title: Cocoa flavonoids attenuate high glucose-induced insulin signalling blockade and modulate glucose uptake and production in human HepG2 cells.
abstract: Insulin resistance is the primary characteristic of type 2 diabetes. Cocoa and its main flavanol, (-)-epicatechin (EC), display some antidiabetic effects, but the mechanisms for their preventive activities related to glucose metabolism and insulin signalling in the liver remain largely unknown. In the present work, the preventive effect of EC and a cocoa polyphenolic extract (CPE) on insulin signalling and on both glucose production and uptake are studied in insulin-responsive human HepG2 cells treated with high glucose. Pre-treatment of cells with EC or CPE reverted decreased tyrosine-phosphorylated and total levels of IR, IRS-1 and -2 triggered by high glucose. EC and CPE pre-treatment also prevented the inactivation of the PI3K/AKT pathway and AMPK, as well as the diminution of GLUT-2 levels induced by high glucose. Furthermore, pre-treatment of cells with EC and CPE avoided the increase in PEPCK levels and the diminished glucose uptake provoked by high glucose, returning enhanced levels of glucose production and decreased glycogen content to control values. These findings suggest that EC and CPE improved insulin sensitivity of HepG2 treated with high glucose, preventing or delaying a potential hepatic dysfunction through the attenuation of the insulin signalling blockade and the modulation of glucose uptake and production.
authors.affiliation: Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cordero-Herrera
authors.affiliation: Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Martín
authors.affiliation: Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Goya
authors.affiliation: Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain. Electronic address: s.ramos@ictan.csic.es.
authors.forename: Sonia
authors.initials: S
authors.lastname: Ramos
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D002099:Cacao / Q000737:chemistry*; D005419:Flavonoids / Q000494:pharmacology*; D005947:Glucose / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D005419:Flavonoids; D051273:Glucose Transporter Type 2; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C495680:SLC2A2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase; D005947:Glucose
keywords: (−)-epicatechin; 2-NBDG; 2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino); 5-bromo-2′-deoxyuridine; 5′-AMP-activated protein kinase; 7-o-MA; 7-o-methylaromadendrin; AKT/PKB; AMPK; BrdU; CPE; Ca(2+)/calmodulin-dependent protein kinase kinase; CaMMK; Cocoa; EC; EGCG; ERK; Epicatechin; FBS; FOXO1; G6Pase; GLUT; GS; GSK-3; GSPE; Glucose production; Glucose uptake; HepG2 cells; IR; IRS; Insulin signalling pathway; JNK; LKB1; MAPK; PEPCK; PI3K; PPAR; PSP; PTP-1B; T2DM; c-Jun N-terminal Kinase; cocoa phenolic extract; epigallocatechin gallate; extracellular regulated kinase; fetal bovine serum; forkhead box protein O1; glucose transporter; glucose-6-phosphatase; glycogen synthase; glycogen synthase kinase-3; grape-seed procyanidin extract; insulin receptor; insulin receptor substrate; liver kinase B1; mitogen-activated protein kinase; peroxisome proliferator-activated receptor; phosphatase 1B; phosphatidylinositol-3-kinase; phosphoenolpyruvate carboxykinase; protein kinase B; purple sweet potato; type 2 diabetes mellitus