Sustained delivery of IL-1Ra from PF127-gel reduces hyperglycemia in diabetic GK-rats.
Sustained delivery of IL-1Ra from PF127-gel reduces hyperglycemia in diabetic GK-rats.
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DOI：
10.1371/journal.pone.0055925
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Akash MS;Rehman K;Sun H;Chen S
白细胞介素-1 β（IL-1β）是诱导各种炎症机制的主要原因，这些炎症机制决定性地参与了2型糖尿病（T2 DM）的发病机制。白细胞介素-1受体拮抗剂（IL-1 Ra）是一种天然存在的IL-1β抗炎拮抗剂，最近已被批准用于治疗T2 DM，但由于其半衰期短，需要更高的剂量和频繁的给药间隔。Pluronic F-127（PF 127）以前已经显示出延长各种蛋白质药物的释放及其血清半衰期。随后，在我们以前的工作中，我们开发了一种新的剂型IL-1 Ra使用PF 127，并研究其在体外和体内的影响。在这里，在目前的工作中，我们已经扩展了这种方法，使用糖尿病Goto-kakizaki（GK）大鼠。我们将负载于PF 127凝胶中的IL-1 Ra皮下注射给GK大鼠一个月。IL-1 Ra负载于PF 127凝胶中对治疗的动物表现出持续和延长的降血糖作用。腹腔葡萄糖耐量试验（IPGTT）结果显示，负载IL-1 Ra的PF 127凝胶可沿着增加大鼠的葡萄糖耐量，同时增加胰岛素敏感性和β细胞分泌功能。此外，还观察到胰岛素原/胰岛素比值、脂质谱和白细胞介素6（IL-6）显著降低。免疫组化显示胰岛内有少量巨噬细胞浸润。组织化学分析显示，PF 127未诱导给药动物皮肤和肾脏的正常生理学改变。因此，我们得出结论，负载在PF 127凝胶中的IL-1 Ra具有表现出广谱抗炎作用的潜力，从而减轻T2 DM的症状。
Interleukin-1beta (IL-1β) is a major cause for induction of various inflammatory mechanisms that are decisively involved to provoke pathogenesis of type 2 diabetes mellitus (T2DM). Interleukin-1 receptor antagonist (IL-1Ra) a naturally occurring anti-inflammatory antagonist of IL-1β has been recently approved for treatment of T2DM but due to its short half-life, higher doses and frequent dosing intervals are required. Pluronic F-127 (PF127) has previously shown to prolong the release of various proteinous drugs and their serum half-lives. Subsequently, in our previous work, we developed a new dosage form of IL-1Ra using PF127 and investigated its in-vitro and in-vivo effects. Here in present work, we have extended this approach using diabetic Goto-kakizaki (GK) rats. We administered IL-1Ra loaded in PF127 gel subcutaneously for one month into GK rats. IL-1Ra loaded in PF127 gel exhibited a sustained and prolonged hypoglycemic effects on treated animals. Intraperitoneal glucose tolerance test (IPGTT) results showed that IL-1Ra loaded in PF127 gel increased glucose tolerance along with increased insulin sensitivity and β-cell’s secretory function in treated rats. Moreover, significant reduction in pro-insulin/insulin ratio, lipid profiles and interleukin 6 (IL-6) were also observed. Immunohistochemical analysis showed slight macrophages infiltration in pancreatic islets. Histochemical analysis revealed no PF127-induced alteration in the normal physiology of skin and kidney of treated animals. Hence, we concluded that IL-1Ra loaded in PF127 gel has potential to exhibit broad spectrum anti-inflammatory effects alleviating the symptoms of T2DM.
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