title: Antihyperglycaemic activity of 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal in diabetic mice.
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-[(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.
authors.affiliation: Department of Pharmacology, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Gruzman
authors.forename: Anna
authors.initials: A
authors.lastname: Elgart
authors.forename: Olga
authors.initials: O
authors.lastname: Viskind
authors.forename: Hana
authors.initials: H
authors.lastname: Billauer
authors.forename: Sharon
authors.initials: S
authors.lastname: Dotan
authors.forename: Guy
authors.initials: G
authors.lastname: Cohen
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
authors.forename: Erol
authors.initials: E
authors.lastname: Cerasi
authors.forename: Shlomo
authors.initials: S
authors.lastname: Sasson
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000080:Acetals / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001597:Benzylidene Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis; D006321:Heart / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013865:Thioglycosides / Q000008:administration & dosage / Q000627:therapeutic use*; D014316:Tritium
chemical_list: C572700:2,4-3,5-dibenzylidenexylose diethyl dithioacetal; D000080:Acetals; D001597:Benzylidene Compounds; D001786:Blood Glucose; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D013865:Thioglycosides; D014316:Tritium; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases