Inhibition of tumor necrosis factor-α with anti-diabetic agents
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.
References (41)
- et al.
Increased in vivo production of tumor necrosis factor after development of diabetes in nontreated, long-term diabetic BB rats
Clin. Immunol. Immunopathol.
(1992) - et al.
Inhibition with N-acetylcysteine of enhanced production of tumor necrosis factor in streptozotocin-induced diabetic rats
Clin. Immunol. Immunopathol.
(1994) - et al.
Tumor necrosis factor-α suppress insulin-induced tyrosine phosphorylation of insulin receptor and its substrates
J. Biol. Chem.
(1993) - et al.
Angiotensin converting enzyme inhibitors suppress production of tumor necrosis factor-α in vitro and in vivo
Immunopharmacology
(1997) - et al.
Inhibitory effect of nicotinamide on in vitro and in vivo production of tumor necrosis factor-α
Immunol. Lett.
(1997) - et al.
Gliclazide inhibits diabetic neuropathy irrespective of blood glucose levels in streptozotocine-induced diabetic rats
Metabolism
(1998) - et al.
Gliclazide: a general free radical scavenger
Eur. J. Pharmacol.
(1991) - et al.
Effect of gliclazide on prostaglandin l2 formation in normal and streptozotocin-induced diabetic animals
Jpn. J. Pharmacol.
(1983) - et al.
Prostacyclin analogs suppress the synthesis of tumor necrosis factor-α in LPS-stimulated human peripheral blood mononuclear cells
Immunopharmacology
(1993) - et al.
An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ)
J. Biol. Chem.
(1995)
Cytotoxic activities of tumor necrosis factor is mediated by early damage of mitochondrial functions
J. Biol. Chem.
The new oral hypoglycemic agent, troglitazone inhibits the lipid peroxidation of human plasma low density lipoprotein in vitro
Biochem. Pharmacol.
Inhibition of tumor necrosis factoralpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat
Neurosci. Lett.
Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro
Diabetes
Tumor necrosis factor a: a key component of the obesity–diabetes link
Diabetes
Serum TNF-α levels and diabetic complications in NIDDM patients
Diabetologia (Suppl.)
Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance
Science
Inhibition of development peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine
Diabetologia
The relationship between the pharmacokinetics and pharmacodynamic effects of oral hypoglycaemic drugs
Clin. Pharmcokinet.
Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats
Diabetes
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