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发现用于治疗胰岛素抵抗和糖尿病的胰抑素抑制剂 PSTi8：在糖尿病啮齿动物模型中的研究。

Discovery of pancreastatin inhibitor PSTi8 for the treatment of insulin resistance and diabetes: studies in rodent models of diabetes mellitus.

机构信息

Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.

Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.

出版信息

Sci Rep. 2018 Jun 7;8(1):8715. doi: 10.1038/s41598-018-27018-8.

DOI:10.1038/s41598-018-27018-8
PMID:29880906
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5992141/
Abstract

Pancreastatin (PST) is an endogenous peptide which regulates glucose and lipid metabolism in liver and adipose tissues. In type 2 diabetic patients, PST level is high and plays a crucial role in the negative regulation of insulin sensitivity. Novel therapeutic agents are needed to treat the diabetes and insulin resistance (IR) against the PST action. In this regard, we have investigated the PST inhibitor peptide-8 (PSTi8) action against diabetogenic PST. PSTi8 rescued PST-induced IR in HepG2 and 3T3L1 cells. PSTi8 increases the GLUT4 translocation to cell surface to promote glucose uptake in L6-GLUT4myc cells. PSTi8 treatment showed an increase in insulin sensitivity in db/db, high fat and fructose fed streptozotocin (STZ) induced IR mice. PSTi8 improved the glucose homeostasis which is comparable to metformin in diabetic mice, characterized by elevated glucose clearance, enhanced glycogenesis, enhanced glycolysis and reduced gluconeogenesis. PST and PSTi8 both were docked to the GRP78 inhibitor binding site in protein-protein docking, GRP78 expression and its ATPase activity studies. The mechanism of action of PSTi8 may be mediated by activating IRS1/2-phosphatidylinositol-3-kinase-AKT (FoxO1, Srebp-1c) signaling pathway. The discovery of PSTi8 provides a promising therapeutic agent for the treatment of metabolic diseases mainly diabetes.

摘要

胰淀素（PST）是一种内源性肽，可调节肝脏和脂肪组织中的葡萄糖和脂质代谢。在 2 型糖尿病患者中，PST 水平升高，在胰岛素敏感性的负调节中起关键作用。需要新型治疗剂来对抗 PST 的作用，以治疗糖尿病和胰岛素抵抗（IR）。在这方面，我们研究了 PST 抑制剂肽-8（PSTi8）对致糖尿病 PST 的作用。PSTi8 挽救了 HepG2 和 3T3L1 细胞中 PST 诱导的 IR。PSTi8 增加 GLUT4 向细胞表面的易位，以促进 L6-GLUT4myc 细胞中的葡萄糖摄取。PSTi8 治疗在 db/db、高脂肪和果糖喂养的链脲佐菌素（STZ）诱导的 IR 小鼠中增加了胰岛素敏感性。PSTi8 改善了葡萄糖稳态，在糖尿病小鼠中与二甲双胍相当，表现为葡萄糖清除率升高、糖生成增强、糖酵解增强和糖异生减少。PST 和 PSTi8 均与 GRP78 抑制剂结合在蛋白-蛋白对接、GRP78 表达及其 ATP 酶活性研究中。PSTi8 的作用机制可能是通过激活 IRS1/2-磷酸肌醇-3-激酶-AKT（FoxO1、Srebp-1c）信号通路来介导的。PSTi8 的发现为治疗代谢疾病（主要是糖尿病）提供了一种有前途的治疗剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/9820b3e61074/41598_2018_27018_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/069a1628b0e8/41598_2018_27018_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/4857a88d6d37/41598_2018_27018_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/5b5241df9b19/41598_2018_27018_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/1483c52d1434/41598_2018_27018_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/acc28f4486b2/41598_2018_27018_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/a769131492dd/41598_2018_27018_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/9820b3e61074/41598_2018_27018_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/069a1628b0e8/41598_2018_27018_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/4857a88d6d37/41598_2018_27018_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/5b5241df9b19/41598_2018_27018_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/1483c52d1434/41598_2018_27018_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/acc28f4486b2/41598_2018_27018_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/a769131492dd/41598_2018_27018_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60b4/5992141/9820b3e61074/41598_2018_27018_Fig7_HTML.jpg

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