title: Casein glycomacropeptide-derived peptide IPPKKNQDKTE ameliorates high glucose-induced insulin resistance in HepG2 cells via activation of AMPK signaling.
abstract: Recently, casein glycomacropeptide (GMP)-derived peptide was found to possess potent antioxidant and anti-inflammatory activities. In this study, the improvement effects and underlying molecular mechanisms of GMP-derived peptide on hepatic insulin resistance were investigated.
  
  
  
  The peptide IPPKKNQDKTE was identified from GMP papain hydrolysates by LC-ESI-MS/MS. Effects of IPPKKNQDKTE on glucose metabolism and expression levels of the hepatic insulin signaling proteins in high glucose-induced insulin-resistant HepG2 cells were evaluated. Results showed that IPPKKNQDKTE dose-dependently increased glucose uptake and intracellular glycogen in insulin-resistant HepG2 cells without affecting cell viability. IPPKKNQDKTE increased the phosphorylation of Akt and GSK3β and decreased the expression levels of p-GS, G6Pase and PEPCK. These IPPKKNQDKTE-mediated protection effects were reversed by PI3K/Akt inhibitor LY294002, showing the mediatory role of PI3K/Akt. Moreover, treatment with IPPKKNQDKTE reduced IRS-1 Ser307 phosphorylation and increased phosphorylation of AMPK. Knockdown AMPK using siRNA in HepG2 cells increased Ser307 phosphorylation of IRS-1 and reduced Akt phosphorylation in IPPKKNQDKTE-treated insulin-resistant cells.
  
  
  
  IPPKKNQDKTE prevents high glucose-induced insulin resistance in HepG2 cells by modulating the IRS-1/PI3K/Akt signaling pathway through AMPK activation, indicating that IPPKKNQDKTE plays a potential role in the prevention and treatment of hepatic insulin resistance and type 2 diabetes.
authors: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, China.|College of Food Science and Nutritional Engineering, Key Laboratory of Functional Dairy, Ministry of Education, China Agricultural University, Beijing, China.
authors: Jia-Jia
authors: JJ
authors: Song
authors: College of Food Science and Nutritional Engineering, Key Laboratory of Functional Dairy, Ministry of Education, China Agricultural University, Beijing, China.
authors: Qian
authors: Q
authors: Wang
authors: Department of Animal Sciences, Washington State University, Pullman, Washington, USA.
authors: Min
authors: M
authors: Du
authors: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, China.|College of Food Science and Nutritional Engineering, Key Laboratory of Functional Dairy, Ministry of Education, China Agricultural University, Beijing, China.
authors: Tian-Ge
authors: TG
authors: Li
authors: Key Laboratory of Space Nutrition and Food Engineering, China Astronauts Research and Training Center, Beijing, China.
authors: Bin
authors: B
authors: Chen
authors: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, China.|College of Food Science and Nutritional Engineering, Key Laboratory of Functional Dairy, Ministry of Education, China Agricultural University, Beijing, China.
authors: Xue-Ying
authors: XY
authors: Mao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002364:Caseins / Q000737:chemistry* / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000009:adverse effects*; D005952:Glucose-6-Phosphatase / Q000235:genetics; D006006:Glycogen Synthase / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006868:Hydrolysis; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002364:Caseins; C526292:IRS1 protein, human; C000625632:Ile-Pro-Pro-Lys-Lys-Asn-Gln-Asp-Lys-Thr-Glu; D055504:Insulin Receptor Substrate Proteins; D010446:Peptide Fragments; D010455:Peptides; C065989:caseinomacropeptide; D006006:Glycogen Synthase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; C000597251:PCK2 protein, human; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose
keywords: AMPK; Akt; Casein glycomacropeptide; HepG2 cells; Insulin resistance