多酚化合物LM49通过改善肠粘膜屏障及抑制代谢性内毒素炎症对2型糖尿病大鼠的保护作用研究

糖尿病是严重危害人类健康的代谢综合征，2型>90%，发病机制复杂。近来，“炎症学说”得到了国内外内分泌学者的广泛认可。多酚化合物LM49可降低T2DM大鼠血糖、血脂及血清炎性因子水平，但生物利用度较低，用经典药代动力学不足于完全解释其作用。根据体外研究发现，LM49对肠上皮Caco-2细胞损伤模型紧密连接蛋白转录水平有调节作用，我们提出了“LM49通过改善肠粘膜屏障，抑制代谢性内毒素（LPS）炎症，发挥抗大鼠T2DM作用”的假说，并拟在多个层面论证该设想。本研究应用Caco-2细胞损伤模型和大鼠T2DM模型，从分子、细胞和动物水平，探讨LM49对肠粘膜机械屏障损伤的保护作用；治疗期间，利用微量渗透泵持续衡量地向LM49治疗组T2DM大鼠体内泵入LPS，维持体内LPS水平，考察LM49的降糖、降脂作用，阐明LM49抗大鼠T2DM的作用机制，为T2DM的治疗研究提供新思路和新靶点。

Diabetes mellitus is a metabolic syndrome hazarded to human health (type 2 >90%)，its pathogenesis was complicated. Recently, the “inflammation theory” has been widely approved by endocrinologists at home and abroad. Polyphenol compound LM49 can reduce the level of blood glucose, serum lipids and inflammatory factors in T2DM rats. However, the bioavailability was low and the classical pharmacokinetics could not fully explain its hypoglycemic and lipid-lowering effects. According to the preliminary study, we found that LM49 has a regulatory effect on the tight junction protein transcription level in intestinal epithelial caco-2 cell injury model. So we propose a hypothesis that “The protective effect of polyphenol compound LM49 on type 2 diabetic rats by improving intestinal mucosal barrier and preventing metabolic endotoxemia-induced inflammation”, and intents to demonstrate it at various levels. The protective effect of LM49 on intestinal mucosal mechanical barrier damage were observed in a caco-2 cell model induced by LPS and T2DM model induced by feeding with a high-fat diet and intraperitoneal injection of streptozotocin at the molecular, cellular, and animal level. During the treatment, microamount of LPS was continuously pumped into T2DM rats treated with LM49 by osmotic pump to maintain the level of LPS in vivo. The hypoglycemic and lipid-lowering effects of LM49 were investigated, and the mechanism of LM49 anti-T2DM in rats was elucidated, providing new ideas and new targets for the treatment of T2DM.