Glycogen synthase kinase-3 inhibition enhances glucose disposal in prediabetic obese rats
Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats.
“Increasing evidence supports a negative role of glycogen synthase kinase-3 (GSK-3) in regulation of skeletal muscle glucose transport. We assessed the effects of chronic treatment of insulin-resistant, prediabetic obese Zucker (fa/fa) rats with a highly selective GSK-3 inhibitor (CT118637) on glucose tolerance, whole body insulin sensitivity, plasma lipids, skeletal muscle insulin signaling, and in vitro skeletal muscle glucose transport activity,” researchers in the United States report.
Text continued belowB.B. Dokken and colleagues at the University of Arizona explained, “Obese Zucker rats were treated with either vehicle or CT118637 (30 mg/kg body wt) twice per day for 10 days.”
Data showed, “Fasting plasma insulin and free fatty acid levels were reduced by 14 and 23% (p<0.05), respectively, in GSK-3 inhibitor-treated animals compared with vehicle-treated controls. The glucose response during an oral glucose tolerance test was reduced by 18% (p<0.05), and whole body insulin sensitivity was increased by 28% (p<0.05).”
The researchers continued, “In vivo insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (50%) and IRS-1-associated phosphatidylinositol-3’ kinase (79%) relative to fasting plasma insulin levels were significantly elevated (p<0.05) in plantaris muscles of GSK-3 inhibitor-treated animals. Whereas basal glucose transport in isolated soleus and epitrochlearis muscles was unaffected by chronic GSK-3 treatments, insulin stimulation of glucose transport above basal was significantly enhanced (32-60%, p<0.05).”
“In summary,” concluded the authors, “chronic treatment of insulin-resistant, prediabetic obese Zucker rats with a specific GSK-3 inhibitor enhances oral glucose tolerance and whole body insulin sensitivity and is associated with an amelioration of dyslipidemia and an improvement in IRS-1-dependent insulin signaling in skeletal muscle. These results provide further evidence that selective targeting of GSK-3 in muscle may be an effective intervention for the treatment of obesity-associated insulin resistance.”
Dokken and colleagues published their study in American Journal of Physiology - Endocrinology and Metabolism (Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats. Am J Physiol Endocrinol Metab, 2006;291(2):E207-E213).
For additional information, contact E.J. Henriksen, University of Arizona, College Medical, Dept. of Physiol, Muscle Metab Laboratory, POB 210093, Tucson, AZ 85721, USA.
Publisher contact information for the American Journal of Physiology - Endocrinology and Metabolism is: American Physiological Society, 9650 Rockville Pike, Bethesda, MD 20814, USA.