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- Title
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.
- Authors
Ma, Shaoxin; Li, Tao; Guo, Keke; Li, Xin; An, Shanshan; Hou, Shanshan; Chen, Ru; Yang, Bo; Liu, Siyu; Fu, Jihua
- Abstract
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- HT2R) in the periphery. The present study examined the effects of inhibitions of both peripheral 5- HT synthesis and 5- HT2R on dexamethasone-induced IR. Materials and Methods Male rats were exposed to dexamethasone for 10 days, then treated with or without a 5- HT2R 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- HT2R (5- HT2AR and 5- HT2BR) 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- HT2R are expected to be a dependable target for treatment of steroid-induced diabetes.
- Subjects
INSULIN resistance; SEROTONIN; DEXAMETHASONE; CARBIDOPA; DYSLIPIDEMIA
- Publication
Journal of Diabetes Investigation, 2016, Vol 7, Issue 6, p833
- ISSN
2040-1116
- Publication type
Article
- DOI
10.1111/jdi.12526