Development of PPAR-agonist GW0742 as antidiabetic drug: study in animals.
BACKGROUND
The development of new drugs for the treatment of diabetes mellitus (DM) is critically important. Insulin resistance (IR) is one of the main problems associated with type-2 DM (T2DM) seen in clinics. GW0742, a selective peroxisome proliferator-activated receptor (PPAR)-δ agonist, has been shown to ameliorate metabolic abnormalities including IR in skeletal muscle in mice fed high-fructose corn syrup. However, the influence of GW0742 on systemic insulin sensitivity has still not been elucidated. Therefore, it is important to investigate the effect of GW0742 on systemic IR in diabetic rats for the development of new drugs.


METHODS
The present study used a T2DM animal model to compare the effect of GW0742 on IR using homeostasis model assessment-IR (HOMA-IR) and hyperinsulinemic euglycemic clamping. Additionally, the insulinotropic action of GW0742 was investigated in type-1 DM (T1DM) rats. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and in liver, respectively, were also identified by Western blots.


RESULTS
GW0742 attenuated the increased HOMA-IR in diabetic rats fed a fructose-rich diet. This action was blocked by GSK0660 at the dose sufficient to inhibit PPAR-δ. Improvement of IR by GW0742 was also characterized in diabetic rats using hyperinsulinemic euglycemic clamping. Additionally, an increase of insulin sensitivity due to GW0742 was observed in these diabetic rats. Moreover, GW0742 reduced the hyperglycemia in T1DM rats lacking insulin. Western blotting analysis indicated that GW0742 reversed the decrease in GLUT4 and markedly reduced the increased PEPCK in liver.


CONCLUSIONS
The data showed that GW0742 has the ability to improve glucose homeostasis in diabetic rats through activation of PPAR-δ. Therefore, PPAR-δ is a good target for the development of antidiabetic drugs in the future.
Department of Nursing, Tzu Chi College of Technology, Hualien City, Taiwan.
Ho-Shan
HS
Niu
Department of Cardiology, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan ; Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan.
Po-Ming
PM
Ku
Department of Nursing, Tzu Chi College of Technology, Hualien City, Taiwan.
Chiang-Shan
CS
Niu
Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan ; Institute of Medical Sciences, Chang Jung Christian University, Guiren, Tainan City, Taiwan.
Juei-Tang
JT
Cheng
Department of Surgery, Division of Neurosurgery, Pingtung Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan ; Department of Surgery, Kaohsiung Medical University, Kaohsiung City, Taiwan ; School of Medicine, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
Kung-Shing
KS
Lee
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D005632:Fructose; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D017208:Rats, Wistar; D013311:Streptozocin; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D010636:Phenols; D013438:Sulfhydryl Compounds
D015415:Biomarkers; D001786:Blood Glucose; D005632:Fructose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D047493:PPAR alpha; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D013311:Streptozocin; D013844:Thiazoles; C495694:Slc2a4 protein, rat; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C582554:Pck1 protein, rat
HOMA-IR; fructose-rich chow; insulin resistance; insulinotropic action; rats; streptozotocin