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

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‐[ 18 F]‐D‐glucose; the rate of glucose uptake in excised soleus muscles was measured with [ 3 H]‐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 Thr 172 ‐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.