Acta Diabetologica

, Volume 49, Issue 6, pp 453–464

A discovery-phase urine proteomics investigation in type 1 diabetes

  • A. Soggiu
  • C. Piras
  • L. Bonizzi
  • H. A. Hussein
  • S. Pisanu
  • P. Roncada
Original Article


Diabetes is a chronic metabolic disease which can lead to serious health problems particularly in and to the development of cardiovascular and renal complications. The aim of this study is to possibly identify distinctive molecular features in urine samples which might correlate to the progression and complications of type 1 diabetes. Diabetic patients with normo- and micro-albuminuria have been analyzed and compared to a group of control subjects. Urine proteins of control and type 1 diabetes subjects were investigated in their proteome profiles, using high-resolution two-dimensional gel electrophoresis separation and protein identifications by MALDI–TOF–MS and LC–MS/MS analysis. Proteomics analysis highlighted differential expression of several proteins between control and type 1 diabetes subjects. In particular, five proteins were found to be down-regulated and four proteins up-regulated. Lower protein representations in diabetic subjects were associated with Tamm–Horsfall urinary glycoprotein, apolipoprotein A-I, apolipoprotein E, α2-thiol proteinase inhibitor, and human complement regulatory protein CD59, while higher protein representations were found for α-1-microglobulin, zinc-α2 glycoprotein, α-1B glycoprotein, and retinol-binding protein 4. These differences were maintained comparing control subjects with type 1 diabetes normo-albuminuric and micro-albuminuric subjects. Furthermore, these proteins are correlated to glycosylated hemoglobin and microalbuminuria, confirming their role in diabetic pathology. This study gives new insights on potential molecular mechanisms associated with the complications of type 1 diabetic disease providing evidences of urine proteins potentially exploitable as putative prognostic biomarkers.


Type 1 diabetes Urine proteomics HbA1c Microalbuminuria Biomarkers Diabetic nephropathy 



Tamm–Horsfall urinary glycoprotein

Apo A-1

Apolipoprotein A-I

Apo E

Apolipoprotein E


Kininogen-1 or α2-thiol proteinase inhibitor


Human complement regulatory protein CD59




Zinc-α2 glycoprotein


α-1B Glycoprotein


Plasma retinol-binding protein


Glycosylated hemoglobin


Insulin-dependent diabetes mellitus


Non-insulin-dependent diabetes mellitus


Matrix-assisted laser desorption ionization–time of flight


Liquid chromatography tandem mass spectrometry


Diabetes nephropathy


Type 1 diabetes


Two-dimensional electrophoresis


Type 2 diabetes


  1. 1.
    Bluestone JA, Herold K, Eisenbarth G (2010) Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464(7293):1293–1300PubMedCrossRefGoogle Scholar
  2. 2.
    Daneman D (2006) Type 1 diabetes. Lancet 367(9513):847–858. doi:10.1016/S0140-6736(06)68341-4 PubMedCrossRefGoogle Scholar
  3. 3.
    Colino E, Alvarez MA, Carcavilla A, Alonso M, Ros P, Barrio R (2010) Insulin dose adjustment when changing from multiple daily injections to continuous subcutaneous insulin infusion in the pediatric age group. Acta Diabetol 47(Suppl 1):1–6. doi:10.1007/s00592-009-0103-x PubMedCrossRefGoogle Scholar
  4. 4.
    Sahin SB, Cetinkalp S, Ozgen AG, Saygili F, Yilmaz C (2010) The importance of anti-insulin antibody in patients with type 1 diabetes mellitus treated with continuous subcutaneous insulin infusion or multiple daily insulin injections therapy. Acta Diabetol 47(4):325–330. doi:10.1007/s00592-010-0221-5 PubMedCrossRefGoogle Scholar
  5. 5.
    Monami M, Lamanna C, Marchionni N, Mannucci E (2010) Continuous subcutaneous insulin infusion versus multiple daily insulin injections in type 1 diabetes: a meta-analysis. Acta Diabetol 47(Suppl 1):77–81. doi:10.1007/s00592-009-0132-5 PubMedCrossRefGoogle Scholar
  6. 6.
    Klupa T, Skupien J, Cyganek K, Katra B, Sieradzki J, Malecki MT (2011) The dual-wave bolus feature in type 1 diabetes adult users of insulin pumps. Acta Diabetol 48(1):11–14. doi:10.1007/s00592-009-0173-9 PubMedCrossRefGoogle Scholar
  7. 7.
    Raman R, Rani PK, Gnanamoorthy P, Sudhir RR, Kumaramanikavel G, Sharma T (2010) Association of obesity with diabetic retinopathy: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS Report no. 8). Acta Diabetol 47(3):209–215. doi:10.1007/s00592-009-0113-8 PubMedCrossRefGoogle Scholar
  8. 8.
    Tarquini R, Lazzeri C, Pala L, Rotella CM, Gensini GF (2011) The diabetic cardiomyopathy. Acta Diabetol 48(3):173–181. doi:10.1007/s00592-010-0180-x PubMedCrossRefGoogle Scholar
  9. 9.
    May O, Arildsen H (2011) Long-term predictive power of simple function tests for cardiovascular autonomic neuropathy in diabetes: a population-based study. Acta Diabetol 48(4):311–316. doi:10.1007/s00592-011-0283-z PubMedCrossRefGoogle Scholar
  10. 10.
    Chen SJ, Chou P, Lee AF, Lee FL, Hsu WM, Liu JH, Tung TH (2010) Microaneurysm number and distribution in the macula of Chinese type 2 diabetics with early diabetic retinopathy: a population-based study in Kinmen, Taiwan. Acta Diabetol 47(1):35–41. doi:10.1007/s00592-009-0095-6 CrossRefGoogle Scholar
  11. 11.
    Gianiorio FE, Casu M, Patrone V, Egan CG, Murialdo G (2011) Effect of pioglitazone on cardiac sympathovagal modulation in patients with type 2 diabetes. Acta Diabetol 48(4):283–290. doi:10.1007/s00592-011-0258-0 PubMedCrossRefGoogle Scholar
  12. 12.
    Greco D, Gambina F, Maggio F (2009) Ophthalmoplegia in diabetes mellitus: a retrospective study. Acta Diabetol 46(1):23–26. doi:10.1007/s00592-008-0053-8 PubMedCrossRefGoogle Scholar
  13. 13.
    Atkins RC, Zimmet P (2010) Diabetic kidney disease: act now or pay later. Acta Diabetol 47(1):1–4. doi:10.1007/s00592-010-0175-7 PubMedCrossRefGoogle Scholar
  14. 14.
    Rossing P, de Zeeuw D (2011) Need for better diabetes treatment for improved renal outcome. Kidney Int Suppl 120:S28–S32. doi:10.1038/ki.2010.513 PubMedCrossRefGoogle Scholar
  15. 15.
    Karlberg C, Falk C, Green A, Sjolie AK, Grauslund J (2011) Proliferative retinopathy predicts nephropathy: a 25-year follow-up study of type 1 diabetic patients. Acta Diabetol. doi:10.1007/s00592-011-0304-y PubMedGoogle Scholar
  16. 16.
    Guo L, Cheng Y, Wang X, Pan Q, Li H, Zhang L, Wang Y (2010) Association between microalbuminuria and cardiovascular disease in type 2 diabetes mellitus of the Beijing Han nationality. Acta Diabetol. doi:10.1007/s00592-010-0205-5 Google Scholar
  17. 17.
    Millioni R, Iori E, Puricelli L, Arrigoni G, Vedovato M, Trevisan R, James P, Tiengo A, Tessari P (2008) Abnormal cytoskeletal protein expression in cultured skin fibroblasts from type 1 diabetes mellitus patients with nephropathy: a proteomic approach. Proteomics Clin Appl 2(4):492–503PubMedCrossRefGoogle Scholar
  18. 18.
    Pan HZ, Zhang L, Guo MY, Sui H, Li H, Wu WH, Qu NQ, Liang MH, Chang D (2010) The oxidative stress status in diabetes mellitus and diabetic nephropathy. Acta Diabetol 47(Suppl 1):71–76. doi:10.1007/s00592-009-0128-1 PubMedCrossRefGoogle Scholar
  19. 19.
    Jia L, Zhang L, Shao C, Song E, Sun W, Li M, Gao Y (2009) An attempt to understand kidney’s protein handling function by comparing plasma and urine proteomes. PLoS ONE 4(4):e5146PubMedCrossRefGoogle Scholar
  20. 20.
    Rao PV, Lu X, Standley M, Pattee P, Neelima G, Girisesh G, Dakshinamurthy K, Roberts CT Jr, Nagalla SR (2007) Proteomic identification of urinary biomarkers of diabetic nephropathy. Diabetes Care 30(3):629–637PubMedCrossRefGoogle Scholar
  21. 21.
    Thongboonkerd V, Klein J, Jevans A, McLeish K (2004) Urinary proteomics and biomarker discovery for glomerular diseases. Contrib Nephrol 141:292–307PubMedCrossRefGoogle Scholar
  22. 22.
    Thongboonkerd V (2004) Proteomics in nephrology: current status and future directions. Am J Nephrol 24(3):360–378PubMedCrossRefGoogle Scholar
  23. 23.
    Thongboonkerd V (2005) Proteomic analysis of renal diseases: unraveling the pathophysiology and biomarker discovery. Expert Rev Proteomics 2(3):349–366PubMedCrossRefGoogle Scholar
  24. 24.
    Thongboonkerd V, Malasit P (2005) Renal and urinary proteomics: current applications and challenges. Proteomics 5(4):1033–1042PubMedCrossRefGoogle Scholar
  25. 25.
    Moon PG, You S, Lee JE, Hwang D, Baek MC (2011) Urinary exosomes and proteomics. Mass Spectrom Rev 30(6):1185–1202. doi:10.1002/mas.20319 PubMedCrossRefGoogle Scholar
  26. 26.
    Papale M, Di Paolo S, Magistroni R, Lamacchia O, Di Palma AM, De Mattia A, Rocchetti MT, Furci L, Pasquali S, De Cosmo S, Cignarelli M, Gesualdo L (2010) Urine proteome analysis may allow noninvasive differential diagnosis of diabetic nephropathy. Diabetes Care 33(11):2409–2415. doi:10.2337/dc10-0345 PubMedCrossRefGoogle Scholar
  27. 27.
    Bellei E, Rossi E, Lucchi L, Uggeri S, Albertazzi A, Tomasi A, Iannone A (2008) Proteomic analysis of early urinary biomarkers of renal changes in type 2 diabetic patients. Proteomics Clin Appl 2(4):478–491. doi:10.1002/prca.200780109 PubMedCrossRefGoogle Scholar
  28. 28.
    Candiano G, Santucci L, Petretto A, Bruschi M, Dimuccio V, Urbani A, Bagnasco S, Ghiggeri GM (2010) 2D-electrophoresis and the urine proteome map: where do we stand? J Proteomics 73(5):829–844. doi:10.1016/j.jprot.2009.12.003 PubMedCrossRefGoogle Scholar
  29. 29.
    Konvalinka A, Scholey JW, Diamandis EP (2012) Searching for new biomarkers of renal diseases through proteomics. Clin Chem 58(2):353–365. doi:10.1373/clinchem.2011.165969 PubMedCrossRefGoogle Scholar
  30. 30.
    Zurbig P, Dihazi H, Metzger J, Thongboonkerd V, Vlahou A (2011) Urine proteomics in kidney and urogenital diseases: Moving towards clinical applications. Proteomics Clin Appl 5(5–6):256–268. doi:10.1002/prca.201000133 PubMedCrossRefGoogle Scholar
  31. 31.
    Decramer S, Gonzalez de Peredo A, Breuil B, Mischak H, Monsarrat B, Bascands JL, Schanstra JP (2008) Urine in clinical proteomics. Mol Cell Proteomics 7(10):1850–1862. doi:10.1074/mcp.R800001-MCP200 PubMedCrossRefGoogle Scholar
  32. 32.
    Merchant ML, Klein JB (2007) Proteomics and diabetic nephropathy. Elsevier, Amsterdam, pp 627–636Google Scholar
  33. 33.
    Torffvit O, Agardh CD (1993) Tubular secretion of Tamm–Horsfall protein is decreased in type 1 (insulin-dependent) diabetic patients with diabetic nephropathy. Nephron 65(2):227–231PubMedCrossRefGoogle Scholar
  34. 34.
    Torffvit O, Agardh CD (1994) Urinary excretion rate of NC1 and Tamm–Horsfall protein in the microalbuminuric type I diabetic patient. J Diabetes Complicat 8(2):77–83PubMedCrossRefGoogle Scholar
  35. 35.
    Schlatzer D, Maahs DM, Chance MR, Dazard JE, Li X, Hazlett F, Rewers M, Snell-Bergeon JK (2012) Novel urinary protein biomarkers predicting the development of microalbuminuria and renal function decline in type 1 diabetes. Diabetes Care. doi:10.2337/dc11-1491 PubMedGoogle Scholar
  36. 36.
    Holmquist P, Torffvit O (2008) Tubular function in diabetic children assessed by Tamm–Horsfall protein and glutathione S-transferase. Pediatr Nephrol 23(7):1079–1083. doi:10.1007/s00467-008-0770-9 PubMedCrossRefGoogle Scholar
  37. 37.
    Torffvit O, Jørgensen P, Kamper AL, Holstein-Rathlou NH, Leyssac P, Poulsen S, Strandgaard S (2000) Urinary excretion of Tamm–Horsfall protein and epidermal growth factor in chronic nephropathy. Nephron 79(2):167–172CrossRefGoogle Scholar
  38. 38.
    Qin X, Goldfine A, Krumrei N, Grubissich L, Acosta J, Chorev M, Hays AP, Halperin JA (2004) Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes 53(10):2653–2661PubMedCrossRefGoogle Scholar
  39. 39.
    Acosta J, Hettinga J, Flückiger R, Krumrei N, Goldfine A, Angarita L, Halperin J (2000) Molecular basis for a link between complement and the vascular complications of diabetes. Proc Nat Acad Sci 97(10):5450PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang J, Gerhardinger C, Lorenzi M (2002) Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes 51(12):3499–3504PubMedCrossRefGoogle Scholar
  41. 41.
    Accardo-Palumbo A, Triolo G, Colonna-Romano G, Potestio M, Carbone M, Ferrante A, Giardina E, Caimi G (2000) Glucose-induced loss of glycosyl-phosphatidylinositol-anchored membrane regulators of complement activation (CD59, CD55) by in vitro cultured human umbilical vein endothelial cells. Diabetologia 43(8):1039–1047. doi:10.1007/s001250051487 PubMedCrossRefGoogle Scholar
  42. 42.
    Ma XW, Chang ZW, Qin MZ, Sun Y, Huang HL, He Y (2009) Decreased expression of complement regulatory proteins, CD55 and CD59, on peripheral blood leucocytes in patients with type 2 diabetes and macrovascular diseases. Chin Med J 122(18):2123–2128PubMedGoogle Scholar
  43. 43.
    Taskinen MR, Kahri J, Koivisto V, Shepherd J, Packard CJ (1992) Metabolism of HDL apolipoprotein A-I and A-II in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 35(4):347–356PubMedCrossRefGoogle Scholar
  44. 44.
    Chen G, Paka L, Kako Y, Singhal P, Duan W, Pillarisetti S (2001) A protective role for kidney apolipoprotein E. J Biol Chem 276(52):49142PubMedCrossRefGoogle Scholar
  45. 45.
    Kim HJ, Cho EH, Yoo JH, Kim PK, Shin JS, Kim MR, Kim CW (2007) Proteome analysis of serum from type 2 diabetics with nephropathy. J Proteome Res 6(2):735–743PubMedCrossRefGoogle Scholar
  46. 46.
    Liu Y, Cao DJ, Sainz IM, Guo YL, Colman RW (2008) The inhibitory effect of HKa in endothelial cell tube formation is mediated by disrupting the uPA-uPAR complex and inhibiting its signaling and internalization. Am J Physiol Cell Physiol 295(1):C257–C267. doi:10.1152/ajpcell.00569.2007 PubMedCrossRefGoogle Scholar
  47. 47.
    Rocchetti MT, Centra M, Papale M, Bortone G, Palermo C, Centonze D, Ranieri E, Di Paolo S, Gesualdo L (2008) Urine protein profile of IgA nephropathy patients may predict the response to ACE-inhibitor therapy. Proteomics 8(1):206–216. doi:10.1002/pmic.200700492 PubMedCrossRefGoogle Scholar
  48. 48.
    Weinberg MS, Azar P, Trebbin WM, Solomon RJ (1985) The role of urinary kininogen in the regulation of kinin generation. Kidney Int 28(6):975–981PubMedCrossRefGoogle Scholar
  49. 49.
    Abdullah-Soheimi SS, Lim BK, Hashim OH, Shuib AS (2010) Patients with ovarian carcinoma excrete different altered levels of urine CD59, kininogen-1 and fragments of inter-alpha-trypsin inhibitor heavy chain H4 and albumin. Proteome Sci 8:58. doi:10.1186/1477-5956-8-58 PubMedCrossRefGoogle Scholar
  50. 50.
    Everaert K, Delanghe J, Vande Wiele C, Hoebeke P, Dierckx RA, Clarysse B, Lameire N, Oosterlinck W (1998) Urinary alpha 1-microglobulin detects uropathy. A prospective study in 483 urological patients. Clinical chemistry and laboratory medicine. CCLM/FESCC 36(5):309–315. doi:10.1515/CCLM.1998.052
  51. 51.
    Pfleiderer S, Zimmerhackl L, Kinne R, Manz F, Schuler G, Brandis M (1993) Renal proximal and distal tubular function is attenuated in diabetes mellitus type 1 as determined by the renal excretion of α 1-microglobulin and Tamm–Horsfall protein. J Mol Med 71(12):972–977Google Scholar
  52. 52.
    Wainai H, Katsukawa F, Takei I, Maruyama H, Kataoka K, Saruta T (1991) Influence of glycemic control and hypertension on urinary microprotein excretion in non-insulin-dependent diabetes mellitus. J Diabetic Complicat 5(2–3):160–161CrossRefGoogle Scholar
  53. 53.
    Hassan MI, Waheed A, Yadav S, Singh TP, Ahmad F (2008) Zinc alpha 2-glycoprotein: a multidisciplinary protein. Mol Cancer Res 6(6):892–906. doi:10.1158/1541-7786.MCR-07-2195 PubMedCrossRefGoogle Scholar
  54. 54.
    Bing C, Bao Y, Jenkins J, Sanders P, Manieri M, Cinti S, Tisdale MJ, Trayhurn P (2004) Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proc Nat Acad Sci USA 101(8):2500–2505PubMedCrossRefGoogle Scholar
  55. 55.
    Rolli V, Radosavljevic M, Astier V, Macquin C, Castan-Laurell I, Visentin V, Guigne C, Carpene C, Valet P, Gilfillan S, Bahram S (2007) Lipolysis is altered in MHC class I zinc-alpha(2)-glycoprotein deficient mice. FEBS Lett 581(3):394–400. doi:10.1016/j.febslet.2006.12.047 PubMedCrossRefGoogle Scholar
  56. 56.
    Agrawal V, Shah A, Rice C, Franklin BA, McCullough PA (2009) Impact of treating the metabolic syndrome on chronic kidney disease. Nat Rev Nephrol 5(9):520–528. doi:10.1038/nrneph.2009.114 PubMedCrossRefGoogle Scholar
  57. 57.
    Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, Arthur JM (2007) Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol 18(3):913–922. doi:10.1681/ASN.2006070767 PubMedCrossRefGoogle Scholar
  58. 58.
    Pesic I, Stefanovic V, Muller GA, Muller CA, Cukuranovic R, Jahn O, Bojanic V, Koziolek M, Dihazi H (2011) Identification and validation of six proteins as marker for endemic nephropathy. J Proteomics 74(10):1994–2007. doi:10.1016/j.jprot.2011.05.020 PubMedCrossRefGoogle Scholar
  59. 59.
    Riaz S, Alam SS, Srai SK, Skinner V, Riaz A, Akhtar MW (2010) Proteomic identification of human urinary biomarkers in diabetes mellitus type 2. Diabetes Technol Ther 12(12):979–988. doi:10.1089/dia.2010.0078 PubMedCrossRefGoogle Scholar
  60. 60.
    Lim SC, Liying DQ, Toy WC, Wong M, Yeoh LY, Tan C, Lau D, Subramaniam T, Sum CF (2011) Adipocytokine zinc alpha(2) glycoprotein (ZAG) as a novel urinary biomarker for normo-albuminuric diabetic nephropathy. Diabet Med. doi:10.1111/j.1464-5491.2011.03564.x Google Scholar
  61. 61.
    Jain S, Rajput A, Kumar Y, Uppuluri N, Arvind AS, Tatu U (2005) Proteomic analysis of urinary protein markers for accurate prediction of diabetic kidney disorder. J Assoc Phys India 53:513–520Google Scholar
  62. 62.
    Ishioka N, Takahashi N, Putnam FW (1986) Amino acid sequence of human plasma alpha 1B-glycoprotein: homology to the immunoglobulin supergene family. Proc Nat Acad Sci USA 83(8):2363–2367PubMedCrossRefGoogle Scholar
  63. 63.
    Araki T, Gejyo F, Takagaki K, Haupt H, Schwick HG, Burgi W, Marti T, Schaller J, Rickli E, Brossmer R et al (1988) Complete amino acid sequence of human plasma Zn-alpha 2-glycoprotein and its homology to histocompatibility antigens. Proc Natl Acad Sci USA 85(3):679–683PubMedCrossRefGoogle Scholar
  64. 64.
    Catanese JJ, Kress LF (1992) Isolation from opossum serum of a metalloproteinase inhibitor homologous to human alpha 1B-glycoprotein. Biochemistry 31(2):410–418PubMedCrossRefGoogle Scholar
  65. 65.
    Kreunin P, Zhao J, Rosser C, Urquidi V, Lubman DM, Goodison S (2007) Bladder cancer associated glycoprotein signatures revealed by urinary proteomic profiling. J Proteome Res 6(7):2631–2639. doi:10.1021/pr0700807 PubMedCrossRefGoogle Scholar
  66. 66.
    Goo YA, Tsai YS, Liu AY, Goodlett DR, Yang CC (2010) Urinary proteomics evaluation in interstitial cystitis/painful bladder syndrome: a pilot study. Int Braz J Urol 36(4):464–478; discussion 478–469, 479Google Scholar
  67. 67.
    Newcomer ME, Ong DE (2000) Plasma retinol binding protein: structure and function of the prototypic lipocalin. Biochimica et Biophysica Acta 1482(1–2):57–64Google Scholar
  68. 68.
    Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB (2005) Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436(7049):356–362. doi:10.1038/nature03711 PubMedCrossRefGoogle Scholar
  69. 69.
    Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB (2006) Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 354(24):2552–2563. doi:10.1056/NEJMoa054862 PubMedCrossRefGoogle Scholar
  70. 70.
    Kotnik P, Fischer-Posovszky P, Wabitsch M (2011) RBP4: a controversial adipokine. Eur J Endocrinol 165(5):703–711. doi:10.1530/EJE-11-0431 PubMedCrossRefGoogle Scholar
  71. 71.
    Christou GA, Tselepis AD, Kiortsis DN (2012) The metabolic role of retinol binding protein 4: an update. Horm Metab Res 44(1):6–14. doi:10.1055/s-0031-1295491 Google Scholar
  72. 72.
    Watts GF, Powell M, Rowe DJ, Shaw KM (1989) Low-molecular-weight proteinuria in insulin-dependent diabetes mellitus: a study of the urinary excretion of beta 2-microglobulin and retinol-binding protein in alkalinized patients with and without microalbuminuria. Diabetes Res 12(1):31–36PubMedGoogle Scholar
  73. 73.
    Pontuch P, Toserova E, Vozar J, Bulas J, Kratochvilova H (1995) 24-h Ambulatory blood pressure, daytime and nighttime urinary albumin and retinol-binding protein excretion in type I diabetic patients. J Diabetes Complicat 9(4):234–236PubMedCrossRefGoogle Scholar
  74. 74.
    Galanti LM, Jamart J, Dell’omo J, Donckier J (1996) Comparison of urinary excretion of albumin, alpha 1-microglobulin and retinol-binding protein in diabetic patients. Diabetes Metab 22(5):324–330PubMedGoogle Scholar
  75. 75.
    Dubrey SW, Beetham R, Miles J, Noble MI, Rowe R, Leslie RD (1997) Increased urinary albumin and retinol-binding protein in type I diabetes. A study of identical twins. Diabetes Care 20(1):84–89PubMedCrossRefGoogle Scholar
  76. 76.
    Shimizu H, Negishi M, Shimomura Y, Mori M (1992) Changes in urinary retinol binding protein excretion and other indices of renal tubular damage in patients with non-insulin dependent diabetes. Diabetes Res Clin Pract 18(3):207–210PubMedCrossRefGoogle Scholar
  77. 77.
    Chen CC, Wu JY, Chang CT, Tsai FJ, Wang TY, Liu YM, Tsui HC, Chen RH, Chiou SC (2009) Levels of retinol-binding protein 4 and uric acid in patients with type 2 diabetes mellitus. Metab Clin Exp 58(12):1812–1816. doi:10.1016/j.metabol.2009.06.013 Google Scholar
  78. 78.
    Akbay E, Muslu N, Nayir E, Ozhan O, Kiykim A (2010) Serum retinol binding protein 4 level is related with renal functions in type 2 diabetes. J Endocrinol Invest 33(10):725–729. doi:10.3275/7024 PubMedGoogle Scholar
  79. 79.
    Li ZZ, Lu XZ, Liu JB, Chen L (2010) Serum retinol-binding protein 4 levels in patients with diabetic retinopathy. J Int Med Res 38(1):95–99PubMedGoogle Scholar
  80. 80.
    Lisowska-Myjak B (2010) Serum and urinary biomarkers of acute kidney injury. Blood Purif 29(4):357–365. doi:10.1159/000309421 PubMedCrossRefGoogle Scholar
  81. 81.
    Varghese SA, Powell TB, Janech MG, Budisavljevic MN, Stanislaus RC, Almeida JS, Arthur JM (2010) Identification of diagnostic urinary biomarkers for acute kidney injury. J Investig Med 58(4):612–620. doi:10.231/JIM.0b013e3181d473e7 PubMedGoogle Scholar
  82. 82.
    Chu CH, Lam HC, Lee JK, Lu CC, Sun CC, Cheng HJ, Wang MC, Chuang MJ (2011) Elevated serum retinol-binding protein 4 concentrations are associated with chronic kidney disease but not with the higher carotid intima-media thickness in type 2 diabetic subjects. Endocr J 58(10):841–847PubMedCrossRefGoogle Scholar
  83. 83.
    Salem MA, el-Habashy SA, Saeid OM, el-Tawil MM, Tawfik PH (2002) Urinary excretion of n-acetyl-beta-D-glucosaminidase and retinol binding protein as alternative indicators of nephropathy in patients with type 1 diabetes mellitus. Pediatr Diabetes 3(1):37–41. doi:10.1034/j.1399-5448.2002.30107.x PubMedCrossRefGoogle Scholar
  84. 84.
    Astorri E, Guglielmi C, Bombardieri M, Alessandri C, Buzzetti R, Maggi D, Valesini G, Pitzalis C, Pozzilli P (2010) Circulating Reg1alpha proteins and autoantibodies to Reg1alpha proteins as biomarkers of beta-cell regeneration and damage in type 1 diabetes. Horm Metab Res 42(13):955–960. doi:10.1055/s-0030-1267206 Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • A. Soggiu
    • 1
  • C. Piras
    • 2
  • L. Bonizzi
    • 1
  • H. A. Hussein
    • 1
  • S. Pisanu
    • 3
  • P. Roncada
    • 4
  1. 1.Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Facoltà di Medicina VeterinariaUniversità Degli Studi di MilanoMilanItaly
  2. 2.Dipartimento di Scienze Zootecniche, Facoltà di AgrariaUniversità Degli Studi di SassariSassariItaly
  3. 3.Porto Conte Ricerche Srl, TramariglioAlgheroItaly
  4. 4.Istituto Sperimentale Italiano “L. Spallanzani”MilanItaly

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