MAP KINASE IN ISLET FUNCTION

Summary

Principal Investigator: Melanie H Cobb
Abstract: DESCRIPTION (provided by applicant): Diabetes mellitus is a huge health burden due to decreased quality of life and the escalating cost of treatment. In the United States alone, ~8% of the population is diabetic and nearly one-third of adults are now estimated to be at risk to develop the disease. Obesity, insulin resistance and metabolic abnormalities in liver, adipose, and muscle are important factors in disease. Yet, most of the gene loci recently found associated with type 2 diabetes encode proteins that enable insulin production from pancreatic cells. Nutrients and hormones regulate not only insulin secretion but also the capacity of cells to continue to produce insulin. In this proposal we focus on mechanisms of action of nutrients and agents that enhance insulin production in cells. The overarching goals are to elucidate mechanisms that can be manipulated to improve -cell function and overcome the physiological changes in cells that occur during prolonged hyperglycemia, contributing to inadequate insulin release. In aim 1 we will determine the functions of the taste receptor complex (T1R1/T1R3) in pancreatic cells. This dimeric G protein-coupled receptor (GPR) is involved in amino acid-sensing. This receptor, identified in gustatory neurons, binds to a variety of amino acids, but has not been studied on cells. We find that stable knockdown of T1R3 reduces insulin secretion, and insulin content, and causes events associated with autophagy. We will explore the bases for these phenotypic changes and we will also examine the underlying signaling mechanisms. In the second aim we will examine molecular mechanisms of action of small molecules that enhance beta-cell function. These molecules stimulate insulin production by cells, improve oral glucose tolerance of db/db mice, and restore insulin production by human islets in long term culture. We have identified a number of changes that take place in cells treated with these drugs, including epigenetic alterations, and changes in concentrations of key transcription factors. We will evaluate candidates that may mediate the actions of these drugs identified by drug-affinity chromatography. Finally, we will continue to investigate ERK1/2-dependent signaling events that control insulin gene transcription by focusing on mechanisms of recruitment of the coactivator p300. These studies should provide new understanding of how amino acids regulate insulin production, stability and release and will exploit a new pharmacological tool to identify mechanisms to enhance insulin production and insulin transcription in normal and failing islets. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus is now found not only in adults but also in children in the United States. These studies will explore new mechanisms to enhance insulin production in diabetes focusing on a nutrient sensing receptor and a novel small molecule that enhances insulin production from poorly functioning islets.
Funding Period: 1998-09-30 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Inhibition of glucose-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 by epinephrine in pancreatic beta-cells
    Tara Beers Gibson
    Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd, Dallas, TX 75390 9041, USA
    Diabetes 55:1066-73. 2006
  2. pmc Off-target effects of MEK inhibitors
    Eric M Wauson
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9041, United States
    Biochemistry 52:5164-6. 2013
  3. pmc Minireview: Nutrient sensing by G protein-coupled receptors
    Eric M Wauson
    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 9041, USA
    Mol Endocrinol 27:1188-97. 2013
  4. pmc NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM
    Jihan K Osborne
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Proc Natl Acad Sci U S A 110:6524-9. 2013
  5. pmc The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy
    Eric M Wauson
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Dallas, TX 75390 9041, USA
    Mol Cell 47:851-62. 2012
  6. pmc A small molecule differentiation inducer increases insulin production by pancreatic β cells
    Elhadji M Dioum
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 108:20713-8. 2011
  7. pmc Calcineurin increases glucose activation of ERK1/2 by reversing negative feedback
    Lingling Duan
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 107:22314-9. 2010
  8. pmc Calcineurin/nuclear factor of activated T cells and MAPK signaling induce TNF-{alpha} gene expression in pancreatic islet endocrine cells
    Michael C Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    J Biol Chem 286:1025-36. 2011
  9. pmc Regulation of CCAAT/enhancer-binding protein homologous protein (CHOP) expression by interleukin-1 beta in pancreatic beta cells
    Chunli Shao
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9041, USA
    J Biol Chem 285:19710-9. 2010
  10. pmc Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription
    Michael C Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 106:22181-6. 2009

Research Grants

Detail Information

Publications17

  1. ncbi Inhibition of glucose-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 by epinephrine in pancreatic beta-cells
    Tara Beers Gibson
    Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd, Dallas, TX 75390 9041, USA
    Diabetes 55:1066-73. 2006
    ..Our findings suggest that alpha2-adrenergic agonists act via a Gi family member on early steps in ERK1/2 activation, supporting the idea that ERK1/2 are regulated in a manner that reflects insulin demand...
  2. pmc Off-target effects of MEK inhibitors
    Eric M Wauson
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9041, United States
    Biochemistry 52:5164-6. 2013
    ..We show that both PD98059 and U0126 reduce agonist-induced entry of calcium into cells in a manner independent of their ability to inhibit ERK1/2. Caution should be used when interpreting results from experiments using these compounds. ..
  3. pmc Minireview: Nutrient sensing by G protein-coupled receptors
    Eric M Wauson
    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 9041, USA
    Mol Endocrinol 27:1188-97. 2013
    ..This review focuses on an array of findings on sensing amino acids and sweet molecules outside of neurons by this cluster of class C GPCRs and some of the physiologic processes regulated by them. ..
  4. pmc NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM
    Jihan K Osborne
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Proc Natl Acad Sci U S A 110:6524-9. 2013
    ..TrkB and NCAM may be therapeutic targets for aggressive neuroendocrine cancers that express NeuroD1...
  5. pmc The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy
    Eric M Wauson
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Dallas, TX 75390 9041, USA
    Mol Cell 47:851-62. 2012
    ..These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals...
  6. pmc A small molecule differentiation inducer increases insulin production by pancreatic β cells
    Elhadji M Dioum
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 108:20713-8. 2011
    ..In summary, we have identified a small molecule with antidiabetic activity, providing a tool for exploring islet function and a possible lead for therapeutic intervention in diabetes...
  7. pmc Calcineurin increases glucose activation of ERK1/2 by reversing negative feedback
    Lingling Duan
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 107:22314-9. 2010
    ..Blocking calcineurin activity in β cells prevents dephosphorylation of B-Raf T401 and decreases B-Raf and ERK1/2 activities. We conclude that the major calcineurin-dependent event in glucose sensing by ERK1/2 is the activation of B-Raf...
  8. pmc Calcineurin/nuclear factor of activated T cells and MAPK signaling induce TNF-{alpha} gene expression in pancreatic islet endocrine cells
    Michael C Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    J Biol Chem 286:1025-36. 2011
    ..Thus, by these mechanisms, pancreatic β cells themselves may contribute to islet inflammation and their own immunological destruction in the pathogenesis of diabetes...
  9. pmc Regulation of CCAAT/enhancer-binding protein homologous protein (CHOP) expression by interleukin-1 beta in pancreatic beta cells
    Chunli Shao
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9041, USA
    J Biol Chem 285:19710-9. 2010
    ..Knocking down CHOP by RNA interference protects beta cells from IL-1beta-induced apoptosis. These studies provide direct mechanistic links between cytokine-induced signaling pathways and CHOP-mediated apoptosis of beta cells...
  10. pmc Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription
    Michael C Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 106:22181-6. 2009
    ....
  11. pmc Sumoylation regulates the transcriptional activity of MafA in pancreatic beta cells
    Chunli Shao
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    J Biol Chem 284:3117-24. 2009
    ..This study suggests that modification of MafA by SUMO modulates gene transcription and thereby beta cell function...
  12. pmc Chromatin-bound mitogen-activated protein kinases transmit dynamic signals in transcription complexes in beta-cells
    Michael C Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 105:13315-20. 2008
    ..These findings imply that MAPK-containing signaling complexes are positioned on sensitive promoters with their protein substrates to modulate transcription in situ in response to incoming signals...
  13. ncbi The roles of MAPKs in disease
    Michael C Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, TX 75390 9041, USA
    Cell Res 18:436-42. 2008
    ..Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders...
  14. ncbi The protein kinases ERK1/2 and their roles in pancreatic beta cells
    M Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 9041, USA
    Acta Physiol (Oxf) 192:11-7. 2008
    ....
  15. pmc Differential regulation of CHOP-10/GADD153 gene expression by MAPK signaling in pancreatic beta-cells
    Michael C Lawrence
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 104:11518-25. 2007
    ..These results indicate that ERK1/2 have dual roles in regulating CHOP gene expression via both promoter and intronic regions, depending on environmental and metabolic stresses imposed on pancreatic beta-cells...
  16. pmc G protein-coupled receptors and the regulation of autophagy
    Eric M Wauson
    Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA Electronic address
    Trends Endocrinol Metab 25:274-82. 2014
    ..Emerging studies show that GPCRs also regulate autophagy by directly detecting extracellular nutrients. We review the role of GPCRs in autophagy regulation, highlighting their potential as therapeutic drug targets. ..

Research Grants30

  1. Role of Chromogranin A in Metabolic Syndrome
    Sushil K Mahata; Fiscal Year: 2013
    ..2. Evaluate the potential therapeutic effects of CST and its variants on insulin sensitivity and baroreflex sensitivity and heart rate variability in high fat diet-induced insulin resistant and in db/db diabetic mice. ..
  2. 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. ..
  3. Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
    Marc R Montminy; Fiscal Year: 2013
    ..By characterizing these chemical changes in TORC2 and understanding how they modify the ability for this switch to trigger glucose production, our studies may lead to new therapies for the treatment of diabetic patients. ..