(D-Ser2)Oxm[mPEG-PAL]: A novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions
(D-Ser2)Oxm[mPEG-PAL]: A novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions
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DOI：
10.1016/j.bcp.2010.08.010
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发表时间：
2010-12-01
影响因子：
5.8
通讯作者：
Gault, Victor A.
中科院分区：
文献类型：
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作者：
Kerr, Barry D.;Flatt, Peter R.;Gault, Victor A.
氧合酶调节蛋白(OXM)是一种激素，已被证明具有缓解肥胖-糖尿病的一系列潜在的有益作用。然而，由于二肽基肽酶-IV(DPP-IV)的降解，基于OXM的治疗方法的开发受到了严重限制。因此，本研究的目的是评价化学修饰的、酶抗性的OXM类似物(D-Ser(2)OXM和(D-Ser(2))OXM[mpeg-PAL])的降糖、胰岛素释放和厌氧作用，并与DPP-IV孵育以评价酶的稳定性，并用胰岛β细胞来评价胰岛素的分泌。用胰升糖素样肽-1(GLP-1)和胰升糖素受体基因转染的细胞检测cAMP的产生。在体内研究了OXM类似物对肥胖糖尿病(ob/ob)小鼠血糖稳态、胰岛素分泌、摄食量和体重的影响。与(D-Ser(2))OXM和OXM相比，(D-Ser(2))OXM[mpeg-PAL]对DPP-IV的抗性增强。所有多肽在体外都表现出相似的cAMP和胰岛素释放作用，这与GLP-1和GLP-1受体的双重作用有关。急性给予(D-Ser(2))OXM[mpeg-PAL]和(D-Ser(2))OXM可降低血糖和食物摄入量，同时升高血浆胰岛素水平。Ob/ob小鼠每日给药一次(D-Ser(2))OXM[mpeg-pal]14天，可降低摄食量、体重、血糖和升高血浆胰岛素。此外，每日(D-Ser(2))OXM[mpeg-pal]改善糖耐量，增加葡萄糖介导的胰岛素分泌，胰腺胰岛素含量，脂联素，并降低内脂素和甘油三酯水平。酶抗性(D-Ser(2))OXM[mpeg-PAL]改善葡萄糖稳态、胰岛素分泌、饱腹感、体重和脂肪代谢标记物的能力表明，基于OXM的肥胖-糖尿病治疗具有重要的前景。(C)2010 Elsevier Inc.版权所有
Oxyntomodulin (Oxm) is a hormone which has been shown to exhibit a range of potentially beneficial actions for alleviation of obesity-diabetes However, exploitation of Oxm-based therapies has been severely restricted due to degradation by the enzyme dipeptidylpeptidase-IV (DPP-IV). Thus, the aim of this study was to assess the glucose-lowering, insulin-releasing and anorexigenic actions of chemically modified, enzyme-resistant analogues of Oxm Oxm, (D-Ser(2))Oxm and (D-Ser(2))Oxm[mPEG-PAL], were incubated with DPP-IV to assess enzyme stability and pancreatic beta-cells to evaluate insulin secretion. cAMP production was assessed using glucagon-like peptide-1 (GLP-1) and glucagon receptor transfected cells. In vivo effects of Oxm analogues on glucose homeostasis, insulin secretion, food Intake and bodyweight were examined in obese diabetic (ob/ob) mice. (D-Ser(2))Oxm[mPEG-PAL] displayed enhanced DPP-IV resistance compared to (D-Ser(2))Oxm and Oxm. All peptides demonstrated similar in vitro cAMP and insulin-releasing actions, which was associated with dual action at GLP-1 and glucagon receptors Acute administration of (D-Ser(2))Oxm[mPEG-PAL] and (D-Ser(2))Oxm reduced plasma glucose and food intake, whilst plasma insulin levels were elevated. Once-daily administration of (D-Ser(2))Oxm[mPEG-PAL] for 14 days to ob/ob mice decreased food intake, bodyweight, plasma glucose and increased plasma insulin. Furthermore, daily (D-Ser(2))Oxm[mPEG-PAL] improved glucose tolerance, increased glucose-mediated insulin secretion, pancreatic insulin content, adiponectin and decreased both visfatin and triglyceride levels. The ability of enzyme-resistant (D-Ser(2))Oxm[mPEG-PAL] to improve glucose homeostasis, insulin secretion, satiety, bodyweight and markers of fat metabolism suggests significant promise for Oxm-based therapies for obesity-diabetes. (C) 2010 Elsevier Inc All rights reserved