Ameliorating Effects of Sulfonylurea Drugs on Insulin Resistance in Otsuka Long-Evans Tokushima Fatty Rats

Jeong-Kwon Park; Sang-Pyo Kim; Dae-Kyu Song

doi:10.4196/kjpp.2008.12.1.7

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Park, Kim, and Song: Ameliorating Effects of Sulfonylurea Drugs on Insulin Resistance in Otsuka Long-Evans Tokushima Fatty Rats

Original Article

Korean J Physiol Pharmacol 2008;12(1):7-12.

Published online: 17 February 2008

DOI: https://doi.org/10.4196/kjpp.2008.12.1.7

Ameliorating Effects of Sulfonylurea Drugs on Insulin Resistance in Otsuka Long-Evans Tokushima Fatty Rats

Jeong-Kwon Park¹, Sang-Pyo Kim², Dae-Kyu Song¹

¹Department of Physiology and Chronic Disease Research Center, Daegu 700-712, Korea

²Department of Pathology, Keimyung University School of Medicine, Daegu 700-712, Korea

Correspondence to: Dae-Kyu Song, Department of Physiology, Keimyung University School of Medicine, 194, Dongsan-dong, Jung-gu, Daegu 700-712, Korea. (Tel) 82-53-250-7490, (Fax) 82-53-252-1605, (E-mail) dksong@kmu.ac.kr; dksong@dsmc.or.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

OLETF (Otsuka Long-Evans Tokushima Fatty) rats are characterized by obesity-related insulin resistance, which is a phenotype of type 2 diabetes. Sulfonylurea drugs or benzoic acid derivatives as inhibitors of the ATP-sensitive potassium (K_ATP) channel are commercially available to treat diabetes. The present study compared sulfonylurea drugs (glimepiride and gliclazide) with one of benzoic acid derivatives (repaglinide) in regard to their long-term effect on ameliorating insulin sensitivity in OLETF rats. Each drug was dissolved and fed with drinking water from 29 weeks of age. On high glucose loading at 45 weeks of age, response of blood glucose recovery was the greatest in the group treated with glimepiride. On immunohistochemistry analysis for the Kir6.2 subunit of K_ATP channels, insulin receptor β-subunits, and glucose transporters (GLUT) type 2 and 4 in liver, fat and skeletal muscle tissues, the sulfonylurea drugs (glimepiride and gliclazide) were more effective than repaglinide in recovery from their decreased expressions in OLETF rats. From these results, it seems to be plausible that K_ATP-channel inhibitors containing sulfonylurea moiety may be much more effective in reducing insulin resistance than those with benzoic acid moiety. In contrast to gliclazide, non-tissue selectivity of glimepiride on K_ATP channel inhibition may further strengthen an amelioration of insulin sensitivity unless considering other side effects.

Keywords: Diabetic rat, Sulfonylureas, K_ATP channel, Glucose transporters

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Fig. 1.

Effect of gliclazide, glimepiride or repaglinide on changes in blood glucose level in response to high glucose loading (2 g/kg, i.p.) in LETO and OLETF rats. Each drug was dissolved in drinking water during 29 through 44 weeks of age. The experiments were done with rats aged at 45 weeks, after fasting for 12 h before the experiments. Data represent mean±S.E. ^# p<0.05 compared to the value of OLETF control rats at the same time period. n=7 except LETO group (n=5).

Fig. 2.

Representative photomicrographs of Kir6.2 staining in murine fat and liver. (A) Kir6.2 is expressed in the cell membrane of adipocytes in LETO rat, whereas Kir6.2 staining is markedly reduced in OLETF rat. It is recovered by treatment with gliclazide or glimepiride. (B) Kir6.2 is expressed on the sinusoids of hepatocytes in LETO rat, but it is markedly reduced in OLETF rat. Staining is increased at the sinusoids by treatment with gliclazide, repaglinide or glimepiride.

Fig. 3.

Representative photomicrographs of IR-β staining in murine fat and liver. (A) IR-β is expressed in the cell membrane of adipocytes of LETO rat, whereas staining is less in the cytoplasmic membrane in OLETF rat. It is recovered by treatment with gliclazide or glimepiride. (B) IR-β is strongly expressed on the sinusoids of hepatocytes in LETO rat, but it is markedly reduced in OLETF rat. Staining is increased at the sinusoids by treatment with gliclazide or glimepiride.

Fig. 4.

Representative photomicrographs of GLUT-2 staining in murine liver. GLUT-2 is expressed in the sinusoids of hepatocytes in LETO rat, whereas GLUT-2 immunoreactivity is reduced in OLETF rat. In the groups treated with gliclazide, repaglinide, or glimepiride, GLUT-2 expression is enhanced.

Fig. 5.

Representative photomicrographs of GLUT-4 staining in murine fat and skeletal muscles. (A) GLUT-4 is expressed in the cell membrane of adipocytes in LETO rat, whereas staining is faintly present in OLETF rat. In the groups treated with gliclazide or glimepiride, expression of GLUT-4 is markedly increased. (B) GLUT-4 is expressed in the sarcolemma of skeletal muscles of LETO rat, whereas staining is reduced in OLETF rat. In the groups treated with gliclazide or glimepiride, the expression of GLUT-4 is increased.

Table 1.

Intensity of immunoflorescence of Kir6.2, IR-β, GLUT2, and GLUT4 in rat fat, liver, and skeletal muscle tissues

	LETO (n=5)	OLETF(O) (n=7)	O+Gliclazide (n=7)	O+Glimepiride (n=7)	O+Repaglinide (n=7)
	(Fluorescence intensity, arbitrary units)
Kir6.2
Fat	3.0±0.45	2.7±0.45	5.7±0.67^∗	5.0±1.00^∗	2.3±0.2
Liver	3.5±0.41	3.0±0.58	5.7±0.88^∗	5.7±0.33^∗	4.7±0.88^∗
Muscle	4.5±0.41	5.3±0.88	4.0±0.55	4.0±1.00	4.3±0.33
IR-β
Fat	4.5±0.41	4.0±0.58	6.3±0.67^∗	6.7±0.33^∗	4.3±0.33
Liver	6.5±0.41	2.7±1.45	5.7±0.33^∗	5.0±0.45^∗	2.3±0.45
Muscle	3.5±0.41	3.7±0.88	2.7±0.33	3.3±0.88	3.0±0.58
GLUT2
Liver	4.0±0.34	1.0±0.12	4.0±0.33^∗	4.7±0.33^∗	4.2±0.67^∗
GLUT4
Fat	4.0±0.82	3.0±0.88	5.0±0.65^∗	5.0±0.67^∗	4.3±0.58
Muscle	4.5±0.22	3.7±0.86	5.0±0.45^∗	5.0±0.58^∗	2.7±0.33

^∗ p<0.05 compared to the values of OLETF control rats. Data represent mean ± S.E. The n is number of animals. One data point was obtained from one rat.

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