In:
Pharmacology, S. Karger AG, Vol. 107, No. 1-2 ( 2022), p. 54-68
Abstract:
〈 b 〉 〈 i 〉 Introduction: 〈 /i 〉 〈 /b 〉 The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic 〈 i 〉 db 〈 /i 〉 / 〈 i 〉 db 〈 /i 〉 mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 〈 b 〉 14b) 〈 /b 〉 improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic 〈 i 〉 db 〈 /i 〉 / 〈 i 〉 db 〈 /i 〉 mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 〈 b 〉 14b 〈 /b 〉 treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 〈 b 〉 14b 〈 /b 〉 decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 〈 b 〉 14b 〈 /b 〉 were associated with the activation of the G-protein-coupled bile acid receptor TGR5. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 Compound 〈 b 〉 14b 〈 /b 〉 exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.
Type of Medium:
Online Resource
ISSN:
0031-7012
,
1423-0313
Language:
English
Publisher:
S. Karger AG
Publication Date:
2022
detail.hit.zdb_id:
206671-3
detail.hit.zdb_id:
1483550-2
SSG:
15,3
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