Hepatocyte Growth Factor and the Pancreatic Beta Cell

Summary

Principal Investigator: Adolfo Garcia-Ocana
Abstract: DESCRIPTION (provided by applicant): We have previously shown that hepatocyte growth factor (HGF) has beneficial effects in beta cell proliferation, function and islet transplantation. More recently, we have deciphered a dual role of HGF in beta cell survival. On one hand, HGF protects beta cells in situations of hypoxia, nutrient deprivation, streptozotocin-mediated cytotoxicity and cytokine-induced cell death. On the other hand, HGF potentiates beta cell death induced by gluco-lipoxicity in vitro. Metabolically, HGF decreases fatty acid oxidation and enhances ceramide content in beta cells. In terms of signaling, HGF-mediated activation of the beta cell pro-survival signal Akt is abolished in the presence of a gluco-lipotoxic insult. Circulating HGF levels are markedly high in obesity. Taken together, these results indicate that HGF might participate in beta cell failure in obesity/Type 2 diabetes in vivo. To address this question, in Specific Aim 1 we will characterize the functional consequences of disrupting HGF/c-met signaling in the pancreatic beta cell in vivo in obese/Type 2 diabetes conditions. Alterations in functional p53 levels often lead to increased apoptosis in many cell types. However, whether p53 has any regulatory role in directly controlling pancreatic beta cell death in obesity/Type 2 diabetes is unknown. Preliminary data from our lab clearly indicate that (i) gluco-lipotoxicity upregulates p53 expression and activation in beta cells;(ii) inhibition of p53 transactivation with the specific p53 inhibitor pifithrin-1 blocks gluco- lipotoxicity-mediated beta cell apoptosis;(iii) p53-null mouse beta cells are more resistant than wild-type beta cells to gluco-lipotoxicity-induced apoptosis;and, (iv) transgenic mice overexpressing p53 in the beta cell display glucose intolerance. Importantly, a recent comprehensive association study of obesity/type 2 diabetes and related quantitative traits has identified a single nucleotide polymorphism variant (Arg72Pro) in the TP53 gene in obese/Type 2 diabetic patients. Arg72-p53 variant has a higher apoptotic potential possibly through increased localization in the mitochondria. Taken together, these studies clearly highlight the potential link between alterations in p53 expression/activation/localization and pancreatic beta cell apoptosis, impaired insulin secretion, gluco-lipotoxicity and obesity/Type 2 diabetes. To address this point, in Specific Aim 2, we will decipher the functional consequences of gain-of-function, loss-of-function and the 72Arg variant of p53 in the beta cell in vivo under basal and obesity conditions. In Specific Aim 3, we will analyze the relevance of p53 in mediating human beta cell apoptosis and the mechanisms involved in p53-induced beta cell apoptosis in a gluco-lipotoxic environment in vitro. The proposed studies in rodent and human beta cells in vitro and in mice in vivo will provide valuable information to identify pathways to protect beta cells against dysfunction and death in situations of obesity- mediated Type 2 diabetes.
Funding Period: 2004-03-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc Glucose infusion in mice: a new model to induce beta-cell replication
    Laura C Alonso
    University of Pittsburgh, Division of Endocrinology, 200 Lothrop St, BST E1140, Pittsburgh, PA 15261, USA
    Diabetes 56:1792-801. 2007
  2. pmc Hepatocyte growth factor/c-Met signaling is required for β-cell regeneration
    Juan Carlos Alvarez-Perez
    Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
    Diabetes 63:216-23. 2014
  3. pmc Human β-cell proliferation and intracellular signaling: driving in the dark without a road map
    Rohit N Kulkarni
    Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
    Diabetes 61:2205-13. 2012
  4. pmc Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes
    Jie Gao
    Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 61:1543-51. 2012
  5. pmc Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus
    Cem Demirci
    Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 61:1143-52. 2012
  6. ncbi Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling
    N Guthalu Kondegowda
    Division of Endocrinology, University of Pittsburgh, 200 Lothrop St, BST E1157, Pittsburgh, PA 15261, USA
    Diabetologia 55:1721-32. 2012
  7. pmc Free fatty acids block glucose-induced β-cell proliferation in mice by inducing cell cycle inhibitors p16 and p18
    Jordan Pascoe
    Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 61:632-41. 2012
  8. pmc Activation of protein kinase C-ζ in pancreatic β-cells in vivo improves glucose tolerance and induces β-cell expansion via mTOR activation
    Silvia Velazquez-Garcia
    Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, USA
    Diabetes 60:2546-59. 2011
  9. pmc Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes
    Jose Mellado-Gil
    Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 60:525-36. 2011
  10. pmc Novel proapoptotic effect of hepatocyte growth factor: synergy with palmitate to cause pancreatic {beta}-cell apoptosis
    Jose A Gonzalez-Pertusa
    Division of Endocrinology, University of Pittsburgh, 200 Lothrop Street, BST E1140, Pittsburgh, Pennsylvania 15261, USA
    Endocrinology 151:1487-98. 2010

Research Grants

Detail Information

Publications16

  1. pmc Glucose infusion in mice: a new model to induce beta-cell replication
    Laura C Alonso
    University of Pittsburgh, Division of Endocrinology, 200 Lothrop St, BST E1140, Pittsburgh, PA 15261, USA
    Diabetes 56:1792-801. 2007
    ..Thus, we have developed a new model to study the regulation of compensatory beta-cell replication, and we describe important novel characteristics of mouse beta-cell responses to glucose in the living pancreas...
  2. pmc Hepatocyte growth factor/c-Met signaling is required for β-cell regeneration
    Juan Carlos Alvarez-Perez
    Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
    Diabetes 63:216-23. 2014
    ..These results indicate that HGF/c-Met signaling is critical for β-cell proliferation in situations of diminished β-cell mass and suggest that activation of this pathway can enhance β-cell regeneration. ..
  3. pmc Human β-cell proliferation and intracellular signaling: driving in the dark without a road map
    Rohit N Kulkarni
    Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
    Diabetes 61:2205-13. 2012
    ....
  4. pmc Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes
    Jie Gao
    Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 61:1543-51. 2012
    ..Our results revealed an essential role of EST in energy metabolism and the pathogenesis of type 2 diabetes. Inhibition of EST, at least in females, may represent a novel approach to manage type 2 diabetes...
  5. pmc Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus
    Cem Demirci
    Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 61:1143-52. 2012
    ..These studies indicate that HGF/c-Met signaling is essential for maternal β-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus...
  6. ncbi Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling
    N Guthalu Kondegowda
    Division of Endocrinology, University of Pittsburgh, 200 Lothrop St, BST E1157, Pittsburgh, PA 15261, USA
    Diabetologia 55:1721-32. 2012
    ..This study evaluates the hypothesis that lactogens can protect beta cells against GLT and examines the mechanism behind the pro-survival effect...
  7. pmc Free fatty acids block glucose-induced β-cell proliferation in mice by inducing cell cycle inhibitors p16 and p18
    Jordan Pascoe
    Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 61:632-41. 2012
    ..If FFAs reduce proliferation induced by obesity and insulin resistance, targeting this pathway may lead to new treatment approaches to prevent diabetes...
  8. pmc Activation of protein kinase C-ζ in pancreatic β-cells in vivo improves glucose tolerance and induces β-cell expansion via mTOR activation
    Silvia Velazquez-Garcia
    Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, USA
    Diabetes 60:2546-59. 2011
    ..In this study, we examined the effects of PKC-ζ activation in β-cell expansion and function in vivo in mice and the mechanisms associated with these effects...
  9. pmc Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes
    Jose Mellado-Gil
    Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Diabetes 60:525-36. 2011
    ..To determine the role of hepatocyte growth factor (HGF)/c-Met on β-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro...
  10. pmc Novel proapoptotic effect of hepatocyte growth factor: synergy with palmitate to cause pancreatic {beta}-cell apoptosis
    Jose A Gonzalez-Pertusa
    Division of Endocrinology, University of Pittsburgh, 200 Lothrop Street, BST E1140, Pittsburgh, Pennsylvania 15261, USA
    Endocrinology 151:1487-98. 2010
    ..Collectively, these studies indicate that HGF can be detrimental for beta-cell survival in an environment with excessive fatty acid supply...
  11. pmc Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets
    Nathalie M Fiaschi-Taesch
    Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    Diabetes 57:2745-54. 2008
    ..Here, we asked whether these prior observations in rodent models extend to nonhuman primate (NHP) islets...
  12. pmc Hepatocyte growth factor is a novel stimulator of glucose uptake and metabolism in skeletal muscle cells
    German Perdomo
    Division of Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    J Biol Chem 283:13700-6. 2008
    ..HGF, through its ability to stimulate glucose transport and metabolism and to impair FAO, may participate in the regulation of glucose disposal in skeletal muscle...
  13. ncbi Improving islet transplantation by gene delivery of hepatocyte growth factor (HGF) and its downstream target, protein kinase B (PKB)/Akt
    Nathalie Fiaschi-Taesch
    Division of Endocrinology, University of Pittsburgh, Pittsburgh, PA, USA
    Cell Biochem Biophys 48:191-9. 2007
    ....
  14. ncbi Protein kinase C-zeta activation markedly enhances beta-cell proliferation: an essential role in growth factor mediated beta-cell mitogenesis
    Rupangi C Vasavada
    Department of Medicine, Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    Diabetes 56:2732-43. 2007
    ....
  15. pmc Human β-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map
    Ernesto Bernal-Mizrachi
    Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, and U S Department of Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI
    Diabetes 63:819-31. 2014
    ..This is a critical aspect in the long-term goal of expanding human β-cells for the prevention and/or cure of type 1 and type 2 diabetes. ..

Research Grants30

  1. Adipose Stromal Cells and Vasculogenesis: Tissue Perfusion and Islet Survival
    KEITH LEONARD MARCH; Fiscal Year: 2013
    ..Successful work to treat diabetes and diabetic vascular disease will markedly improve the effectiveness, and may indeed decrease longterm costs of healthcare in the Veterans Administration system. ..
  2. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  3. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  4. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  5. Beta-cell Proliferation
    Fredric E Wondisford; Fiscal Year: 2013
    ..These studies of in vivo mechanisms of [unreadable]-cell proliferation may provide therapeutic approaches for diabetes mellitus in humans. ..
  6. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  7. Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation
    William L Holland; Fiscal Year: 2013
    ..These studies will hopefully suggest novel therapeutic avenues for the treatment and prevention of diabetes by promoting b-cell functionality, and by promoting regenerative processes within the b-cell population. ..
  8. Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy
    Lonnie D Shea; Fiscal Year: 2013
    ..These scaffolds provide a support for cell growth and can deliver proteins which will be to enhance cell survival and function following islet transplantation. ..
  9. Age-Induced Impairment of Nutrient Signaling Results in Bone Loss
    CARLOS MIGUEL ISALES; Fiscal Year: 2013
    ..Ultimately, we expect the Program Project to identify new therapeutic strategies and develop specific countermeasures for age-associated declines in musculoskeletal function. ..
  10. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..