Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: Molecular characterization in liver and muscle

被引:99
作者
Kaidanovich-Beilin, O [1 ]
Eldar-Finkelman, H [1 ]
机构
[1] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel
关键词
D O I
10.1124/jpet.105.090266
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Glycogen synthase kinase-3 (GSK-3) is critically involved in insulin signaling, and its selective inhibition may present a new therapy for treatment of insulin resistance and type 2 diabetes. The current studies were designed to examine the impact of long-term in vivo inhibition of GSK-3 and its effects in the specific tissues. ob/ob mice were treated daily with one dose (400 nmol, i.p.) of a selective GSK-3 peptide inhibitor, L803-mts, for 3 weeks. Treatment with L803-mts reduced blood glucose levels, improved glucose tolerance, and prevented elevation of hyperglycemia with age. However, L803-mts did not affect either body weight or food consumption and was not toxic, as judged by histopathology and blood chemistry analyses. Consistent with these results, L803-mts suppressed mRNA levels of hepatic phosphoenolpyruvate carboxykinase (PEPCK) (50%) and increased hepatic glycogen content by 50%. On the other hand, L803-mts did not affect glucose 6-phosphate (G-6-P) phosphatase (G-6-Pase) mRNA levels or its enzymatic activity in the liver. Investigation for possible mechanisms responsible for PEPCK suppression indicated that phosphorylation of cAMP-responsive element transcription factor ( CREB) at Ser(133) was reduced remarkably by L803-mts, which was also associated with reduced phosphorylation at Ser(129) and no change in total CREB. This suggested that PEPCK was suppressed by GSK-3 inhibition-mediated inactivation of CREB. In skeletal muscle, treatment with L803-mts led both to up-regulation in GLUT4 expression and to a 20% increase in glycogen content. Our studies show that long-term treatment with GSK-3 inhibitor improves glucose homeostasis in ob/ob mice and demonstrates a novel role of GSK-3 in regulating hepatic CREB activity and expression of muscle GLUT4.
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页码:17 / 24
页数:8
相关论文
共 40 条
[1]   DIURNAL-VARIATIONS OF FOOD-CONSUMPTION, PLASMA GLUCOSE AND PLASMA-INSULIN CONCENTRATIONS IN LEAN AND OBESE HYPERGLYCEMIC MICE [J].
BAILEY, CJ ;
ATKINS, TW ;
CONNER, MJ ;
MANLEY, CG ;
MATTY, AJ .
HORMONE RESEARCH, 1975, 6 (5-6) :380-386
[2]   Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1 [J].
Biggs, WH ;
Meisenhelder, J ;
Hunter, T ;
Cavenee, WK ;
Arden, KC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (13) :7421-7426
[3]   Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (falfa) rats [J].
Cline, GW ;
Johnson, K ;
Regittnig, W ;
Perret, P ;
Tozzo, E ;
Xiao, L ;
Damico, C ;
Shulman, GI .
DIABETES, 2002, 51 (10) :2903-2910
[4]   Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription [J].
Coghlan, MP ;
Culbert, AA ;
Cross, DAE ;
Corcoran, SL ;
Yates, JW ;
Pearce, NJ ;
Rausch, OL ;
Murphy, GJ ;
Carter, PS ;
Cox, LR ;
Mills, D ;
Brown, MJ ;
Haigh, D ;
Ward, RW ;
Smith, DG ;
Murray, KJ ;
Reith, AD ;
Holder, JC .
CHEMISTRY & BIOLOGY, 2000, 7 (10) :793-803
[5]  
Cohen Paul, 2003, Current Drug Targets - Immune Endocrine and Metabolic Disorders, V3, P271, DOI 10.2174/1568008033340117
[6]   Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice [J].
Eldar-Finkelman, H ;
Schreyer, SA ;
Shinohara, MM ;
LeBoeuf, RC ;
Krebs, EG .
DIABETES, 1999, 48 (08) :1662-1666
[7]   Glycogen synthase kinase 3: an emerging therapeutic target [J].
Eldar-Finkelman, H .
TRENDS IN MOLECULAR MEDICINE, 2002, 8 (03) :126-132
[8]   Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action [J].
EldarFinkelman, H ;
Krebs, EG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (18) :9660-9664
[9]   EFFECTS OF GLUCOSE ON THE ACTIVATION AND TRANSLOCATION OF GLYCOGEN-SYNTHASE IN DIABETIC RAT HEPATOCYTES [J].
FERNANDEZNOVELL, JM ;
ARINO, J ;
GUINOVART, JJ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1994, 226 (02) :665-671
[10]  
FIOL CJ, 1994, J BIOL CHEM, V269, P32187