Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo

被引:418
作者
Ring, DB
Johnson, KW
Henriksen, EJ
Nuss, JM
Goff, D
Kinnick, TR
Ma, ST
Reeder, JW
Samuels, I
Slabiak, T
Wagman, AS
Hammond, MEW
Harrison, SD
机构
[1] Univ Arizona, Coll Med, Dept Physiol, Tucson, AZ 85721 USA
[2] Chiron Corp, Emeryville, CA 94608 USA
关键词
D O I
10.2337/diabetes.52.3.588
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K-i < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at similar to100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes.
引用
收藏
页码:588 / 595
页数:8
相关论文
共 46 条
[41]   The role of glycogen synthase kinase 3β in insulin-stimulated glucose metabolism [J].
Summers, SA ;
Kao, AW ;
Kohn, AD ;
Backus, GS ;
Roth, RA ;
Pessin, JE ;
Birnbaum, MJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (25) :17934-17940
[42]   LITHIUM INCREASES SUSCEPTIBILITY OF MUSCLE GLUCOSE-TRANSPORT TO STIMULATION BY VARIOUS AGENTS [J].
TABATA, I ;
SCHLUTER, J ;
GULVE, EA ;
HOLLOSZY, JO .
DIABETES, 1994, 43 (07) :903-907
[43]  
TANTI JF, 1994, J BIOL CHEM, V269, P6051
[44]   A RAPID FILTER PAPER ASSAY FOR UDPGLUCOSE-GLYCOGEN GLUCOSYLTRANSFERASE INCLUDING AN IMPROVEDBIOSYNTHESIS OF UDP-14C-GLUCOSE [J].
THOMAS, JA ;
SCHLENDER, KK ;
LARNER, J .
ANALYTICAL BIOCHEMISTRY, 1968, 25 (1-3) :486-+
[45]  
WANG YH, 1993, J BIOL CHEM, V268, P23876
[46]   Signalling through the insulin receptor [J].
Whitehead, JP ;
Clark, SF ;
Urso, B ;
James, DE .
CURRENT OPINION IN CELL BIOLOGY, 2000, 12 (02) :222-228