title: Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice.
abstract: OBJECTIVE
  In the current study, the effect of a highly specific peptide inhibitor of glycogen synthase kinase 3 (GSK3) (L803-mts) on glucose metabolism and BP was examined in a high-fat (HF) fed mouse model of diabetes.
  
  
  METHODS
  C57/BL6J mice were placed on an HF diet for 3 months and treated with L803-mts for 20 days, following which glucose metabolism was examined by euglycaemic-hyperinsulinaemic clamp studies. BP and heart rate were measured by radio-telemetry.
  
  
  RESULTS
  The HF mice were obese, with impaired glucose tolerance and high plasma insulin and leptin levels. L803-mts treatment significantly reduced the insulin levels and doubled the glucose infusion rate required to maintain a euglycaemic condition in the HF+L803-mts group compared with the HF group. Insulin failed to suppress the endogenous glucose production rate in the HF group while decreasing it by 75% in the HF+L803-mts group, accompanied by increased liver glycogen synthase activity and net hepatic glycogen synthesis. GSK3 inhibition also reduced peripheral insulin resistance. Plasma glucose disappearance rate increased by 60% in the HF+L803-mts group compared with the HF group. In addition, glucose uptake in heart and gastrocnemius muscle was markedly improved. Although mean arterial pressure increased following the HF diet, it did not change significantly during the 12 days of L803-mts treatment.
  
  
  CONCLUSIONS
  These studies demonstrate that GSK3 inhibition improved hepatic and peripheral insulin resistance in a mouse model of HF-induced diabetes, but it failed to have an effect on BP. GSK3 may represent an important therapeutic target for insulin resistance.
authors.affiliation: Division of Nephrology, Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Reena.Rao@Vanderbilt.edu
authors.forename: R
authors.initials: R
authors.lastname: Rao
authors.forename: C-M
authors.initials: CM
authors.lastname: Hao
authors.forename: R
authors.initials: R
authors.lastname: Redha
authors.forename: D H
authors.initials: DH
authors.lastname: Wasserman
authors.forename: O P
authors.initials: OP
authors.lastname: McGuinness
authors.forename: M D
authors.initials: MD
authors.lastname: Breyer
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D004041:Dietary Fats; D005934:Glucagon / Q000097:blood; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; C509073:N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline; D009842:Oligopeptides; D005934:Glucagon; D038362:Glycogen Synthase Kinase 3