J Korean Diabetes Assoc.  2007 Jul;31(4):319-325. 10.4093/jkda.2007.31.4.319.

The Effect of Rosiglitazone on Gluose Metabolism and Insulin Sensitivity in Non Obese Type 2 Diabetic Rat Models

• Kim MJ
• Chung EJ
• Ha BW
• Kim JH
• Nam SM
• Lee MY
• Kho JH
• Shin YG
• Chung CH

• KMID: 2222519
• DOI: http://doi.org/10.4093/jkda.2007.31.4.319

Abstract

BACKGROUND: In Korea, most of type 2 diabetic patients are non obese. We made non obese type 2 diabetic rat models, which were characterized by insulin resistance and insulin secretion defect. Our study aimed to investigate the effect of rosiglitazone on glucose metabolism and insulin sensitivity in non obese type 2 diabetic rat models. Furthermore, we may estimate the effect of rosiglitazone treatment in non obese type 2 diabetic patients in Korea.
METHODS
20 male newborn (12 hours old) Sprague-Dawley rats were made diabetes by streptozotocin (75 mg/kg, intraperitoneal injection). At 16 weeks old, diabetes were confirmed by intraperitoneal glucose tolerance test (IPGTT, 30% D/W, 2 kg/kg). After that, diabetic groups were divided into two groups. One group was fed on normal chow and rosiglitazone (3 mg/kg/day) and the other group was fed on normal chow for eight weeks. At the age of 24 weeks, we measured body weight (BW), plasma glucose, insulin, C-peptide levels. And we performed IPGTT and insulin tolerance test (ITT) in two groups. Thereafter, we determined the insulin content of pancreas and epididymal fat weight.
RESULTS
Body weight was significantly higher in rosiglitazone group than control group. On IPGTT, plasma glucose, insulin and C-peptide levels were not significantly different between two groups. But, on insulin tolerance test, Kitt (%/min) values of rosiglitazone group were significantly higher than control group (2.7 vs. 1.8). The insulin content of pancreas and epididymal fat weight was not different between two groups.
CONCLUSION
These results suggested that rosiglitazone improved insulin sensitivity in non obese type 2 diabetes rat models independent of glucose level.

Keyword

Diabetes Mellitus; Insulin Sensitivity; Rosiglitazone

MeSH Terms

Animals
Blood Glucose
Body Weight
C-Peptide
Diabetes Mellitus
Glucose
Glucose Tolerance Test
Humans
Infant, Newborn
Insulin Resistance*
Insulin*
Korea
Male
Metabolism*
Models, Animal*
Pancreas
Rats*
Rats, Sprague-Dawley
Streptozocin
C-Peptide
Glucose
Insulin
Streptozocin

Figure

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  Fig. 1 Weight changes after eight weeks rosiglitazone treatment. *P < 0.05 between group A and group B.

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  Fig. 2 Immunohistochemical staining (insulin antibody) of pancreatic islets (×100).

Reference

1. Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes. 2002. 51(3):797–802.

2. Walter H, Lubben G. Potential role of oral thiazolidinedione therapy in preserving beta cell function in type 2 diabetes mellitus. Drugs. 2005. 65(1):1–13.

3. Hales CN, Barker DJP. Type 2 (non-insulin dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992. 35:595–603.

5. Blondel O, Bailbe D, Portha B. Relationship of insulin deficiency to impaired insulin action in NIDDM adult rats given streptozotocin as neonates. Diabetes. 1989. 38:610–617.

6. Wang RN, Bouwens L, Kloppel G. Beta cell growth in adolescent and adult rats treated with streptozotocin during the neonatal period. Diabetologia. 1994. 39:548–557.

7. Weir GC, Clore ET, Zmachinski CJ, Bonnerweir S. Islet secretion in a new experimental model for non insulin dependent diabetes. Diabetes. 1981. 30:590–595.

8. Murali B, Goyal RK. Improvement in insulin sensitivity by losartan in non-insulin-dependent diabetes (NIDDM) rats. Pharmacol Res. 2001. 44:385–389.

9. Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM. A new rat model of type 2 diabetes: the fat-fed streptozotocin-treated rat. Metabolism. 2000. 49:1390–1394.

10. Chang Sang Ah, Cha Bong Yun, Yoo Soon Jib, Ahn Yoo Bae, Song Ki Ho, Han Je Ho, Lee Jong Min, Son Hyun Sik, Yoon Kun Ho, Kang Moo Il, Lee Kwang Woo, Son Ho Young, Kang Sung Ku. The effect of Cilostazol on glucose tolerance and insulin resistance in a rat model of non-insulin dependent diabetes mellitus. Korean J Intern Med. 2001. 16:87–92.

11. Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, Leibowitz MD. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-γ binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology. 1996. 137:4189–4195.

12. Kemnitz JW, Elson DF, Roecker EB, Baum ST, Bergman RN, Meglasson MD. Pioglitazone increase insulin sensitivity, reduces blood glucose, insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure in obese, insulin-resistant rhesus monkeys. Diabetes. 1994. 43:204–211.

13. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus; a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998. 128:176–185.

14. Patel J, Anderson RJ, Rappaport EB. Rosiglitazone monotherapy improve glycemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes, Obesity and Metabolism. 1999. 1:165–172.

15. Mori Y, Murakawa Y, Okada K, Horikoshi H, Yokoyama J, Yajima N, Ikeda Y. Effects of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care. 1999. 22:908–912.

16. Inzucchi SE, Maggs D, Spollet GR, Page SL, Rife FS, Walton V, Shulman GI. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Eng J Med. 1998. 338:867–872.

17. Miyazaki Y, Matsuda M, Defronzo R. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes care. 2002. 25:517–523.

18. Burant CF, Sreenan S, Hirano K, Tai TA, Lohmiller J, Lukens J, Davidson NO, Ross S, Graves RA. Troglitazone action is independent of adipose tissue. J Clin Invest. 1997. 100:2900–2908.

19. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T. Troglitazone increase the number of small adipocytes without the change of white adipose tissue in obese Zucker rats. J Clin Invest. 1998. 101:1354–1361.

20. Akinmokun A, Selby PL, Ramaiya K, Alberti KGMN. The short insulin tolerance test for the determination of insulin sensitivity: A comparison with the euglycemic clamp. Diabet Med. 1992. 9:432–437.

21. Hirst S, Phillips DIW, Vines SK, Clark PM, Hales CN. Reproducibility of the short insulin tolerance test. Diabet Med. 1993. 10:839–842.

22. Grulet H, Durlach V, Hecart AC, Gross A, Leutenegger M. Study of the rate of early glucose disappearance following insulin injection: insulin sensitivity index. Diab Res Clin Pract. 1993. 20:201–217.

23. Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nature Med. 1996. 2:800–802.

24. Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell. 1996. 87:377–389.

25. Berg AH, Combs TP, Du X, Brownlee M, Scherer P. The adipocyte-secreted protein Acrp 30 enhances hepatic insulin action. Nature Med. 2001. 7:947–953.

26. Finegood DT, McArthur MD, Kojwang D, Thomas MJ, Topp BG, Leonard T, Buckingham RE. Beta-cell mass dynamic in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes. 2001. 50:1021–1029.