Exendin-4 reduces glycemia by increasing liver glucokinase activity: An insulin independent effect

Exendin-4 is a stable peptide agonist of glp-1 receptor that exhibits insulinotropic actions. some in vivo studies indicated insulinindependent glucoregulatory actions of exendin-4. that finding prompted us to evaluate effects of exendin-4 on liver glucose metabolism. acute and chronic treatment of exendin-4 resulted in increased hepatic glucokinase activity in db/db mice but not in lean c57 mice. the stimulatory effect of exendin-4 on glucokinase activity was abrogated by exendin 9-39,a glp-1 antagonist. exposure of hepatocytes isolated from db/db mice to exendin-4 elicited a rapid increase in camp,which was synergized by ibmx,an inhibitor of campdegradation. the glp-1 antagonist,exendin 9-39,has abolished the campgenerating effects of exendin-4 as well. furthermore,chronic treatment of exendin-4 in streptozotocin-treated c57 mice resulted in restoration of hepatic glycogen,an indicator of improved glucose metabolism,without apparent changes in serum insulin levels. in conclusion,exendin-4 increased glucokinase enzyme protein and activity in liver via a mechanism parallel to and independent of insulin. exendin-4-induced increase in hepatic glucokinase activity is more pronounced in the presence of hepatic insulin resistance. this beneficial effect of exendin-4 on liver glucokinase activity may be mediated by glp-1 receptor. copyright © 2012 by institute of pharmacology polish academy of sciences.