Anti-hyperglycemic activity of myricetin, through inhibition of DPP-4 and enhanced GLP-1 levels, is attenuated by co-ingestion with lectin-rich protein

Dipeptidyl peptidase-4 (DPP-4) is a proteolytic enzyme responsible for the rapid degradation of Glucagon-like peptide 1 (GLP-1) that is required for the secretion of insulin. DPP-4 also influences activation of node like receptor family, pyrin domain containing 3 (NLRP3) inflammasome under diabetic conditions. Although several polyphenols are reported for various bioactivities, they are consumed as part of the food matrix and not in isolation. Horsegram (Macrotyloma uniflorum) is a rich source of myricetin (Myr) (35 μg/g flour), reported for its anti-hyperglycemic effect. In this investigation, we aimed to study the effect of Myr, singly, and in the presence of co-nutrient horsegram protein (HP) on DPP-4 activity and its consequential impact on GLP-1, insulin, and NLRP3 inflammasome in high-fat diet and single low dose streptozotocin (STZ)-induced diabetic male Wistar rats. In diabetic control (DC), the activity of DPP-4 and its expression were higher compared to treated groups. The consequential decrease in the circulating GLP-1 levels in the DC group, but not treated groups, further indicated the effectiveness of our test molecules under diabetic conditions. Specifically, Myr decreased DPP-4 activity and its expression levels with enhanced circulating GLP-1 and insulin levels. Myr administration also resulted in a lessening of diabetes-induced NLRP3 inflammasome activation and enhanced antioxidant enzyme activities. HP also proved to be efficient in reducing elevated blood glucose levels and enhancing antioxidant enzyme activities. However, Myr, in the presence of HP as a co-nutrient, had diminished capacity to inhibit DPP-4 and, consequently, reduced potential in ameliorating diabetic conditions. Myr proved to be a potent inhibitor of DPP-4 in vitro and in vivo, resulting in enhanced circulating GLP-1 and insulin levels, thereby improving diabetic conditions. Though Myr and HP, individually ameliorate diabetic conditions, their dietary combination had reduced efficiency.二肽基肽酶-4 (Dipeptidyl peptidase-4, DPP-4) 是一种蛋白水解酶，负责快速降解胰岛素分泌所必需的胰高血糖素样肽-1 (Glucagon-like peptide 1, GLP-1)。DPP-4还可在糖尿病状态下影响核苷酸结合寡聚化结构域样受体家族pyrin结构域包含3 (NLRP3) 炎性小体的活化。尽管已有多项研究报道了多酚类化合物的多种生物活性，但它们通常作为食物基质的组成部分被摄入，而非单独服用。马豆 (Macrotyloma uniflorum) 是杨梅素 (Myricetin, Myr) 的优质来源（面粉中含量达35 μg/g），其降糖活性已有文献报道。本研究旨在探究单独使用杨梅素，以及与共营养素马豆蛋白 (Horsegram Protein, HP) 联合使用时，对DPP-4活性的影响，及其对高脂饮食联合单次低剂量链脲佐菌素 (Streptozotocin, STZ) 诱导的糖尿病雄性Wistar大鼠体内GLP-1、胰岛素及NLRP3炎性小体的后续影响。糖尿病对照组（DC）中，DPP-4的活性及其表达水平均高于各给药组。糖尿病对照组的循环GLP-1水平出现继发性降低，而给药组未出现该变化，这进一步证实了我们的受试分子在糖尿病状态下的有效性。具体而言，杨梅素可降低DPP-4的活性及其表达水平，同时提升循环GLP-1与胰岛素水平。给予杨梅素还可减轻糖尿病诱导的NLRP3炎性小体活化，并增强抗氧化酶活性。马豆蛋白同样可有效降低升高的血糖水平，并提升抗氧化酶活性。然而，当杨梅素与作为共营养素的马豆蛋白联合使用时，其抑制DPP-4的能力有所减弱，因此改善糖尿病状态的潜力也随之降低。体外与体内实验均证实，杨梅素是一种强效的DPP-4抑制剂，可提升循环GLP-1与胰岛素水平，从而改善糖尿病病症。尽管杨梅素与马豆蛋白单独使用时均可改善糖尿病病症，但二者的膳食联合使用却会降低治疗效果。