Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, H.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India.
Structural Bioinformatics Lab, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, H.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India.
Life Sci. 2023 Jun 1;322:121668. doi: 10.1016/j.lfs.2023.121668. Epub 2023 Apr 5.
The rising prevalence of type 2 diabetes mellitus (T2DM) and accompanying insulin resistance is alarming globally. Natural and synthetic agonists of PPARγ are potentially attractive candidates for diabetics and are known to efficiently reverse adipose and hepatic insulin resistance, but related side effects and escalating costs are the causes of concern. Therefore, targeting PPARγ with natural ligands is advantageous and promising approach for the better management of T2DM. The present research aimed to assess the antidiabetic potential of phenolics Phloretin (PTN) and Phlorizin (PZN) in type 2 diabetic mice.
In silico docking was performed to check the effect of PTN and PZN on PPARγ S273-Cdk5 interactions. The docking results were further validated in preclinical settings by utilizing a mice model of high fat diet-induced T2DM.
Computational docking and further MD-simulation data revealed that PTN and PZN inhibited the activation of Cdk5, thereby blocking the phosphorylation of PPARγ. Our in vivo results further demonstrated that PTN and PZN administration significantly improved the secretory functions of adipocytes by increasing adiponectin and reducing inflammatory cytokine levels, which ultimately reduced the hyperglycaemic index. Additionally, combined treatment of PTN and PZN decreased in vivo adipocyte expansion and increased Glut4 expression in adipose tissues. Furthermore, PTN and PZN treatment reduced hepatic insulin resistance by modulating lipid metabolism and inflammatory markers.
In summary, our findings strongly imply that PTN and PZN are candidates as nutraceuticals in the management of comorbidities related to diabetes and its complications.
2 型糖尿病（T2DM）的患病率不断上升以及随之而来的胰岛素抵抗在全球范围内令人担忧。过氧化物酶体增殖物激活受体γ（PPARγ）的天然和合成激动剂是糖尿病患者的潜在有吸引力的候选药物，已知它们能有效地逆转脂肪组织和肝脏胰岛素抵抗，但相关的副作用和不断上升的成本是令人关注的原因。因此，用天然配体靶向 PPARγ 是更好地管理 T2DM 的一种有利且有前途的方法。本研究旨在评估根皮素（PTN）和根皮苷（PZN）这两种酚类物质对 2 型糖尿病小鼠的抗糖尿病潜力。
通过计算机模拟对接来检查 PTN 和 PZN 对 PPARγ S273-Cdk5 相互作用的影响。通过利用高脂肪饮食诱导的 T2DM 小鼠模型，在临床前环境中进一步验证对接结果。
计算对接和进一步的 MD 模拟数据显示，PTN 和 PZN 抑制了 Cdk5 的激活，从而阻止了 PPARγ 的磷酸化。我们的体内结果进一步表明，PTN 和 PZN 的给药通过增加脂联素和降低炎症细胞因子水平显著改善了脂肪细胞的分泌功能，从而降低了高血糖指数。此外，PTN 和 PZN 的联合治疗减少了体内脂肪细胞的扩张，并增加了脂肪组织中的 Glut4 表达。此外，PTN 和 PZN 治疗通过调节脂质代谢和炎症标志物降低了肝胰岛素抵抗。
总之，我们的研究结果强烈暗示，PTN 和 PZN 是作为管理与糖尿病及其并发症相关的合并症的营养保健品的候选药物。
