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首页> 外文期刊>Cell metabolism >Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus.
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Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus.

机译：β细胞兴奋性的次要后果：在小鼠K（ATP）诱导的新生儿糖尿病模型中的鉴定和预防。

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摘要

ATP-insensitive K(ATP) channel mutations cause neonatal diabetes mellitus (NDM). To explore the mechanistic etiology, we generated transgenic mice carrying an ATP-insensitive mutant K(ATP) channel subunit. Constitutive expression in pancreatic beta cells caused neonatal hyperglycemia and progression to severe diabetes and growth retardation, with loss of islet insulin content and beta cell architecture. Tamoxifen-induced expression in adult beta cells led to diabetes within 2 weeks, with similar secondary consequences. Diabetes was prevented by transplantation of normal islets under the kidney capsule. Moreover, the endogenous islets maintained normal insulin content and secretion in response to sulfonylureas, but not glucose, consistent with reduced ATP sensitivity of beta cell K(ATP) channels. In NDM, transfer to sulfonylurea therapy is less effective in older patients. This may stem from poor glycemic control or lack of insulin because glibenclamide treatment prior to tamoxifen induction prevented diabetes and secondary complications in mice but failed to halt disease progression after diabetes had developed.
机译：ATP不敏感的K（ATP）通道突变会导致新生儿糖尿病（NDM）。为了探索机制的病因，我们生成了携带ATP不敏感突变K（ATP）通道亚基的转基因小鼠。胰腺β细胞中的组成型表达导致新生儿高血糖，并发展为严重的糖尿病和生长迟缓，并伴有胰岛胰岛素含量和β细胞结构的丧失。他莫昔芬诱导的成人β细胞表达在2周内导致糖尿病，并具有类似的继发性后果。通过在肾囊下移植正常的胰岛可以预防糖尿病。此外，内源性胰岛维持正常的胰岛素含量和对磺酰脲类的反应，而不是对葡萄糖的分泌，这与降低的β细胞K（ATP）通道的ATP敏感性相一致。在NDM中，老年患者转用磺酰脲疗法的效果较差。这可能是由于血糖控制不佳或缺乏胰岛素所致，因为在他莫昔芬诱导前进行格列本脲治疗可预防小鼠的糖尿病和继发性并发症，但在糖尿病发生后未能阻止疾病进展。

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