Novel D-xylose derivatives stimulate muscle glucose uptake by activating AMP-activated protein kinase alpha.
Type 2 diabetes mellitus has reached epidemic proportions; therefore, the search for novel antihyperglycemic drugs is intense. We have discovered that D-xylose increases the rate of glucose transport in a non-insulin-dependent manner in rat and human myotubes in vitro. Due to the unfavorable pharmacokinetic properties of D-xylose we aimed at synthesizing active derivatives with improved parameters. Quantitative structure-activity relationship analysis identified critical hydroxyl groups in D-xylose. These data were used to synthesize various hydrophobic derivatives of D-xylose of which compound 19 the was most potent compound in stimulating the rate of hexose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of myotubes. This effect resulted from the activation of AMP-activated protein kinase without recruiting the insulin transduction mechanism. These results show that lipophilic D-xylose derivatives may serve as prototype molecules for the development of novel antihyperglycemic drugs for the treatment of diabetes.
Gruzman
Arie
A
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, 91120 Jerusalem, Israel.
Shamni
Ofer
O
Ben Yakir
Moriya
M
Sandovski
Daphna
D
Elgart
Anna
A
Alpert
Evgenia
E
Cohen
Guy
G
Hoffman
Amnon
A
Katzhendler
Yehoshua
Y
Cerasi
Erol
E
Sasson
Shlomo
S
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy; D015195:Drug Design; D004789:Enzyme Activation; D005947:Glucose / Q000493:pharmacokinetics*; D051275:Glucose Transporter Type 4 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D009132:Muscles / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014994:Xylose / Q000737:chemistry*
D051275:Glucose Transporter Type 4; C495692:SLC2A4 protein, human; D014994:Xylose; D055372:AMP-Activated Protein Kinases; D005947:Glucose