KDT501, a derivative from hops, normalizes glucose metabolism and body weight in rodent models of diabetes.
OBJECTIVE
We 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.


METHODS
KDT501 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.


RESULTS
KDT501 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.


CONCLUSIONS
These 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.
KinDex Therapeutics, LLC, Seattle, Washington, United States of America.
Veera R
VR
Konda
KinDex Therapeutics, LLC, Seattle, Washington, United States of America.
Anuradha
A
Desai
KinDex Therapeutics, LLC, Seattle, Washington, United States of America.
Gary
G
Darland
KinDex Therapeutics, LLC, Seattle, Washington, United States of America.
Neile
N
Grayson
KinDex Therapeutics, LLC, Seattle, Washington, United States of America.
Jeffrey S
JS
Bland
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D005947:Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D047495:PPAR gamma; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D014280:Triglycerides