Department of Pediatrics

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 University, 1987
• PhD, Medical College of Wisconsin, 1993
• MD, Medical College of Wisconsin, 1994

Training

• Pediatric Residency, University of Washington, 1994 - 1997
• Pediatric Endocrinology Fellowship, Washington University, 1997 - 2000
• Certification in Healthcare Ethics, National Catholic Bioethics Center, 2017

Licensure and Board Certification

• 1997 - PresBoard Certified in General Pediatrics
• 2000 - PresMO, Stae License
• 2001 - PresBoard Certified in Pediatric Endocrinology & Metabolism

Honors and Awards

• National Institute of Chemists Research and Recognition Award, 1987
• Phi Beta Kappa, 1987
• Phi Lambda Upsilon (Honorary Chemical Society), 1987
• American Heart Association Predoctoral Fellowship Award, 1988
• Alpha Omega Alpha, 1994
• Armond J. Quick Award for Excellence in Biochemistry, 1994
• NIDDK/Diabetes Branch Most Outstanding Resident, 1994
• Pfizer Postdoctoral Fellowship Award, 1998
• Scholar, Child Health Research Center of Excellence in Developmental Biology at Washington University, 2002
• Julio V Santiago, M.D. Scholar in Pediatrics, 2013
• Redemptor Hominis Award for Outstanding Contributions to the Study of Bioethics, 2017
• Eli Lilly Outstanding Contribution to Drug Discovery: Emerging Biology Award, 2018
• Scholar-Innovator Award, Harrington Discovery Institute, 2018

Recent Publications view all (52)

Publication Co-Authors

Misty Good, M.D., M.S.

David A. Rudnick, M.D., Ph.D.

Brian DeBosch, M.D., Ph.D.

Washington University has a long tradition of collaboration amongst colleagues.The faculty above have co-authored publications with Paul W. Hruz, M.D., Ph.D.

1. Malone WJ, Hruz PW, Mason JW, Beck S. Letter to the Editor from William J. Malone: "Proper Care of Transgender and Gender Diverse Persons in the Setting of Proposed Discrimination: A Policy Perspective". J Clin Endocrinol Metab. 2021. PMID:33772300 
2. Zhang Y, Shaikh N, Ferey JL, Wankhade UD, Chintapalli SV, Higgins CB, Crowley JR, Heitmeier MR, Stothard AI, Mihi B, Good M, Higashiyama T, Swarts BM, Hruz PW, Shankar K, Tarr PI, DeBosch BJ. Lactotrehalose, an Analog of Trehalose, Increases Energy Metabolism Without Promoting Clostridioides difficile Infection in Mice. Gastroenterology. 2020;158(5):1402-1416.e2. PMCID:PMC7103499  PMID:31838076 
3. Hruz PW. Deficiencies in Scientific Evidence for Medical Management of Gender Dysphoria. Linacre Q. 2020;87(1):34-42. PMCID:PMC7016442  PMID:32431446 
4. Heitmeier MR, Hresko RC, Edwards RL, Prinsen MJ, Ilagan MXG, Odom John AR, Hruz PW. Identification of druggable small molecule antagonists of the Plasmodium falciparum hexose transporter PfHT and assessment of ligand access to the glucose permeation pathway via FLAG-mediated protein engineering. PLoS One. 2019;14(5):e0216457. PMCID:PMC6508677  PMID:31071153 
5. Laidlaw MK, Van Meter QL, Hruz PW, Van Mol A, Malone WJ. Letter to the Editor: "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 2019;104(3):686-687. PMID:30476120 
6. Emfinger CH, Yan Z, Welscher A, Hung P, McAllister W, Hruz PW, Nichols CG, Remedi MS. Contribution of systemic inflammation to permanence of K_ATP-induced neonatal diabetes in mice. Am J Physiol Endocrinol Metab. 2018;315(6):E1121-E1132. PMCID:PMC6336961  PMID:30226997 
7. Zhang Y, Higgins CB, Mayer AL, Mysorekar IU, Razani BB, Graham MJ, Hruz PW, DeBosch BJ. TFEB-dependent Induction of Thermogenesis by the Hepatocyte SLC2A Inhibitor Trehalose. Autophagy. 2018. PMID:29996716 
8. Heitmeier MR, Payne MA, Weinheimer C, Kovacs A, Hresko RC, Jay PY, Hruz PW. Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia. Sci Rep. 2018;8(1):6475. PMID:29691457 
9. Wei C, Heitmeier M, Hruz PW, Shanmugam M. Evaluating the Efficacy of GLUT Inhibitors Using a Seahorse Extracellular Flux Analyzer. Methods Mol Biol. 2018;1713:69-75. PMID:29218518 
10. Wei C, Bajpai R, Sharma H, Heitmeier M, Jain AD, Matulis SM, Nooka AK, Mishra RK, Hruz PW, Schiltz GE, Shanmugam M. Development of GLUT4-selective antagonists for multiple myeloma therapy. Eur J Med Chem. 2017;139:573-586. PMCID:PMC5603412  PMID:28837922 
11. Edwards RL, Brothers RC, Wang X, Maron MI, Ziniel PD, Tsang PS, Kraft TE, Hruz PW, Williamson KC, Dowd CS, John ARO. MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis. Sci Rep. 2017;7(1):8400. PMCID:PMC5567135  PMID:28827774 
12. 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 
13. 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 
14. 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 
15. 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 
16. 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 
17. 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 
18. 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 
19. 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 
20. 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 
21. 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 
22. 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 
23. 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 
24. 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 
25. 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 
26. 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 
27. 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 
28. 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 
29. 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 
30. 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 
31. 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 
32. 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 
33. 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 
34. 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 
35. Hruz PW. Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection. Am J Infect Dis. 2006;2(3):187-192. PMCID:PMC1716153  PMID:17186064 
36. 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 
37. 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 
38. 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 
39. 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 
40. 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 
41. Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS. 2002;16(6):859-63. PMID:11919487 
42. 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 
43. 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 
44. Hruz PW, Mueckler MM. Structural analysis of the GLUT1 facilitative glucose transporter (review). Mol Membr Biol. 2001;18(3):183-93. PMID:11681785 
45. 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 
46. 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 
47. 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 
48. 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 
49. 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 
50. 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 
51. 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 
52. 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