Antihyperglycaemic activity of 2,4:3,5‐dibenzylidene‐D‐xylose‐diethyl dithioacetal in diabetic mice

Journal of Cellular and Molecular Medicine

Arie Gruzman¹  Anna Elgart²  Olga Viskind¹  Hana Billauer³  Sharon Dotan³  Guy Cohen¹  Eyal Mishani³  Amnon Hoffman²  Erol Cerasi⁴ 

[1] Department of Pharmacology, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel;Department of Pharmaceutics, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel;Department of Nuclear Medicine, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel;Endocrinology and Metabolism Service, Department of Internal Medicine, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel

关键词: AMPK;    antihyperglycaemic drugs;    D‐xylose derivatives;    diabetes;    glucose transport;    hyperglycaemia;    KKAy mice;   

DOI  :  10.1111/j.1582-4934.2011.01340.x

来源: Wiley

【 摘 要 】

Abstract

We have recently generated lipophilic D-xylose derivatives that increase the rate of glucose uptake in cultured skeletal muscle cells in an AMP-activated protein kinase (AMPK)-dependent manner. The derivative 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal (EH-36) stimulated the rate of glucose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of cultured myotubes. The present study aimed at investigating potential antihyperglycaemic effects of EH-36 in animal models of diabetes. Two animal models were treated subcutaneously with EH-36: streptozotocin-induced diabetes in C57BL/6 mice (a model of insulin-deficient type 1 diabetes), and spontaneously diabetic KKAy mice (Kuo Kondo rats carrying the A^y yellow obese gene; insulin-resistant type 2 diabetes). The in vivo biodistribution of glucose in control and treated mice was followed with the glucose analogue 2-deoxy-2-[¹⁸F]-D-glucose; the rate of glucose uptake in excised soleus muscles was measured with [³H]-2-deoxy-D-glucose. Pharmacokinetic parameters were determined by non-compartmental analysis of the in vivo data. The effective blood EH-36 concentration in treated animals was 2 μM. It reduced significantly the blood glucose levels in both types of diabetic mice and also corrected the typical compensatory hyperinsulinaemia of KKAy mice. EH-36 markedly increased glucose transport in vivo into skeletal muscle and heart, but not to adipose tissue. This stimulatory effect was mediated by Thr¹⁷²-phosphorylation in AMPK. Biochemical tests in treated animals and acute toxicological examinations showed that EH-36 was well tolerated and not toxic to the mice. These findings indicate that EH-36 is a promising prototype molecule for the development of novel antidiabetic drugs.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd