title: Exendin-4 ameliorates diabetic symptoms through activation of glucokinase.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) and its stable analogue exendin-4 maintain glucose homeostasis by modulating insulin secretion from pancreatic β-cells and controlling hepatic glucose output. Glucokinase (GK), by catalysing the first step in glycolysis, plays an important role in glucose-stimulated insulin secretion and hepatic glucose metabolism. In the present study, we investigated the effects of exendin-4 on GK in high fat-fed and alloxan-treated diabetic mice.
  
  
  METHODS
  The effects of alloxan (5, 10 and 20 μmol/L) on insulin release from isolated murine islets, as well as glycogen synthesis by isolated murine hepatocytes, were assessed. The effects of exendin-4 (10 nmol/kg, twice daily for 4 weeks) were assessed in high fat-fed, alloxan (50 mg/kg, i.v.)-treated C57 mice. Glucokinase activity was assessed in the same model.
  
  
  RESULTS
  Pretreatment with exendin-4 attenuated alloxan-induced decreases in insulin release and glycogen synthesis in islets and hepatocytes. The alloxan-induced decrease in the GK activity in islets and hepatocytes was also ameliorated by exendin-4 treatment. Pretreatment with the GLP-1 receptor antagonist exendin-9 (100 nmol/L) blocked the effects of exendin-4 on the liver and pancreas. Treatment of high-fat fed, alloxan-treated diabetic mice with exendin-4 (10 nmol/L, i.p.) reduced the severity of diabetic symptoms. Specifically, exendin-4 treatment reduced serum glucose by 50% and %HbA1c by 24% compared with control and significantly decreased HOMA-IR by 39% and increased HOMA-β by 150%. In addition, exendin-4 treatment significantly reduced body weight by 6.8% and serum triglycerides by 35%.
  
  
  CONCLUSIONS
  The results indicate that glucose-stimulated insulin release and glycogen synthesis are decreased by alloxan due to reduced GK activity. These findings provide further insight into the mechanism by which exendin-4 regulates glucose homeostasis.
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, 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; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004789:Enzyme Activation; D000077270:Exenatide; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D005941:Glucokinase