(D-Ser2)Oxm[Lys38-γ-glu-PAL] improves hippocampal gene expression and cognition in a mouse model of type 1 diabetes -

N. Pathak, N. Irwin, V. Pathak, V. Gault, P. Flatt
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引用次数: 2

Abstract

Objective: Oxyntomodulin (Oxm) is a gastrointestinal hormone with recently noted therapeutic potential for type 1 diabetes mellitus (T1DM). The present study examined the effects of a stable Oxm analogue on anxiety, exploratory behavior, cognitive function, hippocampal gene expression and metabolic control in a mouse model of T1DM. Materials and Methods: Effects of twice daily administration of the stable Oxm analogue, (D-Ser2)Oxm[Lys38-γ-glu-PAL], was assessed in insulin-deficient streptozotocin (STZ)-induced T1DM mice. Results: Induction of diabetes by STZ injection significantly (P < 0.05) impaired learning and memory compared to normal control mice. However, (D-Ser2)Oxm[Lys38-γ-glu-PAL] treatment completely reversed this detrimental effect. Anxiety levels and exploratory behavior were not significantly different between all groups of mice. Hippocampal gene expression of MASH1, SYP and mTOR were reduced (P < 0.01 to P < 0.001) in T1DM mice, but significantly (P < 0.05 to P < 0.001) enhanced by twice daily (D-Ser2)Oxm[Lys38-γ-glu-PAL] intervention. Moreover, expression of SYP, mTOR and IRS-1 were significantly elevated (P < 0.05 to P < 0.001) in (D-Ser2)Oxm[Lys38-γ-glu-PAL] mice compared to both STZ and lean controls. These effects were accompanied by improved (P < 0.001) glucose tolerance and insulin sensitivity compared to STZ controls. Conclusion: The data highlight the potential of (D-Ser2)Oxm[Lys38-γ-glu-PAL] for the treatment of T1DM, and reveal the ability of this Oxm analogue to restore the deficits of learning and memory observed in STZ-induced T1DM.
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(D-Ser2)Oxm[Lys38-γ-glu- pal]改善1型糖尿病小鼠模型海马基因表达和认知
目的:氧合调节素(Oxm)是一种胃肠道激素,近年来被认为具有治疗1型糖尿病(T1DM)的潜力。本研究研究了一种稳定的Oxm类似物对T1DM小鼠模型的焦虑、探索行为、认知功能、海马基因表达和代谢控制的影响。材料与方法:观察稳定的Oxm类似物(D-Ser2)Oxm[Lys38-γ-glu-PAL]每日两次给药对胰岛素缺乏型链脲佐菌素(STZ)诱导的T1DM小鼠的影响。结果:与正常对照组相比,STZ注射液诱导的糖尿病小鼠学习记忆功能明显受损(P < 0.05)。然而,(D-Ser2)Oxm[Lys38-γ- glul - pal]处理完全逆转了这种有害作用。各组小鼠的焦虑水平和探索行为无显著差异。T1DM小鼠海马MASH1、SYP、mTOR基因表达降低(P < 0.01 ~ P < 0.001),但每日2次(D-Ser2)Oxm[Lys38-γ- glul - pal]干预显著提高(P < 0.05 ~ P < 0.001)。此外,与STZ和瘦对照组相比,(D-Ser2)Oxm[Lys38-γ-glu-PAL]小鼠中SYP、mTOR和IRS-1的表达显著升高(P < 0.05 ~ P < 0.001)。与STZ对照组相比,这些效果伴随着葡萄糖耐量和胰岛素敏感性的改善(P < 0.001)。结论:这些数据突出了(D-Ser2)Oxm[Lys38-γ-glu-PAL]治疗T1DM的潜力,并揭示了这种Oxm类似物能够恢复stz诱导的T1DM的学习和记忆缺陷。
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