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

Abstract

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.

Nutraceutical Compounds Targeting Inflammasomes in Human Diseases

“…Verdc.) seed coat, decreased in the liver of streptozotocin-induced diabetic male Wistar rats, the gene expression of NLRP3, ASC and caspase-1, leading to a reduction in blood glucose levels and in liver dipeptidyl peptidase-4 and antioxidant enzyme activities, as well as leading to an improvement in plasma insulin levels [ 101 ]. Furthermore, other plant phenolic compounds exert similar effects: freeze-dried red raspberry powder enriched in polyphenols ameliorated levels of blood glucose, insulin resistance and glucose intolerance and the accumulation of hepatic lipids.…”

A Comprehensive Review and Perspective on Natural Sources as Dipeptidyl Peptidase-4 Inhibitors for Management of Diabetes

“…Recently, sitagliptin was reported to increased muscle mass and muscle/fat ratio in T2DM [ 67 ], and natural DPP-4 inhibitors such as chrysin and galangin were reported to promote SM cell proliferation [ 68 , 69 ]. Furthermore, in a diabetic animal model, myricetin administration reduced DDP-4 expression in muscle [ 70 ]. Overall, these studies revealed that DPP-4 inhibitors have a positive effect on SM, increasing SM cell proliferation and the muscle/fat ratio in diabetic patients.…”

“…Macrotyloma uniflorum (horsegram) is a legume grown mainly in dry regions of Australia, Burma, India, and Sri Lanka and contains high concentrations of myricetin, which has been shown to have anti-hyperglycemic properties. Myricetin also inhibited DPP-4 (IC 50 of 4.8 μM), and thus, increased serum GLP-1 and insulin levels and ameliorated the manifestations of T2DM [ 70 ].…”

Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity

“…In animal studies, GLP-1 secretion can be induced by acute (single) administration of curcumin [ 116 ], as well as the ginsenoside metabolite Rg3 [ 111 ]. Increment of plasma GLP-1 levels following chronic administration (oral or intraperitoneal) of apigenin [ 115 ], genistein combined with metformin [ 117 ], hispidulin [ 112 ], isoquercitrin [ 113 ], luteolin [ 118 ], myricetin [ 119 ], grape seed proanthocyanidins [ 120 ], procyanidin [ 121 ], and resveratrol [ 122 ] have been reported.…”

“…Some compounds (isoquercitrin and myricetin) reportedly possess inhibitory activity against the DPP-4 enzyme, which is considered to contribute to the promotive effect on GLP-1 levels [ 113 , 119 ]. Flavonoids mediate various protective effects against obesity, diabetes, and other metabolic diseases by targeting various organs, tissues, and cells, as described previously.…”