KDT501, a Derivative from Hops, Normalizes Glucose Metabolism and Body Weight in Rodent Models of Diabetes

Abstract

Aims/HypothesisWe developed KDT501, a novel substituted 1,3-cyclopentadione chemically derived from hop extracts, and evaluated it in various in vitro and in vivo models of diabetes and insulin sensitivity.MethodsKDT501 was evaluated for anti-inflammatory effects in monocyte/macrophage cells; agonistic activity for peroxisome proliferator-activated receptors (PPAR); lipogenesis and gene expression profile in human subcutaneous adipocytes. Body composition, glucose, insulin sensitivity, and lipids were assessed in diet-induced obesity (DIO) mice and Zucker Diabetic Fatty (ZDF) rats after oral administration.ResultsKDT501 mediated lipogenesis in 3T3L1 and human subcutaneous adipocytes; however, the gene expression profile of KDT501 differed from that of the full PPARγ agonist rosiglitazone, suggesting that KDT501 has pleiotropic biological activities. In addition, KDT501 showed only modest, partial PPARγ agonist activity and exhibited anti-inflammatory effects in monocytes/macrophages that were not observed with rosiglitazone. In a DIO mouse model, oral administration of KDT501 significantly reduced fed blood glucose, glucose/insulin AUC following an oral glucose bolus, and body fat. In ZDF rats, oral administration of KDT501 significantly reduced fed glucose, fasting plasma glucose, and glucose AUC after an oral glucose bolus. Significant, dose-dependent reductions of plasma hemoglobin A1c, weight gain, total cholesterol, and triglycerides were also observed in animals receiving KDT501.ConclusionThese results indicate that KDT501 produces a unique anti-diabetic profile that is distinct in its spectrum of pharmacological effects and biological mechanism from both metformin and pioglitazone. KDT501 may thus constitute a novel therapeutic agent for the treatment of Type 2 diabetes and associated conditions.

Isohumulones from hops (Humulus lupulus) and their potential role in medical nutrition therapy

“…In examining the influence of isohumulones on obesity, Konda et al reported that a specific molecule synthesized from the isohumulone THIAA mixture had the ability to improve insulin signaling and obesity in both the diet-induced obesity mouse model of type 2 diabetes and the Zucker diabetic fatty rat model [49]. This study demonstrated that the isohumulone pharmacophore represents itself as a privileged structure that influences adipocyte physiology and adiposity.…”

A step ahead of PPARγ full agonists to PPARγ partial agonists: Therapeutic perspectives in the management of diabetic insulin resistance

“…Interestingly, KDT501 administration dose-dependently reduced weight gain in ZDF rats, while pioglitazone gained the weight. In addition, KDT501 reduced total cholesterol unlike pioglitazone, suggesting that the anti-diabetic action of KDT501 differs from that of pioglitazone (Konda et al, 2014). This study suggests that KDT501 might be a novel therapeutic agent for the management of T2DM.…”

“…Administration of KDT501 in the DIO mouse and the ZDF rat improved glucose metabolism and reduced plasma HbA1c while it dose-dependently reduced the weight gain in the ZDF rat (Konda et al, 2014). Amorfrutin B…”

“…A recent study has identified an extract from hops (Humulus lupulus), known as KDT501 as a PPARγ partial agonist (Konda et al, 2014). KDT501 (EC 50 , 14.0 mM) was noted to exhibit weak and partial PPARγ activity, attaining only 297 7% of rosiglitazone's maximal activation (Konda et al, 2014).…”

“…KDT501 (EC 50 , 14.0 mM) was noted to exhibit weak and partial PPARγ activity, attaining only 297 7% of rosiglitazone's maximal activation (Konda et al, 2014). Oral administration of KDT501 in the diet-induced obesity (DIO) mouse and the Zucker Diabetic Fatty (ZDF) rat models of diabetes mellitus improved glucose metabolism and reduced plasma glycated hemoglobin (HbA1c).…”