title: Role of Islet Glucokinase, Glucose Metabolism, and Insulin Pathway in the Enhancing Effect of Islet Neogenesis-Associated Protein on Glucose-Induced Insulin Secretion.
abstract: OBJECTIVE
  To demonstrate the role of islet glucokinase, glucose metabolism, and intracellular insulin mediators in the enhancing effect of islet neogenesis-associated protein pentadecapeptide (INGAP-PP) on glucose-induced insulin secretion.
  
  
  METHODS
  Islets from normal rats were cultured for 4 days in the absence or presence of 10 μg/mL INGAP-PP, with/without Wortmannin or LY294002. Islets were incubated with different glucose concentrations to measure insulin secretion and content, hexokinase and glucokinase activity, glucose oxidation and utilization, glucokinase, insulin receptor, insulin receptor substrate (IRS)-1/2, and PI3K concentration and phosphorylation.
  
  
  RESULTS
  The INGAP-PP significantly increased insulin release at high but not at low glucose concentration, glucokinase activity, glucose metabolism, glucokinase, insulin receptor, IRS-2 and PI3K protein concentration, insulin receptor and IRS-1/2 tyrosine phosphorylation, and the association of p85 with IRS-1. Wortmannin and LY294002 blocked INGAP-PP effect on insulin secretion and glucokinase protein levels in a dose-dependent manner.
  
  
  CONCLUSIONS
  The enhancing effect of INGAP-PP on glucose-induced insulin release could be partly ascribed to its effect on glucokinase activity and glucose metabolism and is mainly mediated by the PI3K/AKT pathway. These results, together with the low hypoglycemia risk associated with the use of INGAP-PP, offer a new alternative for diabetes prevention and treatment.
authors.affiliation: From the *CENEXA-Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET LA PLATA; Centro Colaborador OPS/OMS para Diabetes), Facultad de Ciencias Médicas UNLP, La Plata, Argentina; and †Department of Structural and Functional Biology, IB, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Maiztegui
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Román
authors.forename: Helena C
authors.initials: HC
authors.lastname: Barbosa-Sampaio
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Boschero
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gagliardino
mesh_terms: D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D016207:Cytokines; D007004:Hypoglycemic Agents; C500438:INGAP peptide; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C000612141:REG3A protein, human; D012333:RNA, Messenger; D006593:Hexokinase; D058539:Phosphatidylinositol 3-Kinase; D005941:Glucokinase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose