Bechtel Laura K, Haverstick Doris M, Holstege Christopher P
Division of Medical Toxicology, Department of Emergency Medicine, University of Virginia, Charlottesville, VA, USA.
Acad Emerg Med. 2008 Apr;15(4):368-74. doi: 10.1111/j.1553-2712.2008.00088.x.
Recent animal research and clinical case reports suggest benefit from high-dose insulin therapy (HDIT) for the treatment of calcium channel blocker (CCB) toxicity. One molecular signaling pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, that contributes to CCB toxicity and the efficacy of HDIT, was examined for a role in this phenomenon.
A differentiated 3T3-L1 adipocyte model system was utilized to characterize metabolic and molecular signaling events dysregulated in response to acute CCB toxicity. Glucose uptake assays were performed in the presence of representatives of three classes of CCB drugs, and the ability of HDIT to reverse observed inhibition was assessed. Western blot analyses were utilized to probe which insulin-dependent signaling pathway was inhibited by CCB toxicity.
Representative compounds from the dihydropyridine and phenylalkylamine classes of CCBs were more effective at inhibiting glucose uptake in differentiated 3T3-L1 adipocytes than a representative from the benzothiazepine class. Phosphorylation at serine 473 of the Akt protein (P-Akt), a protein representing a common pathway for insulin receptors (IR), insulinlike growth factor receptors (IGFR), and hybrid receptors formed by IR and IGFR subunits, was abolished in the presence of toxic doses of the phenylalkylamine CCB verapamil. Phosphorylation at serine 473 of Akt was rescued in the presence high concentrations of insulin.
These data suggest that dysregulation of the insulin-dependent PI3K pathway is partially responsible for insulin resistance and the hyperglycemic state observed in response to acute CCB toxicity.
近期的动物研究和临床病例报告表明，高剂量胰岛素疗法（HDIT）对治疗钙通道阻滞剂（CCB）中毒有益。研究了一种导致CCB毒性和HDIT疗效的分子信号通路——磷脂酰肌醇3激酶（PI3K）通路在这一现象中的作用。
利用分化的3T3-L1脂肪细胞模型系统来表征因急性CCB毒性而失调的代谢和分子信号事件。在三类CCB药物的代表物存在的情况下进行葡萄糖摄取试验，并评估HDIT逆转所观察到的抑制作用的能力。利用蛋白质免疫印迹分析来探究CCB毒性抑制了哪条胰岛素依赖性信号通路。
与苯并噻氮䓬类的一种代表物相比，二氢吡啶类和苯烷基胺类CCB的代表性化合物在抑制分化的3T3-L1脂肪细胞中的葡萄糖摄取方面更有效。在存在毒性剂量的苯烷基胺类CCB维拉帕米的情况下，Akt蛋白（P-Akt）丝氨酸473处的磷酸化被消除，Akt蛋白代表胰岛素受体（IR）、胰岛素样生长因子受体（IGFR）以及由IR和IGFR亚基形成的杂合受体的共同信号通路。在高浓度胰岛素存在的情况下，Akt丝氨酸473处的磷酸化得以恢复。
这些数据表明，胰岛素依赖性PI3K通路的失调部分导致了急性CCB毒性反应中观察到的胰岛素抵抗和高血糖状态。
