Abstract
Aim:
To study whether T33, a new synthesized non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR) γ/α dual agonist has an antidiabetic effect on ob/ob mice.
Methods:
Ob/ob mice were treated with 4 mg/kg or 8 mg/kg T33 by gavage for 20 d. Blood glucose levels were measured regularly. An oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT) were preformed on d 8 and d 12, respectively. The levels of insulin, triglyceride and free fatty acid (FFA) in the serum were measured at the end of administration. The intramuscular and liver triglyceride content was also determined.
Results:
T33 reduced the hyperglycemia, hyperinsulinemia and hyperlipidemia of the ob/ob mice. The OGTT and ITT showed that the insulin resistance state of the ob/ob mice was obviously ameliorated after T33 treatment. After 20 d treatment with 8 mg/kg T33, the triglyceride content in the gastrocnemius muscle decreased significantly. T33 did not have any effect on triglyceride content in the liver, whereas rosiglitazone significantly increased the hepatocyte lipid deposition.
Conclusion:
The PPARγ/α dual agonist T33 has antidiabetic and insulin-sensitizing effects in ob/ob mice. It has the potential to be a new therapeutic candidate for the treatment of type 2 diabetes.
Similar content being viewed by others
Article PDF
References
DeFronzo RA, Bondonna RC, Ferranini E . Pathogenesis of NIDDM: A balanced overview. Diabetes Care 1992; 15: 318–67.
DeFronzo RA, Ferrannnini E . Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–94.
Schoonjans K, Staels B, Auwerx J . The peroxisome proliferator activated receptors (PPARs) and then effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996; 1302: 93–109.
Kliewer SA, Xu HE, Lambert MH, Willson TM . Peroxisome proliferator-activated receptor: from genes to physiology. Recent Prog Horm Res 2001; 56: 239–65.
Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, et al. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 1996; 15: 5336–48.
Loviscach M, Rehman N, Carter L, Mudaliar S, Mohadeen P, Ciaraldi TP, et al. Distribution of peroxisome proliferators-activated receptors (PPARs) in human skeletal muscle and adipose tissue: relation to insulin action. Diabetologia 2000; 43: 304–11.
Berger J, Moller DE . The mechanisms of action of PPARs. Annu Rev Med 2002; 53: 409–35.
Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, et al. Peroxisome proliferators-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000; 275: 16638–42.
Shearer BG, Hoekstra WJ . Recent advances in peroxisome proliferator-activated receptor science. Curr Med Chem 2003; 10: 267–80.
Young PW, Cawthorne MA, Coyle PJ, Holder JC, Holman GD, Kozka IJ, et al. Repeat treatment of obese mice with BRL 49653, a new and potent insulin sensitizer, enhances insulin action in white adipocyte. Diabetes 1995; 44: 1087–92.
Beeson M, Sajan MP, Dazon M, Grebenev D, Gomez-Daspet J, Miura A, et al. Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: Amelioration by rosiglitazone and exercise. Diabetes 2003; 52: 1926–34.
Miyazaki Y, He H, Mandarino LJ, DeFronzo RA . Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Diabetes 2003; 52: 1943–50.
Zierath JR, Ryder JW, Doebber T, Woods J, Wu M, Ventre J, et al. Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARgamma agonist) action. Endocrinology 1998; 139: 5034–41.
Robins S, Collins D, Wittes J, Papademetriou V, Deedwania P, Schaefer E, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. J Am Med Assoc 2001; 285: 1585–91.
Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary artery disease in type 2 diabetes: The Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001; 357: 905–10.
Tang L, Yu J, Leng Y, Feng Y, Yang Y, Ji R . Synthesis and insulin-sensitizing activity of a novel kind of benzopyran derivative. Bioorg Med Chem Lett 2003; 13: 3437–40.
Chakrabarti R, Misra P, Vikramadithyan RK, Premkumar M, Hiriyan J, Datla SR, et al. Antidiabetic and hypolipidemic potential of DRF 2519-a dual activator of PPAR-alpha and PPARgamma. Eur J Pharmacol 2004; 491: 195–206.
Haluzik M, Colombo C, Gavrilova O, Chua S, Wolf N, Chen M, et al. Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. Endocrinology 2004; 145: 3258–64.
Ljung B, Bamberg K, Dahllof B, Kjellstedt A, Oakes ND, Ostling J, et al. AZ242, a novel PPARα/γ agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. J Lipid Res 2002; 43: 1855–63.
Cha BS, Ciaraldi TP, Park KS, Carter L, Mudaliar SR, Henry RR . Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARgamma agonists. Am J Physiol Endocrinol Metab 2005; 289: E151–9.
Sinha S, Perdomo G, Brown NF, O'Doherty RM . Fatty acid-induced insulin resistance in l6 myotubes is prevented by inhibition of activation and nuclear localization of nuclear factor kappa B. J Biol Chem 2004; 279: 41294–301.
Wiegman CH, Bandsma RH, Ouwens M, van der Sluijs FH, Havinga R, Boer T, et al. Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin. Diabetes 2003; 52: 1081–9.
Chen X, Osborne MC, Rybczynski PJ, Zeck R, Yang M, Xu J, et al. Pharmacological profile of a novel, non-TZD PPARgamma agonist. Diabetes Obes Metab 2005; 7: 536–46.
DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP . The effect of insulin on the disposal of intravenvous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30: 1000–7.
Marin P, Rebuffe-Scrive M, Smith U, Bjorntorp P . Glucose up-take in human adipose tissue. Metabolism 1987; 36: 1154–60.
Kelley DE, Goodpaster BH, Storlein L . Muscle triglyceride and insulin resistance. Annu Rev Nutr 2002; 22: 325–46.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the National Natural Science Foundation of China (No 30472046), Shanghai Rising-Star Foundation (No 04QMX1465) and the State Key Program of Basic Research of China (No 2004CB518905).
Rights and permissions
About this article
Cite this article
Hu, X., Feng, Y., Shen, Y. et al. Antidiabetic effect of a novel non-thiazolidinedione PPAR γ/α agonist on ob/ob mice. Acta Pharmacol Sin 27, 1346–1352 (2006). https://doi.org/10.1111/j.1745-7254.2006.00427.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2006.00427.x
Keywords
This article is cited by
-
T33, a novel peroxisome proliferator-activated receptor γ/α agonist, exerts neuroprotective action via its anti-inflammatory activities
Acta Pharmacologica Sinica (2011)
-
Effect of a novel non-thiazolidinedione peroxisome proliferator-activated receptor α/γ agonist on glucose uptake
Diabetologia (2007)