Treatment with exendin-4 improves the antidiabetic efficacy and reverses hepatic steatosis in glucokinase activator treated db/db mice

Eur J Pharmacol. 2013 Aug 15;714(1-3):188-92. doi: 10.1016/j.ejphar.2013.06.015. Epub 2013 Jun 25.


The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex-4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver.

Keywords: Diabetes; Exendin-4; Glucokinase; Obesity; Steatosis; db/db mice.

MeSH terms

  • Animals
  • Benzeneacetamides / pharmacology*
  • Benzeneacetamides / therapeutic use
  • Body Weight / drug effects
  • Drug Synergism
  • Eating / drug effects
  • Enzyme Activation / drug effects
  • Exenatide
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Glucokinase / metabolism*
  • Glucose / metabolism
  • Glycogen / metabolism
  • Homeostasis / drug effects
  • Hyperglycemia / drug therapy
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptides / pharmacology*
  • Venoms / pharmacology*


  • Benzeneacetamides
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • Venoms
  • Glycogen
  • Exenatide
  • piragliatin
  • Glucokinase
  • Glucose