Inhibition of tumor necrosis factor-α with anti-diabetic agents

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Abstract

It has recently been indicated that tumor necrosis factor-α (TNF-α) production is increased under chronic hyperglycemia and TNF-α has harmful effects on insulin sensitivity and possibly on chronic diabetic complications. Therefore it will be favorable for diabetes treatment if anti-diabetic agents also have anti-TNF-α activities. In this study, we have investigated effects of hypoglycemic sulfonylureas (gliclazide and glibenclamide) and a thiazolidinedione (troglitazone) on lipopolysaccharide-induced TNF-α production, which was evaluated by immunoassay and bioassay, in vivo using mice and partly in vitro using human peripheral blood mononuclear cells. Gliclazide significantly inhibited TNF-α production in vivo and also in vitro at a concentration of 10−3 mol/l. However, glibenclamide had neither effect on TNF-α production nor action. On the other hand, troglitazone inhibited action rather than production of TNF-α in vivo. In vitro troglitazone (10−4 mol/l) significantly reduced cytolytic activity of TNF-α against LM cells. These results indicate that gliclazide and troglitazone have inhibitory effect on TNF-α.

Introduction

It has been reported that tumor necrosis factor-α (TNF-α) production is increased under chronic hyperglycemia in diabetic animals [1], [2] and high concentration of glucose per se also increases expression of TNF-α by human peripheral blood mononuclear cells in vitro [3]. Furthermore, it has been recently reported that TNF-α expression of adipocytes significantly increased in obese animals [4]. The increased TNF-α production has been indicated to mediate some pathological condition in diabetes mellitus such as insulin resistance [4] and diabetic complications [5]. TNF-α induces insulin resistance by suppressing the insulin signal transduction in muscles and adipose tissues [6] and neutralization of TNF-α ameliorates insulin resistance in an obese animal model [7]. We have recently reported that angiotensin converting enzyme (ACE) inhibitors, which are known to have insulin sensitizing effect, suppress TNF-α production by human peripheral blood mononuclear cells (PBMC) and in mice [8]. Furthermore, we have reported that administration of N-acetylcysteine which is an inhibitor of TNF-α production and a free radical scavenger suppresses development of diabetic neuropathy in diabetic rats [9]. Thus, inhibition of the increased production of TNF-α in diabetic state may be beneficial in terms of insulin resistance and chronic diabetic complications. In this study, therefore, we investigated inhibitory effects on TNF-α of hypoglycemic sulfonylureas (gliclazide and glibenclamide) and an insulin sensitizer, thiazolidinedione (troglitazone).

Section snippets

Anti-diabetic agents

Gliclazide (Dainippon Pharmaceutical Co., Osaka, Japan), glibenclamide (Yamanouchi Pharmaceutical Co., Tokyo, Japan) and troglitazone (Sankyo Co., Tokyo, Japan), kindly provided by the companies, were used as anti-diabetic agents. Ascorbic acid (Sigma, St. Louis, MO, USA), a free radical scavenger, was used as a control for gliclazide in in vitro study. Gliclazide as a form of gliclazide sodium and ascorbic acid were dissolved in phosphate-buffered saline (PBS). Troglitazone and glibenclamide

Effect of anti-diabetic agents on LPS-induced serum TNF-α in vivo

To investigate the effect of anti-diabetic agents on TNF-α in vivo, gliclazide, glibenclamide and troglitazone were pre-administered to Balb/c mice and then LPS was intraperitoneally injected. Then blood was taken and serum was measured for TNF activities by bioassay and TNF-α immunoreactivity by ELISA. As shown in Fig. 1, serum TNF activities were significantly inhibited by pre-administration of gliclazide with dose of more than 10-fold of the common clinical use for man and was also inhibited

Discussion

In this study, we have shown that gliclazide and troglitazone have inhibitory effect on production or action of TNF-α. In vivo gliclazide significantly inhibited LPS-induced TNF-α measured by bioassay (Fig. 1) and immunoassay (Fig. 2). Doses of gliclazide and glibenclamide administered in the experiment were determined based on the common clinical use, and both gliclazide and glibenclamide gave the similar hypoglycemic effects in mice (Table 1). However, glibenclamide had no effect on TNF-α in

Acknowledgements

This work was supported in part by a grant for Diabetes Research from the Ministry of Health and Public Welfare of Japan and by Grants-in-Aid for Scientific Research (06670997) from the Ministry of Education, Science, Sports and Culture, Japan.

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