ABOUT THE RESEARCHER

OVERVIEW

Morris White investigates the molecular basis of insulin signal transduction to understand the pathophysiology of diabetes and other disorders, including obesity, infertility, and cardiovascular and retinal diseases. His studies of the insulin-signaling network reveal common elements that promote peripheral insulin action, pancreatic beta-cell growth and function, and hypothalamic control of nutrient homeostasis and fertility. His work may reveal new strategies to treat dysregulated nutrient metabolism and type 2 diabetes.

 

BACKGROUND

Morris White received his PhD degree from the University of Michigan. He completed a postdoctoral fellowship at Joslin Diabetes Institute. Dr. White in an investigator in the Howard Hughes Medical Institute. He has been a Pew scholar in the biomedical sciences and has received the Boehringer Mannheim/Juvenile Diabetes Foundation International Diabetes Care Research Award and the Outstanding Scientific Achievement Award from the American Diabetes Association.

PUBLICATIONS

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  1. TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiologic states. Elife. 2021 Oct 08; 10. View abstract
  2. Insulin action at a molecular level - 100 years of progress. Mol Metab. 2021 Oct; 52:101304. View abstract
  3. Erratum. Inhibition of TNF-a Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes. Diabetes 2012;61:2134-2145. Diabetes. 2021 Jun; 70(6):1416. View abstract
  4. Irs2 deficiency alters hippocampus-associated behaviors during young adulthood. Biochem Biophys Res Commun. 2021 06 25; 559:148-154. View abstract
  5. Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice. J Biol Chem. 2021 Jan-Jun; 296:100646. View abstract
  6. FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance. Cell Rep. 2021 03 23; 34(12):108893. View abstract
  7. From population to neuron: exploring common mediators for metabolic problems and mental illnesses. Mol Psychiatry. 2020 Nov 10. View abstract
  8. Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance. Sci Rep. 2020 03 26; 10(1):5546. View abstract
  9. Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling. JCI Insight. 2020 03 26; 5(6). View abstract
  10. Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice. Endocrinology. 2019 05 01; 160(5):1333-1347. View abstract
  11. Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1-mediated p53/KLF4 complex stabilization. J Biol Chem. 2019 02 15; 294(7):2407-2421. View abstract
  12. Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver. PLoS Biol. 2018 12; 16(12):e2006249. View abstract
  13. Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. J Clin Invest. 2018 12 03; 128(12):5335-5350. View abstract
  14. Publisher Correction: Inactivating hepatic follistatin alleviates hyperglycemia. Nat Med. 2018 Oct; 24(10):1628. View abstract
  15. Inactivating hepatic follistatin alleviates hyperglycemia. Nat Med. 2018 07; 24(7):1058-1069. View abstract
  16. Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis. Proc Natl Acad Sci U S A. 2018 04 17; 115(16):4228-4233. View abstract
  17. Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity. Nat Commun. 2017 07 25; 8(1):131. View abstract
  18. Correction for Long et al., "Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways". Mol Cell Biol. 2017 08 01; 37(15). View abstract
  19. Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation. J Biol Chem. 2017 02 03; 292(5):2009-2020. View abstract
  20. G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway. J Biol Chem. 2016 12 30; 291(53):27160-27169. View abstract
  21. IRS proteins and diabetic complications. Diabetologia. 2016 11; 59(11):2280-2291. View abstract
  22. Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma. Proc Natl Acad Sci U S A. 2016 08 02; 113(31):8795-800. View abstract
  23. Trimeprazine increases IRS2 in human islets and promotes pancreatic ß cell growth and function in mice. JCI Insight. 2016; 1(3). View abstract
  24. Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase. J Biol Chem. 2016 Apr 15; 291(16):8602-17. View abstract
  25. Longevity: Mapping the path to a longer life. Nature. 2015 Aug 13; 524(7564):170-1. View abstract
  26. Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training. Mol Cell Biol. 2014 Sep 15; 34(18):3450-60. View abstract
  27. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep. 2014 May 22; 7(4):1227-38. View abstract
  28. Insulin and metabolic stress stimulate multisite serine/threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation. J Biol Chem. 2014 May 02; 289(18):12467-84. View abstract
  29. IRS1Ser³°7 phosphorylation does not mediate mTORC1-induced insulin resistance. Biochem Biophys Res Commun. 2014 Jan 10; 443(2):689-93. View abstract
  30. Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38a MAPK during insulin resistance. Diabetes. 2013 Nov; 62(11):3887-900. View abstract
  31. Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. J Clin Invest. 2013 Dec; 123(12):5319-33. View abstract
  32. Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Mol Metab. 2014 Feb; 3(1):55-63. View abstract
  33. Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes. PLoS One. 2013; 8(8):e71997. View abstract
  34. Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling. Sci Signal. 2013 Jul 30; 6(286):ra64. View abstract
  35. Direct autocrine action of insulin on ß-cells: does it make physiological sense? Diabetes. 2013 Jul; 62(7):2157-63. View abstract
  36. Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Mol Cell Biol. 2013 Aug; 33(16):3227-41. View abstract
  37. Nerve growth factor receptor TrkA, a new receptor in insulin signaling pathway in PC12 cells. J Biol Chem. 2013 Aug 16; 288(33):23807-13. View abstract
  38. Insulin receptor substrate-2 is expressed in kidney epithelium and up-regulated in diabetic nephropathy. FEBS J. 2013 Jul; 280(14):3232-43. View abstract
  39. Chronic activation of a designer G(q)-coupled receptor improves ß cell function. J Clin Invest. 2013 Apr; 123(4):1750-62. View abstract
  40. Integrating metabolism and longevity through insulin and IGF1 signaling. Endocrinol Metab Clin North Am. 2013 Mar; 42(1):127-48. View abstract
  41. Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review. Environ Health Perspect. 2013 Feb; 121(2):170-80. View abstract
  42. Inhibition of TNF-a improves the bladder dysfunction that is associated with type 2 diabetes. Diabetes. 2012 Aug; 61(8):2134-45. View abstract
  43. Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling. Diabetes. 2012 Sep; 61(9):2269-79. View abstract
  44. IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell Metab. 2012 May 02; 15(5):703-12. View abstract
  45. kNOXing on the door of selective insulin resistance. Arterioscler Thromb Vasc Biol. 2012 May; 32(5):1063-5. View abstract
  46. The AKTion in non-canonical insulin signaling. Nat Med. 2012 Mar 06; 18(3):351-3. View abstract
  47. Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K). J Biol Chem. 2012 Feb 10; 287(7):4518-30. View abstract
  48. IRS-2 Deficiency impairs NMDA receptor-dependent long-term potentiation. Cereb Cortex. 2012 Aug; 22(8):1717-27. View abstract
  49. IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. J Clin Invest. 2011 Oct; 121(10):4070-81. View abstract
  50. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat Med. 2011 Mar; 17(3):356-65. View abstract
  51. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Mol Cell Biol. 2011 Feb; 31(3):430-41. View abstract
  52. Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1. Am J Physiol Endocrinol Metab. 2011 Feb; 300(2):E312-20. View abstract
  53. Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models. Antioxid Redox Signal. 2011 Feb 15; 14(4):649-61. View abstract
  54. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab. 2010 Oct; 21(10):589-98. View abstract
  55. Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3beta? BMC Dev Biol. 2010 Jul 06; 10:73. View abstract
  56. Diabetes forum: Extreme makeover of pancreatic alpha-cells. Nature. 2010 Apr 22; 464(7292):1132-3. View abstract
  57. Foxo1 in hepatic lipid metabolism. . 2010 Jan 15; 9(2):219-20. View abstract
  58. Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab. 2010 Jan; 11(1):84-92. View abstract
  59. Insulin-like growth factor 2 and the insulin receptor, but not insulin, regulate fetal hepatic glycogen synthesis. Endocrinology. 2010 Feb; 151(2):741-7. View abstract
  60. The IRS2 Gly1057Asp variant is associated with human longevity. J Gerontol A Biol Sci Med Sci. 2010 Mar; 65(3):282-6. View abstract
  61. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med. 2009 Nov; 15(11):1307-11. View abstract
  62. The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol. 2009 Sep; 29(18):5070-83. View abstract
  63. Insulin receptor substrate-2 in beta-cells decreases diabetes in nonobese diabetic mice. Endocrinology. 2009 Oct; 150(10):4531-40. View abstract
  64. Metformin and insulin meet in a most atypical way. Cell Metab. 2009 Jun; 9(6):485-7. View abstract
  65. Targeted disruption of ROCK1 causes insulin resistance in vivo. J Biol Chem. 2009 May 01; 284(18):11776-80. View abstract
  66. Breathing room: the (un)natural history of adipose microhypoxia and insulin resistance. Diabetes. 2009 Jan; 58(1):26-7. View abstract
  67. Irs2 inactivation suppresses tumor progression in Pten+/- mice. Am J Pathol. 2009 Jan; 174(1):276-86. View abstract
  68. Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle. Diabetes. 2008 Oct; 57(10):2644-51. View abstract
  69. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 2008 Jul; 8(1):65-76. View abstract
  70. Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol. 2008 Mar; 15(3):251-8. View abstract
  71. Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol. 2008 Feb; 6(2):e37. View abstract
  72. Insulin-like signaling, nutrient homeostasis, and life span. Annu Rev Physiol. 2008; 70:191-212. View abstract
  73. The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic beta-cell apoptosis. Diabetes. 2008 Mar; 57(3):635-44. View abstract
  74. Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology. J Cell Physiol. 2007 Nov; 213(2):519-27. View abstract
  75. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science. 2007 Jul 20; 317(5836):369-72. View abstract
  76. Phosphorylation of Irs1 at SER-522 inhibits insulin signaling. Mol Endocrinol. 2007 Sep; 21(9):2294-302. View abstract
  77. Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. Am J Physiol Endocrinol Metab. 2007 Jun; 292(6):E1694-701. View abstract
  78. Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice. Front Biosci. 2007 Jan 01; 12:2291-8. View abstract
  79. Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. Mol Cell Biol. 2006 Dec; 26(24):9338-51. View abstract
  80. The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Mol Endocrinol. 2006 Dec; 20(12):3389-99. View abstract
  81. Regulating insulin signaling and beta-cell function through IRS proteins. Can J Physiol Pharmacol. 2006 Jul; 84(7):725-37. View abstract
  82. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest. 2006 Jan; 116(1):101-14. View abstract
  83. RIP-Cre revisited, evidence for impairments of pancreatic beta-cell function. J Biol Chem. 2006 Feb 03; 281(5):2649-53. View abstract
  84. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005 Dec; 115(12):3587-93. View abstract
  85. Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem. 2006 Jan 13; 281(2):1159-68. View abstract
  86. Phosphatase and tensin homolog regulation of islet growth and glucose homeostasis. J Biol Chem. 2005 Nov 25; 280(47):39388-93. View abstract
  87. Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: role of IRS phosphorylation. Life Sci. 2005 Oct 28; 77(24):3068-77. View abstract
  88. Attenuation of accumulation of neointimal lipid by pioglitazone in mice genetically deficient in insulin receptor substrate-2 and apolipoprotein E. J Histochem Cytochem. 2005 May; 53(5):603-10. View abstract
  89. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol. 2005 May; 25(9):3752-62. View abstract
  90. Alterations in growth and apoptosis of insulin receptor substrate-1-deficient beta-cells. Am J Physiol Endocrinol Metab. 2005 Aug; 289(2):E337-46. View abstract
  91. Insulin receptor substrate 2 plays diverse cell-specific roles in the regulation of glucose transport. J Biol Chem. 2005 Apr 15; 280(15):14536-44. View abstract
  92. Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells. J Neurosci. 2005 Feb 02; 25(5):1240-8. View abstract
  93. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med. 2005 Feb; 11(2):175-82. View abstract
  94. Signaling pathways: the benefits of good communication. Curr Biol. 2004 Dec 14; 14(23):R1005-7. View abstract
  95. IRS-2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes. Hepatology. 2004 Dec; 40(6):1285-94. View abstract
  96. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol. 2004 Nov; 24(22):9726-35. View abstract
  97. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest. 2004 Oct; 114(7):908-16. View abstract
  98. Insulin resistance in thermally-injured rats is associated with post-receptor alterations in skeletal muscle, liver and adipose tissue. Int J Mol Med. 2004 Oct; 14(4):653-8. View abstract
  99. Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Mol Cell Biol. 2004 Sep; 24(17):7435-43. View abstract
  100. Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation. Biochem Biophys Res Commun. 2004 Apr 02; 316(2):533-9. View abstract
  101. Insulin receptor substrate proteins and diabetes. Arch Pharm Res. 2004 Apr; 27(4):361-70. View abstract
  102. Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity. . 2004 Jul; 287(1):C200-8. View abstract
  103. Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Diabetes. 2004 Jan; 53(1):61-6. View abstract
  104. Insulin signaling in health and disease. Science. 2003 Dec 05; 302(5651):1710-1. View abstract
  105. Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. J Biol Chem. 2004 Jan 30; 279(5):3447-54. View abstract
  106. Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. J Biol Chem. 2004 Feb 06; 279(6):3941-8. View abstract
  107. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest. 2003 Nov; 112(10):1521-32. View abstract
  108. Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Diabetes. 2003 Sep; 52(9):2239-48. View abstract
  109. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci. 2003 Aug 06; 23(18):7084-92. View abstract
  110. cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev. 2003 Jul 01; 17(13):1575-80. View abstract
  111. Essential role of protein kinase C zeta in the impairment of insulin-induced glucose transport in IRS-2-deficient brown adipocytes. FEBS Lett. 2003 Feb 11; 536(1-3):161-6. View abstract
  112. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest. 2002 Dec; 110(12):1839-47. View abstract
  113. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002 Dec 27; 277(52):50230-6. View abstract
  114. Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications. Cancer Res. 2002 Nov 01; 62(21):6035-8. View abstract
  115. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem. 2003 Jan 31; 278(5):2896-902. View abstract
  116. Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J Clin Invest. 2002 Oct; 110(7):1011-9. View abstract
  117. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem. 2002 Nov 01; 277(44):42394-8. View abstract
  118. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 2002 Sep; 283(3):E413-22. View abstract
  119. Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL. J Biol Chem. 2002 Jul 26; 277(30):27169-75. View abstract
  120. Pdx1 restores beta cell function in Irs2 knockout mice. J Clin Invest. 2002 May; 109(9):1193-201. View abstract
  121. Insulin signaling after exercise in insulin receptor substrate-2-deficient mice. Diabetes. 2002 Feb; 51(2):479-83. View abstract
  122. Specificity of interleukin-2 receptor gamma chain superfamily cytokines is mediated by insulin receptor substrate-dependent pathway. J Biol Chem. 2002 Mar 08; 277(10):8091-8. View abstract
  123. Stat6 and IRS-2 cooperate in interleukin 4 (IL-4)-induced proliferation and differentiation but are dispensable for IL-4-dependent rescue from apoptosis. Mol Cell Biol. 2002 Jan; 22(1):117-26. View abstract
  124. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002 Jan 11; 277(2):1531-7. View abstract
  125. Perspective: The Insulin Signaling System-A Common Link in the Pathogenesis of Type 2 Diabetes. Endocrinology. 2000 Jun 01; 141(6):1917-1921. View abstract
  126. Differential Regulation of Insulin Receptor Substrate-2 and Mitogen-Activated Protein Kinase Tyrosine Phosphorylation by Phosphatidylinositol 3-Kinase Inhibitors in SH-SY5Y Human Neuroblastoma Cells* * This work was supported by NIH Grants R29-NS-32843 and R01-NS-36778, grants from the American Diabetes Association and Juvenile Diabetes Foundation (to E.L.F.), and a grant from the Millie Schembechler Adrenal Research Fund of the University of Michigan Comprehensive Cancer Center (to E.L.F. and P.S.L.). Endocrinology. 1998 Dec 01; 139(12):4881-4889. View abstract