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Hepatocyte growth factor ameliorates hyperglycemia and corrects ?-cell mass in IRS2-deficient mice.

ABSTRACT: Insulin resistance, when combined with decreased ?-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 ?-cell failure. Hepatocyte growth factor (HGF) activates the phosphatidylinositol 3-kinase/Akt signaling pathway in ?-cells without recruitment of IRS1 or IRS2 and increases ?-cell proliferation, survival, mass, and function when overexpressed in ?-cells of transgenic (TG) mice. We therefore hypothesized that HGF may protect against ?-cell failure in IRS2 deficiency. For that purpose, we cross-bred TG mice overexpressing HGF in ?-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 ?-cells, we measured ?-cell mass, proliferation, and death in these mice. ?-Cell proliferation was increased and death was decreased in TG/KO mice compared with those in KO mice. As a result, ?-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 ?-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 ?-cell mass and increasing circulating insulin. HGF may be of value as a therapeutic agent against ?-cell failure.

SUBMITTER: Alvarez-Perez JC

PROVIDER: S-EPMC4250367 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Hepatocyte growth factor ameliorates hyperglycemia and corrects β-cell mass in IRS2-deficient mice.

Alvarez-Perez Juan C JC Rosa Taylor C TC Casinelli Gabriella P GP Valle Shelley R SR Lakshmipathi Jayalakshmi J Rosselot Carolina C Rausell-Palamos Francisco F Vasavada Rupangi C RC García-Ocaña Adolfo A

Molecular endocrinology (Baltimore, Md.) 20141201 12

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 trans ...[more]

PMID: 25361392

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Project description:Fibroblasts are major cellular components of the tumor microenvironment, regulating tumor cell behavior in part through secretion of extracellular matrix proteins, growth factors, and angiogenic factors. In previous studies, conditional deletion of the type II transforming growth factor-beta (TGF-beta) receptor in fibroblasts (Tgfbr2FspKO) was shown to promote mammary tumor metastasis in fibroblast-epithelial cell cotransplantation studies in mice, correlating with increased expression of hepatocyte growth factor (HGF). Here, we advance our findings to show that Tgfbr2(FspKO) fibroblasts enhance HGF/c-Met and HGF/Ron signaling to promote scattering and invasion of mammary carcinoma cells. Blockade of c-Met and Ron by small interfering RNA silencing and pharmacologic inhibitors significantly reduced mammary carcinoma cell scattering and invasion caused by Tgfbr2FspKO fibroblasts. Moreover, neutralizing antibodies to c-Met and Ron significantly inhibited HGF-induced cell scattering and invasion, correlating with reduced Stat3 and p42/44MAPK phosphorylation. Investigation of the signal transducer and activator of transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways by pharmacologic inhibition and small interfering RNA silencing revealed a cooperative interaction between the two pathways to regulate HGF-induced invasion, scattering, and motility of mammary tumor cells. Furthermore, whereas c-Met was found to regulate both the Stat3 and MAPK signaling pathways, Ron was found to regulate Stat3 but not MAPK signaling in mammary carcinoma cells. These studies show a tumor-suppressive role for TGF-beta signaling in fibroblasts, in part by suppressing HGF signaling between mammary fibroblasts and epithelial cells. These studies characterize complex functional roles for HGF and TGF-beta signaling in mediating tumor-stromal interactions during mammary tumor cell scattering and invasion, with important implications in the metastatic process.

Dataset Information

Hepatocyte growth factor ameliorates hyperglycemia and corrects ?-cell mass in IRS2-deficient mice.

Publications

Hepatocyte growth factor ameliorates hyperglycemia and corrects β-cell mass in IRS2-deficient mice.

Similar Datasets

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