;Gloyn AL;Light PE
在胰腺β细胞中，atp敏感的K+ (KATP)通道将代谢与兴奋性结合起来，分别由KCNJ11和ABCC8编码的Kir6.2和SUR1亚基组成。抑制KATP通道的磺脲类药物被用于治疗2型糖尿病。罕见的激活突变导致新生儿糖尿病，而常见的变异，KCNJ11中的E23K和ABCC8中的S1369A，处于强烈的连锁不平衡状态，构成了易患2型糖尿病的单倍型。到目前为止，还不可能确定其中哪一个代表病因变异，功能研究也不一致。此外，还没有关于S1369A变异体或两者对KATP通道功能的联合影响的研究。采用膜片钳技术研究了含有K23/A1369或E23/S1369变异的重组人KATP通道的核苷酸敏感性和磺脲抑制作用。K23/A1369突变体的KATP通道ATP敏感性降低（半最大抑制浓度[IC50] = 8.0 vs. E23/S1369突变体的2.5 μmol/l），但ADP敏感性没有差异。K23/A1369变体对格列齐特（a位点磺脲类药物）的抑制作用也增强（E23/S1369变体的IC50 = 52.7 vs. 188.7 nmol/l），但对格列本脲（AB位点）或瑞格列奈（B位点）没有抑制作用。我们的研究结果表明，常见的K23/A1369变体KATP通道显示ATP抑制降低，这可能导致观察到的2型糖尿病风险增加。此外，K23/A1369变异对a位点磺酰脲类药物格列齐特的敏感性增加，可能为两种风险等位基因纯合的2型糖尿病患者提供药物基因组学治疗方法。
In the pancreatic β-cell, ATP-sensitive K+ (KATP) channels couple metabolism with excitability and consist of Kir6.2 and SUR1 subunits encoded by KCNJ11 and ABCC8, respectively. Sulfonylureas, which inhibit the KATP channel, are used to treat type 2 diabetes. Rare activating mutations cause neonatal diabetes, whereas the common variants, E23K in KCNJ11 and S1369A in ABCC8, are in strong linkage disequilibrium, constituting a haplotype that predisposes to type 2 diabetes. To date it has not been possible to establish which of these represents the etiological variant, and functional studies are inconsistent. Furthermore, there have been no studies of the S1369A variant or the combined effect of the two on KATP channel function. The patch-clamp technique was used to study the nucleotide sensitivity and sulfonylurea inhibition of recombinant human KATP channels containing either the K23/A1369 or E23/S1369 variants. ATP sensitivity of the KATP channel was decreased in the K23/A1369 variant (half-maximal inhibitory concentration [IC50] = 8.0 vs. 2.5 μmol/l for the E23/S1369 variant), although there was no difference in ADP sensitivity. The K23/A1369 variant also displayed increased inhibition by gliclazide, an A-site sulfonylurea drug (IC50 = 52.7 vs. 188.7 nmol/l for the E23/S1369 variant), but not by glibenclamide (AB site) or repaglinide (B site). Our findings indicate that the common K23/A1369 variant KATP channel displays decreased ATP inhibition that may contribute to the observed increased risk for type 2 diabetes. Moreover, the increased sensitivity of the K23/A1369 variant to the A-site sulfonylurea drug gliclazide may provide a pharmacogenomic therapeutic approach for patients with type 2 diabetes who are homozygous for both risk alleles.
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DOI：
10.1016/j.tig.2008.09.004
发表时间：
2008-12
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Prokopenko I;McCarthy MI;Lindgren CM
通讯作者：
Lindgren CM
影响因子：
16.2
作者：
Feng Y;Mao G;Ren X;Xing H;Tang G;Li Q;Li X;Sun L;Yang J;Ma W;Wang X;Xu X
通讯作者：
Xu X
影响因子：
7.7
作者：
Gloyn, AL;Weedon, MN;Frayling, TM
通讯作者：
Frayling, TM
影响因子：
7.7
作者：
Minami, K;Miki, T;Seino, S
通讯作者：
Seino, S
影响因子：
7.7
作者：
Riedel, MJ;Boora, P;Light, PE
通讯作者：
Light, PE