a Division of Endocrinology, Department of Pediatrics , The Children's Hospital of Philadelphia , Philadelphia , Pennsylvania.
b XOMA Corporation , Berkeley , California.
MAbs. 2018 Jul;10(5):796-802. doi: 10.1080/19420862.2018.1457599. Epub 2018 Jun 1.
Loss-of-function mutations of the ß-cell ATP-sensitive potassium channels (K) cause the most common and severe form of congenital hyperinsulinism (KHI), a disorder of ß-cell function characterized by severe hypoglycemia. Children with KHI are typically unresponsive to medical therapy and require pancreatectomy for intractable hypoglycemia. We tested the hypothesis that inhibition of insulin receptor signaling may prevent hypoglycemia in KHI. To test this hypothesis, we examined the effect of an antibody allosteric inhibitor of the insulin receptor, XMetD, on fasting plasma glucose in a mouse model of KHI (SUR-1 mice). SUR-1 and wild-type mice received twice weekly intraperitoneal injections of either XMetD or control antibody for 8 wks. Treatment with XMetD significantly decreased insulin sensitivity, and increased hepatic glucose output and fasting plasma glucose. These findings support the potential use of insulin receptor antagonists as a therapeutic approach to control the hypoglycemia in congenital hyperinsulinism.
β细胞三磷酸腺苷敏感性钾通道（K）的功能丧失性突变导致最常见和最严重形式的先天性高胰岛素血症（KHI），这是一种β细胞功能障碍的疾病，其特征是严重低血糖。患有 KHI 的儿童通常对药物治疗无反应，需要进行胰腺切除术以治疗难治性低血糖。我们检验了抑制胰岛素受体信号转导可能预防 KHI 低血糖的假说。为了检验这一假说，我们在 KHI 的小鼠模型（SUR-1 小鼠）中研究了胰岛素受体的一种变构抑制剂 XMetD 对空腹血糖的影响。SUR-1 和野生型小鼠每周接受两次腹腔注射 XMetD 或对照抗体，共 8 周。用 XMetD 治疗显著降低了胰岛素敏感性，增加了肝葡萄糖输出和空腹血糖。这些发现支持将胰岛素受体拮抗剂用作治疗方法来控制先天性高胰岛素血症的低血糖。
