Paul W. Hruz, M.D., Ph.D.  Hruz_P@kids.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

  • B.S., Marquette University1987
  • Ph.D., Medical College of Wisconsin1993
  • M.D., 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 Pediatrics1997
  • MO, Stae License2000
  • Board Certified in Pediatric Endocrinology & Metabolism2001

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 (46)


Publication Co-Authors

  1. Edwards, R, Brothers RC, Wang X, Maron MI, Tsang PS, Kraft TE, Hruz PW, Williamson KC, Dowd CS, Odom John AR. MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis Sci Rep. 2016;Submitted. 
  2. Shanmugam M, Heitmeier MR, Hruz PW and Schiltz G. Development of selective GLUT4 antagonists for treating multiple myeloma J Med Chem. 2016;Submitted. 
  3. Mayer AL, Higgins CB, Heitmeier MR, Kraft TE, Qian X, Crowley JR, Hyrc KL, Beatty WL, Yarasheski KE, Hruz PW, DeBosch BJ. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Sci Rep. 2016;6:38586. PMCID:PMC5138640  PMID:27922102  
  4. Kraft TE, Heitmeier MR, Putanko M, Edwards RL, Ilagan MX, Payne MA, Autry JM, Thomas DD, Odom AR, Hruz PW. 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  
  5. Hresko RC, Kraft TE, Quigley A, Carpenter EP, Hruz PW. Mammalian Glucose Transporter Activity is Dependent upon Anionic and Conical Phospholipids. J Biol Chem. 2016. doi:10.1074/jbc.M116.730168  PMID:27302065  
  6. DeBosch BJ, Heitmeier MR, Mayer AL, Higgins CB, Crowley JR, Kraft TE, Chi M, Newberry EP, Chen Z, Finck BN, Davidson NO, Yarasheski KE, Hruz PW, Moley KH. 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  
  7. Kraft TE, Armstrong C, Heitmeier MR, Odom AR, Hruz PW. 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  
  8. Kraft TE, Hresko RC, Hruz PW. Expression, purification, and functional characterization of the insulin-responsive facilitative glucose transporter GLUT4. Protein Sci. 2015. doi:10.1002/pro.2812  PMID:26402434  
  9. Mishra RK, Wei C, Hresko RC, Bajpai R, Heitmeier M, Matulis SM, Nooka AK, Rosen ST, Hruz PW, Schiltz GE, Shanmugam M. 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  
  10. Hruz PW. HIV and endocrine disorders. Endocrinol Metab Clin North Am. 2014;43(3):xvii-xviii. PMID:25169571  
  11. Hresko RC, Kraft TE, Tzekov A, Wildman SA, Hruz PW. 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  
  12. Vyas AK, Aerni-Flessner LB, Payne MA, Kovacs A, Jay PY, Hruz PW. 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  
  13. Aerni-Flessner L, Abi-Jaoude M, Koenig A, Payne M, Hruz PW. 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  
  14. Remedi MS, Agapova SE, Vyas AK, Hruz PW, Nichols CG. 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  
  15. Hruz PW. 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  
  16. Hruz PW, Yan Q, Tsai L, Koster J, Xu L, Cihlar T, Callebaut C. 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  
  17. Vyas AK, Yang KC, Woo D, Tzekov A, Kovacs A, Jay PY, Hruz PW. 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  
  18. Hresko RC, Hruz PW. 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  
  19. Gazit V, Weymann A, Hartman E, Finck BN, Hruz PW, Tzekov A, Rudnick DA. 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  
  20. Vyas AK, Koster JC, Tzekov A, Hruz PW. 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  
  21. Guo W, Wong S, Pudney J, Jasuja R, Hua N, Jiang L, Miller A, Hruz PW, Hamilton JA, Bhasin S. 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  
  22. Tu P, Bhasin S, Hruz PW, Herbst KL, Castellani LW, Hua N, Hamilton JA, Guo W. 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  
  23. Flint OP, Noor MA, Hruz PW, Hylemon PB, Yarasheski K, Kotler DP, Parker RA, Bellamine A. 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  
  24. Hruz PW. 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  
  25. Hruz PW, Yan Q, Struthers H, Jay PY. 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  
  26. Hruz PW, Yan Q. 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  
  27. Turmelle YP, Shikapwashya O, Tu S, Hruz PW, Yan Q, Rudnick DA. Rosiglitazone inhibits mouse liver regeneration. FASEB J. 2006;20(14):2609-11. doi:10.1096/fj.06-6511fje  PMID:17077279  
  28. Hruz PW. Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection. Am J Infect Dis. 2006;2(3):187-192. PMCID:PMC1716153  PMID:17186064  
  29. Yan Q, Hruz PW. 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  
  30. Hertel J, Struthers H, Horj CB, Hruz PW. 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  
  31. Shteyer E, Liao Y, Muglia LJ, Hruz PW, Rudnick DA. 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  
  32. Liao Y, Shikapwashya ON, Shteyer E, Dieckgraefe BK, Hruz PW, Rudnick DA. 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  
  33. Koster JC, Remedi MS, Qiu H, Nichols CG, Hruz PW. HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes. 2003;52(7):1695-700. PMCID:PMC1403824  PMID:12829635  
  34. Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS. 2002;16(6):859-63. PMID:11919487  
  35. Hruz PW, Murata H, Qiu H, Mueckler M. Indinavir induces acute and reversible peripheral insulin resistance in rats. Diabetes. 2002;51(4):937-42. PMID:11916910  
  36. Murata H, Hruz PW, Mueckler M. 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  
  37. Hruz PW, Murata H, Mueckler M. 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  
  38. Hruz PW, Mueckler MM. Structural analysis of the GLUT1 facilitative glucose transporter (review). Mol Membr Biol. 2001;18(3):183-93. PMID:11681785  
  39. Hruz PW, Mueckler MM. Cysteine-scanning mutagenesis of transmembrane segment 11 of the GLUT1 facilitative glucose transporter. Biochemistry. 2000;39(31):9367-72. PMID:10924131  
  40. Murata H, Hruz PW, Mueckler M. 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  
  41. Hruz PW, Mueckler MM. Cysteine-scanning mutagenesis of transmembrane segment 7 of the GLUT1 glucose transporter. J Biol Chem. 1999;274(51):36176-80. PMID:10593902  
  42. Roberts JR, Narasimhan C, Hruz PW, Mitchell GA, Miziorko HM. 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  
  43. Hruz PW, Anderson VE, Miziorko HM. 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  
  44. Mitchell GA, Robert MF, Hruz PW, Wang S, Fontaine G, Behnke CE, Mende-Mueller LM, Schappert K, Lee C, Gibson KM, Miziorko HM. 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  
  45. Hruz PW, Miziorko HM. 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  
  46. Hruz PW, Narasimhan C, Miziorko HM. 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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