Paul W. Hruz, M.D., Ph.D.  Hruz_P@wustl.edu

Division Chief, Endocrinology and Diabetes
Associate Professor of Pediatrics, Endocrinology and Diabetes
Associate Professor of Pediatrics, Cell Biology & Physiology
Cell Biology & PhysiologyDevelopmental BiologyEndocrinology and Diabetes

phone: (314) 454-6051

Clinical Interests

Dr. Hruz has clinical interest in a wide range of endocrine disorders, with a special interest in diabetes mellitus. Dr. Hruz's research interests include intermediary carbohydrate metabolism, glucose transporter structure and function and mechanism of insulin action. Currently, the mechanism(s) by which HIV protease inhibitors cause serious adverse metabolic effects including peripheral lipoatrophy, visceral adiposity, hypertriglyceridemia, and insulin resistance are being investigated. The laboratory has discovered that HIV protease inhibitors selectively and reversibly inhibit the GLUT4 facilitative glucose transporter. Ongoing studies are being directed toward elucidating the selectivity of these drugs in blocking the activity of each of the known facilitative glucose transport proteins. The tertiary structure of the facilitative glucose transporters is also being investigated using state-of-the-art biophysical approaches.

Education

  • BS, Marquette University1987
  • PhD, Medical College of Wisconsin1993
  • MD, Medical College of Wisconsin1994

Training

  • Pediatric Residency, University of Washington1994 - 1997
  • Pediatric Endocrinology Fellowship, Washington University1997 - 2000

Licensure and Board Certification

  • Board Certified in General Pediatrics 1997
  • MO, Stae License 2000
  • Board Certified in Pediatric Endocrinology & Metabolism 2001

Honors

  • National Institute of Chemists Research and Recognition Award1987
  • Phi Beta Kappa1987
  • Phi Lambda Upsilon (Honorary Chemical Society)1987
  • American Heart Association Predoctoral Fellowship Award1988
  • Alpha Omega Alpha1994
  • Armond J. Quick Award for Excellence in Biochemistry1994
  • NIDDK/Diabetes Branch Most Outstanding Resident1994
  • Pfizer Postdoctoral Fellowship Award1998
  • Scholar, Child Health Research Center of Excellence in Developmental Biology at Washington University2002
  • Julio V Santiago, M.D. Scholar in Pediatrics2013

Recent Publications view all (48)


Publication Co-Authors

  1. Transcription Factor EB (TFEB)-dependent Induction of Thermogenesis by the Hepatocyte GLUT Inhibitor, Trehalose EMBO Reports. 2017;Submitted. 
  2. Development of selective GLUT4 antagonists for treating multiple myeloma Eur J Med Chem. 2017;In press. 
  3. MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis Sci Rep. 2017;In press. 
  4. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Sci Rep. 2016;6:38586. PMCID:PMC5138640  PMID:27922102 
  5. A Novel Fluorescence Resonance Energy Transfer-Based Screen in High-Throughput Format To Identify Inhibitors of Malarial and Human Glucose Transporters. Antimicrob Agents Chemother. 2016;60(12):7407-7414. PMCID:PMC5119023  PMID:27736766 
  6. Mammalian Glucose Transporter Activity is Dependent upon Anionic and Conical Phospholipids. J Biol Chem. 2016. doi:10.1074/jbc.M116.730168  PMID:27302065 
  7. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016;9(416):ra21. doi:10.1126/scisignal.aac5472  PMID:26905426 
  8. Commentary. Clin Chem. 2015;61(12):1444. PMID:26614228 
  9. The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir. Antimicrob Agents Chemother. 2015;59(10):6203-9. doi:10.1128/AAC.00899-15  PMCID:PMC4576095  PMID:26248369 
  10. Expression, purification, and functional characterization of the insulin-responsive facilitative glucose transporter GLUT4. Protein Sci. 2015. doi:10.1002/pro.2812  PMID:26402434 
  11. In Silico Modeling-based Identification of Glucose Transporter 4 (GLUT4)-selective Inhibitors for Cancer Therapy. J Biol Chem. 2015;290(23):14441-53. doi:10.1074/jbc.M114.628826  PMID:25847249 
  12. HIV and endocrine disorders. Endocrinol Metab Clin North Am. 2014;43(3):xvii-xviii. PMID:25169571 
  13. Isoform-selective inhibition of facilitative glucose transporters: elucidation of the molecular mechanism of HIV protease inhibitor binding. J Biol Chem. 2014;289(23):16100-16113. doi:10.1074/jbc.M113.528430  PMCID:PMC4047383  PMID:24706759 
  14. Saxagliptin Improves Glucose Tolerance but not Survival in a Murine Model of Dilated Cardiomyopathy. Cardiovasc Endocrinol. 2012;1(4):74-82. doi:10.1097/XCE.0b013e32835bfb24  PMCID:PMC3686315  PMID:23795310 
  15. GLUT4, GLUT1, and GLUT8 are the dominant GLUT transcripts expressed in the murine left ventricle. Cardiovasc Diabetol. 2012;11:63. doi:10.1186/1475-2840-11-63  PMCID:PMC3416696  PMID:22681646 
  16. Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes. Diabetes. 2011;60(10):2515-22. doi:10.2337/db11-0538  PMCID:PMC3178299  PMID:21813803 
  17. Molecular mechanisms for insulin resistance in treated HIV-infection. Best Pract Res Clin Endocrinol Metab. 2011;25(3):459-68. doi:10.1016/j.beem.2010.10.017  PMCID:PMC3115529  PMID:21663839 
  18. GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system. Antimicrob Agents Chemother. 2011;55(4):1377-82. doi:10.1128/AAC.01184-10  PMCID:PMC3067185  PMID:21245443 
  19. Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy. PLoS One. 2011;6(2):e17178. doi:10.1371/journal.pone.0017178  PMCID:PMC3040766  PMID:21359201 
  20. HIV protease inhibitors act as competitive inhibitors of the cytoplasmic glucose binding site of GLUTs with differing affinities for GLUT1 and GLUT4. PLoS One. 2011;6(9):e25237. doi:10.1371/journal.pone.0025237  PMCID:PMC3179492  PMID:21966466 
  21. Liver regeneration is impaired in lipodystrophic fatty liver dystrophy mice. Hepatology. 2010;52(6):2109-17. doi:10.1002/hep.23920  PMCID:PMC2991544  PMID:20967828 
  22. Effects of the HIV protease inhibitor ritonavir on GLUT4 knock-out mice. J Biol Chem. 2010;285(47):36395-400. doi:10.1074/jbc.M110.176321  PMCID:PMC2978568  PMID:20864532 
  23. Acipimox, an inhibitor of lipolysis, attenuates atherogenesis in LDLR-null mice treated with HIV protease inhibitor ritonavir. Arterioscler Thromb Vasc Biol. 2009;29(12):2028-32. doi:10.1161/ATVBAHA.109.191304  PMCID:PMC2783673  PMID:19762785 
  24. Genetic disruption of myostatin reduces the development of proatherogenic dyslipidemia and atherogenic lesions in Ldlr null mice. Diabetes. 2009;58(8):1739-48. doi:10.2337/db09-0349  PMCID:PMC2712781  PMID:19509018 
  25. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol Pathol. 2009;37(1):65-77. doi:10.1177/0192623308327119  PMCID:PMC3170409  PMID:19171928 
  26. HIV protease inhibitors and insulin resistance: lessons from in-vitro, rodent and healthy human volunteer models. Curr Opin HIV AIDS. 2008;3(6):660-5. doi:10.1097/COH.0b013e3283139134  PMCID:PMC2680222  PMID:19373039 
  27. HIV protease inhibitors that block GLUT4 precipitate acute, decompensated heart failure in a mouse model of dilated cardiomyopathy. FASEB J. 2008;22(7):2161-7. doi:10.1096/fj.07-102269  PMID:18256305 
  28. Tipranavir without ritonavir does not acutely induce peripheral insulin resistance in a rodent model. J Acquir Immune Defic Syndr. 2006;43(5):624-5. doi:10.1097/01.qai.0000245883.66509.b4  PMID:17133213 
  29. Rosiglitazone inhibits mouse liver regeneration. FASEB J. 2006;20(14):2609-11. doi:10.1096/fj.06-6511fje  PMID:17077279 
  30. Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection. Am J Infect Dis. 2006;2(3):187-192. PMCID:PMC1716153  PMID:17186064 
  31. Direct comparison of the acute in vivo effects of HIV protease inhibitors on peripheral glucose disposal. J Acquir Immune Defic Syndr. 2005;40(4):398-403. PMCID:PMC1360159  PMID:16280693 
  32. A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity. J Biol Chem. 2004;279(53):55147-52. doi:10.1074/jbc.M410826200  PMCID:PMC1403823  PMID:15496402 
  33. Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice. Hepatology. 2004;40(6):1322-32. doi:10.1002/hep.20462  PMID:15565660 
  34. Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1-deficient mice. J Biol Chem. 2004;279(41):43107-16. doi:10.1074/jbc.M407969200  PMID:15265859 
  35. HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes. 2003;52(7):1695-700. PMCID:PMC1403824  PMID:12829635 
  36. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS. 2002;16(6):859-63. PMID:11919487 
  37. Indinavir induces acute and reversible peripheral insulin resistance in rats. Diabetes. 2002;51(4):937-42. PMID:11916910 
  38. Investigating the cellular targets of HIV protease inhibitors: implications for metabolic disorders and improvements in drug therapy. Curr Drug Targets Infect Disord. 2002;2(1):1-8. PMID:12462148 
  39. Adverse metabolic consequences of HIV protease inhibitor therapy: the search for a central mechanism. Am J Physiol Endocrinol Metab. 2001;280(4):E549-53. PMID:11254460 
  40. Structural analysis of the GLUT1 facilitative glucose transporter (review). Mol Membr Biol. 2001;18(3):183-93. PMID:11681785 
  41. Cysteine-scanning mutagenesis of transmembrane segment 11 of the GLUT1 facilitative glucose transporter. Biochemistry. 2000;39(31):9367-72. PMID:10924131 
  42. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem. 2000;275(27):20251-4. doi:10.1074/jbc.C000228200  PMID:10806189 
  43. Cysteine-scanning mutagenesis of transmembrane segment 7 of the GLUT1 glucose transporter. J Biol Chem. 1999;274(51):36176-80. PMID:10593902 
  44. 3-Hydroxy-3-methylglutaryl-CoA lyase: expression and isolation of the recombinant human enzyme and investigation of a mechanism for regulation of enzyme activity. J Biol Chem. 1994;269(27):17841-6. PMID:8027038 
  45. 3-Hydroxy-3-methylglutaryldithio-CoA: utility of an alternative substrate in elucidation of a role for HMG-CoA lyase's cation activator. Biochim Biophys Acta. 1993;1162(1-2):149-54. PMID:8095409 
  46. 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency. J Biol Chem. 1993;268(6):4376-81. PMID:8440722 
  47. Avian 3-hydroxy-3-methylglutaryl-CoA lyase: sensitivity of enzyme activity to thiol/disulfide exchange and identification of proximal reactive cysteines. Protein Sci. 1992;1(9):1144-53. doi:10.1002/pro.5560010908  PMCID:PMC2142181  PMID:1304393 
  48. 3-Hydroxy-3-methylglutaryl coenzyme A lyase: affinity labeling of the Pseudomonas mevalonii enzyme and assignment of cysteine-237 to the active site. Biochemistry. 1992;31(29):6842-7. PMID:1637819 
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