Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3.
Glycogen synthase kinase-3 (GSK-3) was shown to be a key factor in attenuation of the cellular action of insulin. We speculated that inhibition of GSK-3 might have a potential therapeutic value in treatment of insulin resistance and type 2 diabetes. Here, we present a novel class of specific phosphorylated peptides inhibitors of GSK-3, which in sharp contrast to other protein kinase inhibitors that are ATP analogs, are substrate-competitive. We show that the GSK-3 peptide inhibitor activated glycogen synthase activity 2.5-fold in human embryonic kidney 293 cells, and increased glucose uptake in primary mouse adipocytes in the absence or presence of insulin compared with cells treated with two respective peptide controls. In addition, an i.p. administration of GSK-3 peptide inhibitor to normal or insulin-resistant obese C57BL/6J mice, improved their performance on glucose tolerance tests compared with control-treated animals. We present here a novel rational strategy for developing specific GSK-3 inhibitors and point toward GSK-3 as a promising therapeutic target in insulin resistance and type-2 diabetes.
Plotkin
Batya
B
Department of Human Genetics and Molecular Medicine, Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Kaidanovich
Oksana
O
Talior
Ilana
I
Eldar-Finkelman
Hagit
H
D017667:Adipocytes; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004041:Dietary Fats; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation
D004041:Dietary Fats; D007328:Insulin; D010455:Peptides; D006006:Glycogen Synthase; D038362:Glycogen Synthase Kinase 3