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DA-1229, a novel and potent DPP4 inhibitor, improves insulin resistance and delays the onset of diabetes

机译：DA-1229是一种新型有效的DPP4抑制剂，可改善胰岛素抵抗并延缓糖尿病的发作

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Aim: To characterize the pharmacodynamic profile of DA-1229, a novel dipeptidyl peptidase (DPP) 4 inhibitor. Main methods: Enzyme inhibition assays against DPP4, DPP8 and DPP9. Antidiabetic effects of DA-1229 in HF-DIO mice and young db/db mice. Key findings: DA-1229 was shown to potently inhibit the DPP4 enzyme in human and murine soluble forms and the human membrane-bound form with IC 50 values of 0.98, 3.59 and 1.26 nM, respectively. As a reversible and competitive inhibitor, DA-1229 was more selective to human DPP4 (6000-fold) than to human DPP8 and DPP9. DA-1229 (0.1-3 mg/kg) dose-dependently inhibited plasma DPP4 activity, leading to increased levels of plasma GLP-1 and insulin, and thereby lowering blood glucose levels in mice. In high fat diet-fed (HF) mice, a single oral dose of 100 mg/kg of DA-1229 reduced plasma DPP4 activity by over 80% during a 24 h period. Long-term treatment with DA-1229 for 8 weeks revealed significant improvements in glucose intolerance and insulin resistance, accompanied by significant body weight reduction. However, it remains unclear whether there is a direct causal relationship between DPP4 inhibition and body weight reduction. In young db/db mice, the DA-1229 treatment significantly reduced blood glucose excursions for the first 2 weeks, resulting in significantly lower levels of HbA1c at the end of the study. Furthermore, the pancreatic insulin content of the treatment group was significantly higher than that of the db/db control. Significance: DA-1229 as a novel and selective DPP4 inhibitor improves the insulin sensitivity in HF mice and delays the onset of diabetes in young db/db mice.
机译：目的：鉴定新型二肽基肽酶（DPP）4抑制剂DA-1229的药效学特征。主要方法：针对DPP4，DPP8和DPP9的酶抑制试验。 DA-1229对HF-DIO小鼠和db / db小鼠的抗糖尿病作用。关键发现：已显示DA-1229以人和鼠可溶形式和人膜结合形式有效抑制DPP4酶，IC 50值分别为0.98、3.59和1.26 nM。作为一种可逆和竞争性抑制剂，DA-1229对人DPP4（6000倍）的选择性比对人DPP8和DPP9的选择性更高。 DA-1229（0.1-3 mg / kg）剂量依赖性地抑制血浆DPP4活性，导致血浆GLP-1和胰岛素水平升高，从而降低小鼠血糖水平。在高脂饮食喂养（HF）小鼠中，单次口服剂量100 mg / kg的DA-1229在24小时内可使血浆DPP4活性降低80％以上。用DA-1229长期治疗8周后，发现葡萄糖耐量和胰岛素抵抗显着改善，并伴有明显的体重减轻。但是，尚不清楚DPP4抑制与体重减轻之间是否存在直接因果关系。在年轻的db / db小鼠中，DA-1229处理可在头2周内显着降低血糖波动，从而在研究结束时显着降低HbA1c的水平。此外，治疗组的胰腺胰岛素含量显着高于db / db对照组。启示：DA-1229作为一种新型的选择性DPP4抑制剂，可以改善HF小鼠的胰岛素敏感性，并延缓db / db小鼠的糖尿病发作。

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