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

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.

• Authors: Shaoxin Ma, Tao Li, Keke Guo, Xin Li, Shanshan An, Shanshan Hou, Ru Chen, Bo Yang, Siyu Liu, Jihua Fu
• Journal: Journal of diabetes investigation (J Diabetes Investig) Vol. 7 Issue 6 Pg. 833-844 (Nov 2016) ISSN: 2040-1124 [Electronic] Japan
• PMID: 27177506 (Publication Type: Journal Article)
• Copyright: © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Chemical References

• Receptors, Serotonin, 5-HT2
• Serotonin 5-HT2 Receptor Antagonists
• Succinates
• sarpogrelate
• Serotonin
• Dexamethasone
• Carbidopa

Topics

• Animals
• Body Weight (drug effects)
• Carbidopa (administration & dosage)
• Dexamethasone (administration & dosage)
• Drug Therapy, Combination
• Eating (drug effects)
• Energy Metabolism (drug effects)
• Hyperglycemia (drug therapy)
• Insulin Resistance
• Intra-Abdominal Fat (drug effects, metabolism)
• Liver (drug effects)
• Male
• Muscle, Skeletal (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin, 5-HT2 (metabolism)
• Serotonin (biosynthesis)
• Serotonin 5-HT2 Receptor Antagonists (administration & dosage)
• Succinates (administration & dosage)