XOMA 052, an Anti-IL-1β Monoclonal Antibody, Improves Glucose Control and β-Cell Function in the Diet-Induced Obesity Mouse Model
XOMA 052, an Anti-IL-1β Monoclonal Antibody, Improves Glucose Control and β-Cell Function in the Diet-Induced Obesity Mouse Model
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DOI：
10.1210/en.2009-1124
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发表时间：
2010-06-01
期刊：
影响因子：
4.8
通讯作者：
Kantak, Seema
中科院分区：
文献类型：
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作者：
Owyang, Alexander M.;Maedler, Kathrin;Kantak, Seema
最近的证据表明，IL-1β介导的糖毒性在2型糖尿病中起着重要作用。尽管以前的工作表明抑制IL-1β可以改善血糖控制和β细胞功能，但我们假设，用一种新的单抗XOMA 052更有效地靶向IL-1β将揭示对影响代谢性疾病的其他参数的影响。在饮食诱导肥胖模型中，XOMA 052被给予喂食正常或高脂饮食(HFD)的小鼠长达19wk。Xoma 052作为预防治疗或治疗给予。对小鼠进行葡萄糖耐量、胰岛素耐量、胰岛素分泌和血脂谱分析。此外，还分析了胰腺中的β细胞凋亡、增殖和β细胞质量。服用HFD的小鼠表现出葡萄糖和糖化血红蛋白水平升高，糖耐量和胰岛素分泌受损，以及血脂水平升高，这些都可以被XOMA 052预防。Xoma 052还减少了β细胞的凋亡，促进了β细胞的增殖。Xoma 052维持了HFD诱导的β细胞质量的代偿性增加，同时也防止了因延长HFD喂养而出现的β细胞质量的损失。对空腹胰岛素和血糖水平的分析表明，XOMA 052预防了HFD诱导的胰岛素抵抗。这些研究提供了新的证据，表明在体内靶向IL-1β可以改善胰岛素敏感性，并导致β细胞的保留。这是对先前报道的血糖控制益处的补充。综上所述，这些数据表明，XOMA 052可能对治疗2型糖尿病的许多方面有效。(内分泌学151：2515-2527,2010)
Recent evidence suggests that IL-1 beta-mediated glucotoxicity plays a critical role in type 2 diabetes mellitus. Although previous work has shown that inhibiting IL-1 beta can lead to improvements in glucose control and beta-cell function, we hypothesized that more efficient targeting of IL-1 beta with a novel monoclonal antibody, XOMA 052, would reveal an effect on additional parameters affecting metabolic disease. In the diet-induced obesity model, XOMA 052 was administered to mice fed either normal or high-fat diet (HFD) for up to 19 wk. XOMA 052 was administered as a prophylactic treatment or as a therapy. Mice were analyzed for glucose tolerance, insulin tolerance, insulin secretion, and lipid profile. In addition, the pancreata were analyzed for beta-cell apoptosis, proliferation, and beta-cell mass. Mice on HFD exhibited elevated glucose and glycated hemoglobin levels, impaired glucose tolerance and insulin secretion, and elevated lipid profile, which were prevented by XOMA 052. XOMA 052 also reduced beta-cell apoptosis and increased beta-cell proliferation. XOMA 052 maintained the HFD-induced compensatory increase in beta-cell mass, while also preventing the loss in beta-cell mass seen with extended HFD feeding. Analysis of fasting insulin and glucose levels suggests that XOMA 052 prevented HFD-induced insulin resistance. These studies provide new evidence that targeting IL-1 beta in vivo could improve insulin sensitivity and lead to beta-cell sparing. This is in addition to previously reported benefits on glycemic control. Taken together, the data presented suggest that XOMA 052 could be effective for treating many aspects of type 2 diabetes mellitus. (Endocrinology 151: 2515-2527, 2010)