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.
abstract: OBJECTIVE
  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.
  
  
  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 threonine389/412phosphorylation were also abolished markedly by sarpogrelate or/and carbidopa. Co-treatment with sarpogrelate and carbidopa showed a synergistic effect on suppressing dexamethasone actions.
  
  
  CONCLUSIONS
  Inhibitions of both peripheral 5-HT synthesis and 5-HT2R are expected to be a dependable target for treatment of steroid-induced diabetes.
authors.affiliation: Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Shaoxin
authors.initials: S
authors.lastname: Ma
authors.affiliation: Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Keke
authors.initials: K
authors.lastname: Guo
authors.affiliation: Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: An
authors.affiliation: Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Hou
authors.affiliation: Postgraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Chen
authors.affiliation: Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Undergraduates of China Pharmaceutical University, Nanjing, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Physiology, China Pharmaceutical University, Nanjing, China. jihua_fu@cpu.edu.cn.
authors.forename: Jihua
authors.initials: J
authors.lastname: Fu
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002230:Carbidopa / Q000008:administration & dosage*; D003907:Dexamethasone / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006943:Hyperglycemia / Q000188:drug therapy*; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage*; D013386:Succinates / Q000008:administration & dosage*
chemical_list: D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin; D003907:Dexamethasone; D002230:Carbidopa
keywords: 5-Hydroxytryptamine 2 receptor antagonist; 5-Hydroxytryptamine synthetic inhibitor; Glucocorticoid-induced insulin resistance