Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations
Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations
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DOI：
10.1056/nejmoa061759
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发表时间：
2006-08-03
影响因子：
158.5
通讯作者：
Hattersley, Andrew T.
中科院分区：
文献类型：
--
作者：
Pearson, Ewan R.;Flechtner, Isabelle;Hattersley, Andrew T.
背景：编码ATP敏感钾（K（亚ATP））通道Kir6.2亚基的KCNJ11的杂合激活突变导致30%至58%的6个月以下诊断为糖尿病的患者。伴有酮症酸中毒或严重高血糖的患者，需胰岛素治疗。糖尿病是由于β细胞K（亚ATP）通道因细胞内ATP增加而关闭失败而导致胰岛素分泌受损。磺脲类化合物通过与ATP无关的途径关闭K（亚ATP）通道。方法：我们评估了49例连续接受适当剂量磺脲类药物治疗的Kir6.2突变患者的血糖控制情况，并在较小的亚组中研究了静脉注射和口服葡萄糖、混合膳食和胰高血糖素对胰岛素分泌的反应。在爪蟾卵母细胞中研究了突变体K（亚ATP）通道对磺酰脲磺丁酰胺的反应。结果：44例患者（90%）在接受磺脲类药物治疗后成功停用胰岛素。在体外，甲磺丁胺阻断K（亚ATP）通道的程度反映了在患者中看到的反应。在所有改用磺脲类药物治疗的患者中，糖化血红蛋白水平都有所改善（从治疗前的8.1%提高到治疗12周后的6.4%）
BACKGROUND:Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(sub ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(sub ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(sub ATP) channel by an ATP-independent route.METHODS:We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(sub ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes.RESULTS:A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(sub ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P