Korean Diabetes J.  2010 Jun;34(3):191-199. 10.4093/kdj.2010.34.3.191.

Effects of Rosiglitazone on Inflammation in Otsuka Long-Evans Tokushima Fatty Rats

• Lee JW
• Nam-Goong
• Kim JG
• Yun CH
• Kim SJ
• Choi JI
• Kim YI
• Kim ES

• KMID: 2222375
• DOI: http://doi.org/10.4093/kdj.2010.34.3.191

Abstract

BACKGROUND
Inflammation plays a role in the response to metabolic stress in type 2 diabetes. However, the effects of rosiglitazone on inflammation of skeletal muscle have not been fully examined in type 2 diabetes.
METHODS
We investigated the effects of the insulin-sensitizing anti-diabetic agent, rosiglitazone, on the progression of skeletal muscle inflammation in Otsuka Long-Evans Tokushima Fatty (OLETF) type 2 diabetic rats. We examined the expression of serologic markers (serum glucose, insulin and free fatty acid) and inflammatory cytokines (tumor-necrosis factor-alpha, interleukin [IL]-1beta and IL-6) in OLETF rats from early to advanced diabetic stage (from 28 to 40 weeks of age).
RESULTS
Serum glucose and insulin concentrations were significantly decreased in rosiglitazone-treated OLETF rats compared to untreated OLETF rats. Rosiglitazone treatment significantly decreased the concentrations of serum inflammatory cytokines from 28 to 40 weeks of age. The mRNA expression of various cytokines in skeletal muscle was reduced in rosiglitazone-treated OLETF rats compared with untreated OLETF rats. Furthermore, rosiglitazone treatment resulted in the downregulation of ERK1/2 phosphorylation and NF-kappaB expression in the skeletal muscle of OLETF rats.
CONCLUSION
These results suggest that rosiglitazone may improve insulin sensitivity with its anti-inflammatory effects on skeletal muscle.

Keyword

Diabetes mellitus, type 2; Inflammation; Muscle, skeletal; Rats, inbred OLETF; Rosiglitazone

MeSH Terms

Animals
Cytokines
Diabetes Mellitus, Type 2
Down-Regulation
Glucose
Inflammation
Insulin
Insulin Resistance
Interleukins
Muscle, Skeletal
NF-kappa B
Phosphorylation
Rats
Rats, Inbred OLETF
RNA, Messenger
Stress, Physiological
Thiazolidinediones
Cytokines
Glucose
Insulin
Interleukins
NF-kappa B
RNA, Messenger
Thiazolidinediones

Figure

• 

  Fig. 1 Experimental schedule in Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats.

• 

  Fig. 2 Changes of body weight in Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Body weights were measured at 28, 32, 36, and 40 weeks, and changes are represented as the average weights on indicated days. Values are presented as mean ± standard deviation. ROSI, rosiglitazone. aP < 0.001 as compared to LETO rats.

• 

  Fig. 3 Changes in concentration of serological markers in Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Glucose, insulin and free fatty acid in sera of LETO or OLETF rats were measured by colorimetric and enzymatic assay at 28 and 40 weeks. Values were represented as mean ± standard deviation. FFA, free fatty acid. aP < 0.05 and bP < 0.01 as compared to each group. ROSI is an abbreviation for rosiglitazone.

• 

  Fig. 4 Changes in inflammatory cytokine levels in Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Tumor-necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 levels in sera of LETO or OLETF rats were measured by enzyme-linked immunosorbent assay at 28 and 40 weeks. Values are represented as the mean ± standard deviation. ROSI, rosiglitazone. aP < 0.05 and bP < 0.001 as compared to each group.

• 

  Fig. 5 Changes in inflammatory cytokine gene expression in Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The expression of Tumor-necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 mRNA in skeletal muscle tissues of LETO and OLETF mice were determined by RT-PCR at 40 weeks. There are no significant differences between the groups. This is a representative figure from three independent experiments. ROSI is an abbreviation for rosiglitazone.

• 

  Fig. 6 Changes in levels of inflammatory signaling molecules in Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. (A) ERK1/2 phosphorylation in cytosol and (B) NF-κB p65 expression in nucleus of skeletal muscle tissues were determined by Western blot analysis at 40 weeks. This is a representative figure from three independent experiments. There are no significant differences between the groups. ROSI is an abbreviation for rosiglitazone.

Reference

1. Donath MY, Storling J, Berchtold LA, Billestrup N, Mandrup-Poulsen T. Cytokines and beta-cell biology: from concept to clinical translation. Endocr Rev. 2008. 29:334–350.

2. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006. 116:1793–1801.

3. Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab. 2000. 11:327–332.

4. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005. 11:183–190.

5. Winkler G, Salamon F, Harmos G, Salamon D, Speer G, Szekeres O, Hajos P, Kovacs M, Simon K, Cseh K. Elevated serum tumor necrosis factor-alpha concentrations and bioactivity in type 2 diabetics and patients with android type obesity. Diabetes Res Clin Pract. 1998. 42:169–174.

6. Mishima Y, Kuyama A, Tada A, Takahashi K, Ishioka T, Kibata M. Relationship between serum tumor necrosis factor-alpha and insulin resistance in obese men with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2001. 52:119–123.

7. Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The expression of TNF alpha by human muscle: relationship to insulin resistance. J Clin Invest. 1996. 97:1111–1116.

8. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996. 271:665–668.

9. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005. 54:2939–2945.

10. Bouzakri K, Zierath JR. MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance. J Biol Chem. 2007. 282:7783–7789.

11. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998. 391:82–86.

12. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998. 391:79–82.

13. Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P. Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab. 2004. 89:2728–2735.

14. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992. 41:1422–1428.

15. Nagaraju K, Raben N, Merritt G, Loeffler L, Kirk K, Plotz P. A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli. Clin Exp Immunol. 1998. 113:407–414.

16. Friedman JE, Kirwan JP, Jing M, Presley L, Catalano PM. Increased skeletal muscle tumor necrosis factor-alpha and impaired insulin signaling persist in obese women with gestational diabetes mellitus 1 year postpartum. Diabetes. 2008. 57:606–613.

17. Sriwijitkamol A, Christ-Roberts C, Berria R, Eagan P, Pratipanawatr T, DeFronzo RA, Mandarino LJ, Musi N. Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. Diabetes. 2006. 55:760–767.

18. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995. 95:2409–2415.

19. Sethi JK, Hotamisligil GS. The role of TNF alpha in adipocyte metabolism. Semin Cell Dev Biol. 1999. 10:19–29.

20. Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flanigan A, Murthy S, Lazar MA, Wu GD. A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest. 1999. 104:383–389.

21. Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001. 169:453–459.

22. Rasouli N, Raue U, Miles LM, Lu T, Di Gregorio GB, Elbein SC, Kern PA. Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Am J Physiol Endocrinol Metab. 2005. 288:E930–E934.

23. Staels B. Metformin and pioglitazone: Effectively treating insulin resistance. Curr Med Res Opin. 2006. 22:Suppl 2. S27–S37.

24. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001. 108:437–446.

25. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001. 293:1673–1677.

26. Rohl M, Pasparakis M, Baudler S, Baumgartl J, Gautam D, Huth M, De Lorenzi R, Krone W, Rajewsky K, Bruning JC. Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance. J Clin Invest. 2004. 113:474–481.

27. Ghanim H, Dhindsa S, Aljada A, Chaudhuri A, Viswanathan P, Dandona P. Low-dose rosiglitazone exerts an antiinflammatory effect with an increase in adiponectin independently of free fatty acid fall and insulin sensitization in obese type 2 diabetics. J Clin Endocrinol Metab. 2006. 91:3553–3558.