title: Exendin-4 reduces glycemia by increasing liver glucokinase activity: an insulin independent effect.
abstract: Exendin-4 is a stable peptide agonist of GLP-1 receptor that exhibits insulinotropic actions. Some in vivo studies indicated insulin-independent 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 cAMP degradation. The GLP-1 antagonist, exendin 9-39, has abolished the cAMP generating 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.
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India.
authors.forename: Nirav
authors.initials: N
authors.lastname: Dhanesha
authors.forename: Amit
authors.initials: A
authors.lastname: Joharapurkar
authors.forename: Gaurang
authors.initials: G
authors.lastname: Shah
authors.forename: Vipin
authors.initials: V
authors.lastname: Dhote
authors.forename: Samadhan
authors.initials: S
authors.lastname: Kshirsagar
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bahekar
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D014688:Venoms / Q000494:pharmacology*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D006003:Glycogen; D000077270:Exenatide; D000242:Cyclic AMP; D005941:Glucokinase; D005947:Glucose