title: Neuregulin improves response to glucose tolerance test in control and diabetic rats.
abstract: Neuregulin (NRG) is an EGF-related growth factor that binds to the tyrosine kinase receptors ErbB3 and ErbB4, thus inducing tissue development and muscle glucose utilization during contraction. Here, we analyzed whether NRG has systemic effects regulating glycemia in control and type 2 diabetic rats. To this end, recombinant NRG (rNRG) was injected into Zucker diabetic fatty (ZDF) rats and their respective lean littermates 15 min before a glucose tolerance test (GTT) was performed. rNRG enhanced glucose tolerance without promoting the activation of the insulin receptor (IR) or insulin receptor substrates (IRS) in muscle and liver. However, in control rats, rNRG induced the phosphorylation of protein kinase B (PKB) and glycogen synthase kinase-3 (GSK-3) in liver but not in muscle. In liver, rNRG increased ErbB3 tyrosine phosphorylation and its binding to phosphatidylinositol 3-kinase (PI3K), thus indicating that rNRG activates the ErbB3/PI3K/PKB signaling pathway. rNRG increased glycogen content in liver but not in muscle. rNRG also increased the content of fructose-2,6-bisphosphate (Fru-2,6-P2), an activator of hepatic glycolysis, and lactate in liver but not in muscle. Increases in lactate were abrogated by wortmannin, a PI3K inhibitor, in incubated hepatocytes. The liver of ZDF rats showed a reduced content of ErbB3 receptors, entailing a minor stimulation of the rNRG-induced PKB/GSK-3 cascade and resulting in unaltered hepatic glycogen content. Nonetheless, rNRG increased hepatic Fru-2,6-P2 and augmented lactate both in liver and in plasma of diabetic rats. As a whole, rNRG improved response to the GTT in both control and diabetic rats by enhancing hepatic glucose utilization.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Center for Biomedical Investigation in Net of Diabetes and Associated Metabolic Pathologies, Madrid, Spain;
authors.forename: Iliana
authors.initials: I
authors.lastname: López-Soldado
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain;
authors.forename: Katrin
authors.initials: K
authors.lastname: Niisuke
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain;
authors.forename: Catarina
authors.initials: C
authors.lastname: Veiga
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain;
authors.forename: Anna
authors.initials: A
authors.lastname: Adrover
authors.affiliation: Department of Physiological Sciences II, Faculty of Medicine, University of Barcelona-IDIBELL: Bellvitge Institute for Biomedical Research, Barcelona, Spain; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Manzano
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain;
authors.forename: Vicente
authors.initials: V
authors.lastname: Martínez-Redondo
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; Center for Biomedical Investigation in Net of Diabetes and Associated Metabolic Pathologies, Madrid, Spain; Institute of Biomedicine from the University of Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Camps
authors.affiliation: Department of Physiological Sciences II, Faculty of Medicine, University of Barcelona-IDIBELL: Bellvitge Institute for Biomedical Research, Barcelona, Spain; and.
authors.forename: Ramon
authors.initials: R
authors.lastname: Bartrons
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Center for Biomedical Investigation in Net of Diabetes and Associated Metabolic Pathologies, Madrid, Spain;
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; Center for Biomedical Investigation in Net of Diabetes and Associated Metabolic Pathologies, Madrid, Spain; Institute of Biomedicine from the University of Barcelona, Barcelona, Spain aguma@ub.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Gumà
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005635:Fructosediphosphates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins / Q000187:drug effects / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D020880:Neuregulins / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D020893:Receptor, ErbB-3 / Q000187:drug effects / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005635:Fructosediphosphates; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008112:Liver Glycogen; D020880:Neuregulins; D019344:Lactic Acid; C027652:fructose 2,6-diphosphate; D058539:Phosphatidylinositol 3-Kinase; D020893:Receptor, ErbB-3; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose
keywords: ErbB3; glucose tolerance; liver; neuregulin; protein kinase B