Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this “glucose effectiveness” is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.

中文翻译：

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中央 KATP 通道调节人类和啮齿动物的葡萄糖有效性

高血糖是内源性葡萄糖生成 (EGP) 的有效调节剂。这种“葡萄糖有效性”的丧失是导致 2 型糖尿病 (T2D) 血浆葡萄糖浓度升高的主要因素。中枢神经系统中的 KATP 通道已被证明可以调节人类和啮齿动物的 EGP。我们检查了中央 KATP 通道对葡萄糖有效性的贡献。在固定的荷尔蒙条件下（使用胰腺钳的研究），在没有糖尿病的人和正常的 Sprague-Dawley 大鼠中，高血糖将 EGP 抑制了约 50%。相比之下，KATP 通道与格列本脲的拮抗作用显着降低了人和大鼠高血糖的 EGP 降低作用。此外，通过在大鼠脑室内施用 KATP 通道激动剂二氮嗪，格列本脲对 EGP 和糖异生酶的影响被消除。这些发现表明，高血糖对 EGP 的抑制大约有一半是由中枢 KATP 通道介导的。这些中心机制可能为改善 T2D 患者的血糖控制提供新的治疗靶点。