title: Hepatocyte growth factor ameliorates hyperglycemia and corrects β-cell mass in IRS2-deficient mice.
abstract: Insulin resistance, when combined with decreased β-cell mass and relative insufficient insulin secretion, leads to type 2 diabetes. Mice lacking the IRS2 gene (IRS2(-/-) mice) develop diabetes due to uncompensated insulin resistance and β-cell failure. Hepatocyte growth factor (HGF) activates the phosphatidylinositol 3-kinase/Akt signaling pathway in β-cells without recruitment of IRS1 or IRS2 and increases β-cell proliferation, survival, mass, and function when overexpressed in β-cells of transgenic (TG) mice. We therefore hypothesized that HGF may protect against β-cell failure in IRS2 deficiency. For that purpose, we cross-bred TG mice overexpressing HGF in β-cells with IRS2 knockout (KO) mice. Glucose homeostasis analysis revealed significantly reduced hyperglycemia, compensatory hyperinsulinemia, and improved glucose tolerance in TG/KO mice compared with those in KO mice in the context of similar insulin resistance. HGF overexpression also increased glucose-stimulated insulin secretion in IRS2(-/-) islets. To determine whether this glucose homeostasis improvement correlated with alterations in β-cells, we measured β-cell mass, proliferation, and death in these mice. β-Cell proliferation was increased and death was decreased in TG/KO mice compared with those in KO mice. As a result, β-cell mass was significantly increased in TG/KO mice compared with that in KO mice, reaching levels similar to those in wild-type mice. Analysis of the intracellular targets involved in β-cell failure in IRS2 deficiency showed Pdx-1 up-regulation, Akt/FoxO1 phosphorylation, and p27 down-regulation in TG/KO mouse islets. Taken together, these results indicate that HGF can compensate for IRS2 deficiency and subsequent insulin resistance by normalizing β-cell mass and increasing circulating insulin. HGF may be of value as a therapeutic agent against β-cell failure.
authors.affiliation: Diabetes, Obesity and Metabolism Institute (J.C.A.-P., J.L., C.R., F.R.-P., R.C.V., A.G.-O.), Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mt Sinai, New York, New York 10029; and Department of Medicine (T.C.R., G.P.C., S.R.V.), Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Alvarez-Perez
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Rosa
authors.forename: Gabriella P
authors.initials: GP
authors.lastname: Casinelli
authors.forename: Shelley R
authors.initials: SR
authors.lastname: Valle
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Lakshmipathi
authors.forename: Carolina
authors.initials: C
authors.lastname: Rosselot
authors.forename: Francisco
authors.initials: F
authors.lastname: Rausell-Palamos
authors.forename: Rupangi C
authors.initials: RC
authors.lastname: Vasavada
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Ocaña
mesh_terms: D000818:Animals; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006943:Hyperglycemia / Q000235:genetics / Q000628:therapy*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency* / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D017228:Hepatocyte Growth Factor