Effective treatment with combination of peripheral 5‐hydroxytryptamine synthetic inhibitor and 5‐hydroxytryptamine 2 receptor antagonist on glucocorticoid‐induced whole‐body insulin resistance with hyperglycemia

AIMS/INTRODUCTION Our previous study found that dexamethasone-induced insulin resistance (IR) was involved in 5-hydroxytryptamine (5-HT) synthesis and 5-hydroxytryptamine 2 receptor (5-HT2 R) in the periphery. The present study examined the effects of inhibitions of both peripheral 5-HT synthesis and 5-HT2 R on dexamethasone-induced IR. MATERIALS AND METHODS Male rats were exposed to dexamethasone for 10 days, then treated with or without a 5-HT2 R antagonist, sarpogrelate, a 5-HT synthetic inhibitor, carbidopa, alone or in combination for 20 days. RESULTS Dexamethasone-induced whole-body IR, with glucose intolerance, decreased insulin sensitivity, hyperglycemia, hyperinsulinemia and dyslipidemia, could be effectively abolished by sarpogrelate or/and carbidopa, whereas IR-related actions of dexamethasone in tissues were accompanied by increased 5-HT synthesis in the liver and visceral adipose, and upregulated 5-HT2 R (5-HT2A R and 5-HT2B R) expression in these two tissues as well as in skeletal muscle. Sarpogrelate or/and carbidopa treatment significantly abolished dexamethasone-caused tissue-specific IR. In the liver, increased gluconeogenesis, triglycerides and very low-density lipoprotein syntheses with steatosis, and downregulated expression of plasmalemmal glucose transporter-2 were markedly reversed. In the visceral adipose and skeletal muscle, downregulated expression of plasmalemmal glucose transporter-4 was significantly reversed, and increased lipolysis was also reversed in the visceral adipose. Dexamethasone-induced activations of hepatic mammalian target of rapamycin serine2448 , and S6K threonine389/412 phosphorylation were also abolished markedly by sarpogrelate or/and carbidopa. Co-treatment with sarpogrelate and carbidopa showed a synergistic effect on suppressing dexamethasone actions. CONCLUSION Inhibitions of both peripheral 5-HT synthesis and 5-HT2 R are expected to be a dependable target for treatment of steroid-induced diabetes.