INSULIN RECEPTOR STRUCTURE AND TURNOVER

Summary

Principal Investigator: C Ronald Kahn
Abstract: DESCRIPTION (provided by applicant): This is a competitive renewal of NIH grant DK31036. This grant is now completing 28 years and a 10-year cycle since receiving a merit extension by NIDDK. Since its inception, the grant has been focused on the insulin receptor, and to a lesser extent IGF-1 receptor, and their signaling capabilities and their alterations in physiologic and pathologic states. Since the last renewal, we have made very substantial progress in understanding the signaling and biological roles of these receptors through both in vitro and in vivo studies. The largest body of studies derived from the use of homologous recombination gene targeting to study the role of the insulin receptor in insulin action in vivo. This has included the use of single gene knockouts of the insulin and IGF-1 receptors;combinatorial homozygous and heterozygous knockouts as polygenic models of Type 2 diabetes;and tissue-specific knockouts using the Cre-lox approach to determine the role of the insulin and IGF-1 receptors in individual tissues in the physiology of glucose and lipid homeostasis and the pathophysiology of diabetes and metabolic syndrome. In addition, we have performed a series of in vitro studies focusing on differential signaling by the insulin and IGF-1 receptors in the actions of insulin and IGF-1. As a result, since the last competitive renewal, this grant has provided support for a total of 90 published papers (including 48 original articles, 26 collaborative articles and 16 reviews). This work has led to development of new hypotheses about the nature of the insulin/IGF-1 signaling network, the contribution of insulin resistance in different organs to diabetes and the metabolic syndrome, as well as new evidence on how tissues communicate with one another in insulin resistant states, a role for insulin signaling in fat in longevity and a role for insulin signaling in the brain in neurodegeneration. In unpublished studies, we have also developed data on the role of the insulin receptor in brain in the control of CNS cholesterol metabolism and a novel role of signaling from the unoccupied insulin and IGF-1 receptors in control of apoptosis which appears to be kinase independent. The specific aims for the next grant period are: 1) Explore the role of insulin and IGF-1 signaling in increased longevity, stress resistance and mitochondrial metabolism in mice with selective insulin resistance in fat or brain. 2) Study the role of insulin signaling in the brain on regulation of brain cholesterol metabolism and the relationship of CNS insulin resistance and altered cholesterol metabolism to neurodegeneration. 3) Determine the nature of tyrosine kinase independent signaling by the unoccupied insulin and IGF-1 receptors involved in control of apoptosis. 4) Define the differential nature of insulin and IGF-1 receptor signaling in vivo by creation of a new generation of mouse models in which the insulin receptor is replaced by knocking of the IGF1 receptor or a chimeric insulin/IGF-1 receptor to produce mice and cell lines that express each receptor or chimeric receptor in the tissue and temporal pattern of the other receptor. PUBLIC HEALTH RELEVANCE: This grant, now completing 28 years and a merit extension, is focused on the insulin receptor, and to a lesser extent the highly related IGF-1 receptor, their signaling capabilities and their alterations in physiologic and pathologic states such as diabetes and metabolic syndrome. Since the last renewal, we have made very substantial progress in understanding the roles of these receptors through creation and characterization of a large number of mice genetically engineered to have insulin or IGF-1 resistance in only one tissue at a time. This work has led an integrated view of the role of insulin resistance in diabetes and metabolic syndrome, as well as a number of new insights into previously unrecognized aspects of insulin signaling, which form the basis of the proposed experiments going forward.
Funding Period: 1982-04-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, One Joslin Pl, Boston, MA 02215, USA
    Diabetes 55:2032-41. 2006
  2. pmc Diabetes and insulin in regulation of brain cholesterol metabolism
    Ryo Suzuki
    Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
    Cell Metab 12:567-79. 2010
  3. ncbi A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis
    Jeremie Boucher
    Joslin Diabetes Center and Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Sci Signal 3:ra87. 2010
  4. pmc Insulin-like growth factor 1-mediated hyperthermia involves anterior hypothalamic insulin receptors
    Manuel Sanchez-Alavez
    Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 286:14983-90. 2011
  5. pmc PKCĪ“ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans
    Olivier Bezy
    Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    J Clin Invest 121:2504-17. 2011
  6. pmc Cross-talk between insulin and Wnt signaling in preadipocytes: role of Wnt co-receptor low density lipoprotein receptor-related protein-5 (LRP5)
    Jane Palsgaard
    Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 287:12016-26. 2012
  7. pmc Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling
    Jeremie Boucher
    Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA
    Nat Commun 3:902. 2012
  8. pmc Leptin regulation of Hsp60 impacts hypothalamic insulin signaling
    Andr Kleinridders
    J Clin Invest . 2013
  9. pmc A zebrafish embryo culture system defines factors that promote vertebrate myogenesis across species
    Cong Xu
    Division of Hematology Oncology, Children s Hospital Boston and Dana Farber Cancer Institute, Boston, MA 02115, USA Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA 02115, USA Harvard Medical School, Boston, MA 02115, USA
    Cell 155:909-21. 2013
  10. pmc Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance
    Jan Mauer
    Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany
    PLoS Genet 6:e1000938. 2010

Detail Information

Publications23

  1. ncbi Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, One Joslin Pl, Boston, MA 02215, USA
    Diabetes 55:2032-41. 2006
    ..Thus, the effect of leptin on SCD1 in liver is independent of insulin and SREBP-1c, and leptin, rather than insulin, is the major regulator of hepatic MUFA synthesis in obesity-linked diabetes...
  2. pmc Diabetes and insulin in regulation of brain cholesterol metabolism
    Ryo Suzuki
    Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
    Cell Metab 12:567-79. 2010
    ..Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states...
  3. ncbi A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis
    Jeremie Boucher
    Joslin Diabetes Center and Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Sci Signal 3:ra87. 2010
    ..Insulin and IGF-1 binding stimulates receptor tyrosine kinase activity and blocks apoptosis, whereas unliganded IR and IGF1R, acting through a mechanism independent of their catalytic activity, exert a permissive effect on cell death...
  4. pmc Insulin-like growth factor 1-mediated hyperthermia involves anterior hypothalamic insulin receptors
    Manuel Sanchez-Alavez
    Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 286:14983-90. 2011
    ..These central effects of IGF-1 signaling may play a role in regulation of metabolic rate, aging, and the risk of developing type 2 diabetes...
  5. pmc PKCĪ“ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans
    Olivier Bezy
    Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    J Clin Invest 121:2504-17. 2011
    ....
  6. pmc Cross-talk between insulin and Wnt signaling in preadipocytes: role of Wnt co-receptor low density lipoprotein receptor-related protein-5 (LRP5)
    Jane Palsgaard
    Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 287:12016-26. 2012
    ..Thus, altered Wnt and LRP5 activity can serve as modifiers of insulin action and insulin resistance in the pathophysiology of diabetes and metabolic syndrome...
  7. pmc Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling
    Jeremie Boucher
    Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA
    Nat Commun 3:902. 2012
    ..Thus, insulin/IGF-1 signalling has a crucial role in the control of brown and white fat development, and, when disrupted, leads to defective thermogenesis and a paradoxical increase in basal metabolic rate...
  8. pmc Leptin regulation of Hsp60 impacts hypothalamic insulin signaling
    Andr Kleinridders
    J Clin Invest . 2013
    ..Moreover, leptin/insulin crosstalk in the hypothalamus impacts energy homeostasis in obesity and insulin-resistant states...
  9. pmc A zebrafish embryo culture system defines factors that promote vertebrate myogenesis across species
    Cong Xu
    Division of Hematology Oncology, Children s Hospital Boston and Dana Farber Cancer Institute, Boston, MA 02115, USA Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA 02115, USA Harvard Medical School, Boston, MA 02115, USA
    Cell 155:909-21. 2013
    ..In summary, these studies reveal functionally conserved pathways regulating myogenesis across species and identify chemical compounds that expand mouse satellite cells and differentiate human iPSCs into engraftable muscle...
  10. pmc Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance
    Jan Mauer
    Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany
    PLoS Genet 6:e1000938. 2010
    ..These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and in the development of obesity-associated insulin resistance...
  11. pmc Insulin and insulin-like growth factor-1 receptors act as ligand-specific amplitude modulators of a common pathway regulating gene transcription
    Jeremie Boucher
    Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts 02215, USA
    J Biol Chem 285:17235-45. 2010
    ..Thus, IR and IGF1R act as identical portals to the regulation of gene expression, with differences between insulin and IGF-1 effects due to a modulation of the amplitude of the signal created by the specific ligand-receptor interaction...
  12. pmc Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism
    Yazmin Macotela
    Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA
    Diabetes 58:803-12. 2009
    ..To investigate how insulin sensitivity and glucose metabolism differ in adipocytes between different fat depots of male and female mice and how sex steroids contribute to these differences...
  13. pmc Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function
    Palle G Laustsen
    Joslin Diabetes Center, Boston, MA 02215, USA
    Mol Cell Biol 27:1649-64. 2007
    ....
  14. ncbi Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance
    Bingzhong Xue
    Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
    J Biol Chem 282:23829-40. 2007
    ..Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes...
  15. ncbi High circulating leptin receptors with normal leptin sensitivity in liver-specific insulin receptor knock-out (LIRKO) mice
    Shmuel E Cohen
    Joslin Diabetes Center, Boston, Massachusetts 02215, USA
    J Biol Chem 282:23672-8. 2007
    ..In this manner, insulin signaling in liver plays an important role in leptin homeostasis and fine modulation of leptin action...
  16. ncbi Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes
    J Andrew Pospisilik
    Institute of Molecular Biotechnology of the Austrian Academy of Science, Dr Bohrgasse 3, 1030, Vienna, Austria
    Cell 131:476-91. 2007
    ..These findings establish that tissue-specific as well as global OxPhos defects in mice can counteract the development of insulin resistance, diabetes, and obesity...
  17. ncbi Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice
    Masa Katic
    Joslin Diabetes Center, One Joslin Place and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
    Aging Cell 6:827-39. 2007
    ..Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse...
  18. pmc Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
    Cell Metab 7:125-34. 2008
    ..Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome...
  19. pmc Beneficial effects of subcutaneous fat transplantation on metabolism
    Thien T Tran
    Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
    Cell Metab 7:410-20. 2008
    ..These data suggest that SC fat is intrinsically different from VIS fat and produces substances that can act systemically to improve glucose metabolism...
  20. pmc Hepatic insulin resistance directly promotes formation of cholesterol gallstones
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA
    Nat Med 14:778-82. 2008
    ..As a result, after twelve weeks on a lithogenic diet, all of the LIRKO mice develop gallstones. Thus, hepatic insulin resistance provides a crucial link between the metabolic syndrome and increased cholesterol gallstone susceptibility...
  21. pmc SOCS-1 deficiency does not prevent diet-induced insulin resistance
    Brice Emanuelli
    Hormone and Obesity Research, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
    Biochem Biophys Res Commun 377:447-52. 2008
    ..Thus, despite the role of SOCS proteins in obesity-related insulin resistance, SOCS-1 deficiency alone is not able to prevent insulin resistance induced by a diet rich in fat...

Research Grants30

  1. Atypical PKC Knockout Models: Effect on Glucose and Lipid Homeostasis
    Robert V Farese; Fiscal Year: 2013
    ..abstract_text> ..
  2. Pathogenesis of the Metabolic Syndrome
    W Timothy Garvey; Fiscal Year: 2013
    ..These data will predictably identify new diagnostic biomarkers for insulin resistance and T2DM, and advance our understanding of molecular mechanisms underlying human insulin resistance. ..
  3. Trauma and Hemorrhage-Induced Skeletal Muscle Insulin Resistance
    JOSEPH LOUIS MESSINA; Fiscal Year: 2013
    ..abstract_text> ..
  4. Adiponectin, placental nutrient transport and fetal growth
    Theresa L Powell; Fiscal Year: 2013
    ....
  5. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  6. Lifespan Extension Despite Greatly Elevated Insulin and Body Fat
    David E Harrison; Fiscal Year: 2013
    ..Effects of DR that extend life spans in both normal control and ob/ob mice in this study are likely targets for interventions to retard aging and extend healthy lifespan in human beings. ..
  7. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..