Isolation and characterization of a dipeptidyl peptidase-IV (DPP-IV) inhibitor from the ayurvedic herb Syzygium cumini (Linn.) Skeels.

摘要

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia and is becoming an increasingly serious worldwide epidemic. The effects of unregulated glucose control can result in severe macro and microvascular complications that can ultimately result in death. There is no cure for the disease and all current pharmacological agents are aimed at maintaining glycemic control (FPG between 90-120 mg/dl). Understanding of the mechanisms underlying glucose homeostasis has increased considerably upon discovery of the incretins, GLP-1 and GIP, which stimulate insulin secretion and inhibit glucagon secretion in a glucose dependent manner following a meal (i.e. incretin effect). Inhibition of DPP-IV, the enzyme responsible for the degradation of GLP-1, enhances the incretin effect and is now a viable method in the treatment of type 2 diabetes.;Throughout the world over 1200 species of plants have been used traditionally to treat diabetes and many of these have originated in India. For over 5000 years Ayurvedic medicine has been practiced in India for the treatment of many diseases, including diabetes, and is primarily based on the use of plants. In this study 41 different plant extracts were screened for inhibition of DPP-IV in an in vitro assay and 70% ethanol Syzygium cumini seed kernel extract was identified as an inhibitor with IC 50 = 65.8 +/- 3.6 mug/ml. The extract was also capable of lowering the glycemia of ZDF rats during an oral glucose tolerance test, which validates its use as an antidiabetic agent in traditional medicine.;The active component of DPP-IV inhibition was isolated and identified as a high molecular weight ellagitannin composed of ellagic acid, gallic acid and glucose. It has an IC50 = 4.4 +/- 0.3 mug/ml, comparable to the control diprotin A (IC50 = 4.9 +/- 0.4 microg/ml), and determined to be a noncompetitive inhibitor of DPP-IV. Ellagic acid and gallic acid were also isolated from S. cumini and while ellagic acid showed modest inhibition, gallic acid was completely inactive.;Since hyperlipidemia is a complication of diabetes mellitus several statins were screened for inhibition of DPP-IV and atorvastatin was identified as a competitive inhibitor with Ki = 57.8 +/- 2.3 muM. Surprisingly, none of the other statins tested (rosuvastatin, fluvastatin and simvastatin) showed inhibition at the concentrations tested.