Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle

Betsy B. Dokken, Julie A. Sloniger, Erik J. Henriksen
2005 American Journal of Physiology. Endocrinology and Metabolism  
Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle. Glycogen synthase kinase-3 (GSK3) has been implicated in the multifactorial etiology of skeletal muscle insulin resistance in animal models and in human type 2 diabetic subjects. However, the potential molecular mechanisms involved are not yet fully understood. Therefore, we determined if selective GSK3 inhibition in vitro leads to an improvement in insulin
more » ... n on glucose transport activity in isolated skeletal muscle of insulin-resistant, prediabetic obese Zucker rats and if these effects of GSK3 inhibition are associated with enhanced insulin signaling. Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 M CT118637, Ki Ͻ 10 nM for GSK3␣ and GSK3␤). Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. GSK3 inhibition enhanced (P Ͻ0.05) basal glycogen synthase activity and insulin-stimulated glucose transport in obese epitrochlearis (81 and 24%) and soleus (108 and 20%) muscles. GSK3 inhibition did not modify insulin-stimulated tyrosine phosphorylation of IR ␤-subunit in either muscle type. However, in obese soleus, GSK3 inhibition enhanced (all P Ͻ 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3␤ serine phosphorylation (39%). Substantially smaller GSK3 inhibitor-mediated enhancements of insulin action on these insulin signaling factors were observed in obese epitrochlearis. These results indicate that selective GSK3 inhibition enhances insulin action in insulin-resistant skeletal muscle of the prediabetic obese Zucker rat, at least in part by relieving the deleterious effects of GSK3 action on post-IR insulin signaling. These effects of GSK3 inhibition on insulin action are greater in type I muscle than in type IIb muscle from these insulin-resistant animals. insulin receptor; insulin resistance INSULIN RESISTANCE of skeletal muscle glucose disposal, resulting from defective myocellular insulin signaling, is the earliest and most prominent feature of the prediabetic state, a condition in which individuals are at great risk for the conversion to overt type 2 diabetes (11, 30). Type 2 diabetes is a world-wide epidemic, predicted to affect Ͼ300 million people by the year 2025 (17). Prediabetes, thought to affect ϳ40 million people in the United States, is identified by fasting plasma glucose levels between 100 and 125 mg/dl, which do not reach the diagnostic criteria (Ն126 mg/dl) for diabetes (1). The insulin resistance in
doi:10.1152/ajpendo.00547.2004 pmid:15671078 fatcat:bun5ulxx7ze4rgvckh3lz65ety