amorfrutin-b and Diabetes-Mellitus--Type-2

PPARγ is an essential regulator of lipid, glucose, and insulin metabolism. PPARγ full agonists, such as thiazolidinediones, are the mainstay drugs for the treatment of type 2 diabetes; however, undesirable clinical side effects have contributed to poor compliance with therapy and limited their full therapeutic potential. In the last few years, many efforts have been made in the discovery and development of selective PPARγ modulators (SPPARγMs) as safer alternatives to PPARγ full agonists.. This application claims the plant-derived amorfrutins or their synthetic analogs as SPPARγMs with potential to exhibit glucose-lowering effects without provoking side effects associated with full PPARγ activation. Specifically, the in vivo glucose-lowering properties of the high-affinity SPPARγM amorfrutin B are described. Moreover, examples of this class of compounds exhibit interesting antiproliferative activities.. The patent (WO2014177593 A1) under discussion proposes enriching functional food products or phytomedical extracts with safe licorice extracts, containing sufficient amounts of amorfrutins, with the ultimate goal of inhibiting the early development of disorders such as insulin resistance. Interestingly, some example compounds show anticancer properties in colon, prostate, and breast malignancies. However, further in vivo investigations of the claimed compounds for these specific indications will be necessary to definitively support their clinical applications.

Topics: Animals; Antineoplastic Agents; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Neoplasms; Patents as Topic; PPAR gamma; Salicylates

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARγ-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose-lowering compound that selectively modulates PPARγ. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARγ-binding and pharmacological properties of this family of plant metabolites.. Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg(-1) day(-1) amorfrutin B.. Amorfrutin B showed low nanomolar binding affinity to PPARγ, and micromolar binding to the isotypes PPARα and PPARβ/δ. Amorfrutin B selectively modulated PPARγ activity at low nanomolar concentrations. In insulin-resistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention.. The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Salicylates