Short-term in vitro inhibition of glycogen synthase kinase 3 potentiates insulin signaling in type I skeletal muscle of Zucker Diabetic Fatty rats.
Overactivity of glycogen synthase kinase 3 (GSK-3) is associated with insulin resistance of skeletal muscle glucose transport in prediabetic and type 2 diabetic rodent models. However, limited information is available concerning the potential molecular mechanisms underlying the role GSK-3 plays in the etiology of insulin resistance in the male Zucker Diabetic Fatty (ZDF) rat, a model of type 2 diabetes mellitus. Therefore, we assessed the functionality of proximal and distal insulin signaling elements in isolated type I (slow-twitch oxidative) soleus muscles of ZDF rats after in vitro exposure to a selective GSK-3 inhibitor (1 micromol/L CT98014, K(i) <10 nmol/L for GSK-3alpha and GSK-3beta). Moreover, Ser307 phosphorylation of insulin receptor substrate 1 (IRS-1), which has been implicated in the development of insulin resistance, was also determined in the absence or presence of this GSK-3 inhibitor. Maximally insulin-stimulated (5 mU/mL) GSK-3beta serine phosphorylation was significantly less (35%, P < .05) in soleus muscle of ZDF rats compared with insulin-sensitive lean Zucker rats, indicating GSK-3 overactivity. In the absence of insulin, no effects of GSK-3 inhibition were detected. GSK-3 inhibition led to significant enhancement (28%) of insulin-stimulated glucose transport activity that was associated with significant up-regulation of tyrosine phosphorylation of IR (52%) and IRS-1 (50%), and with enhanced Akt Ser473 phosphorylation (48%) and GSK-3beta Ser9 phosphorylation (36%). Moreover, the selective GSK-3 inhibitor induced a significant reduction in the phosphorylation of IRS-1 Ser307 (26%) and c-jun N-terminal kinases 1 and 2 (31%), a mediator of IRS-1 Ser307 phosphorylation. These results indicate that selective inhibition of GSK-3 activity in type I skeletal muscle from overtly diabetic ZDF rats enhances IRS-1-dependent insulin signaling, possibly by a decrease in c-jun N-terminal kinase activation and a diminution of the deleterious effects of IRS-1 Ser307 phosphorylation.
Henriksen
Erik J
EJ
Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA. ejhenrik@u.arizona.edu
Teachey
Mary K
MK
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D051550:I-kappa B Kinase / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3; D005947:Glucose