Background/Aims: Inhibiting nonenzymatic glycation with GLY-230 lowers glycated albumin without affecting hyperglycemia and ameliorates renal dysfunction in the db/db mouse, but the effects of this compound in man have not been assessed. We report results from the first clinical trial in patients with diabetes of this new glycation inhibitor. Methods: 21 diabetic men were randomly assigned to receive a total dose of 250, 500 or 750 mg of GLY-230 or placebo (1:1:1:1.2 ratio) daily for 14 days to evaluate safety and the effect of drug on plasma concentrations of glycated albumin and on urinary albumin. Results: GLY-230 dose-responsively decreased glycated albumin in all participants, in whom HbA1c did not change. Among participants exhibiting microalbuminuria at baseline, mean albumin excretion significantly decreased in patients receiving GLY-230 (µg albumin/mg creatinine = 61.4 ± 15.8 and 29.8 ± 10.4 at baseline and completion, respectively; p = 0.001), but not placebo. There were no serious adverse events or laboratory abnormalities, and all safety parameters remained within normal limits. Conclusions: This first-in-diabetic man study indicates that GLY-230 lowers glycated albumin and that this decrease is associated with a reduction in urine albumin excretion in patients with preexisting microalbuminuria. These data encourage further evaluation of GLY-230 in diabetic renal dysfunction.

King H, Aubert R, Herman W: Global burden of diabetes, 1995–2025; prevalence, numerical estimates, and projection. Diabetes Care 1998;21:1414–1431.
Ritz E, Rychlik I, Locatelli F, Halimi S: End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis 1999;34:795–808.
Lane PH, Steffes MW, Fioretto P, Mauer SM: Renal interstitial expansion in insulin-dependent diabetes mellitus in the kidney. Kidney Int 1993;43:661–667.
Mauer M, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz FC: Structural-functional relationships in diabetic nephropathy. J Clin Invest 1984;73:1143–1155.
Osterby R, Parving HH, Hommel E, Jorgensen JE, Lokkegard H: Glomerular structure and function in diabetic nephropathy: early to advanced stages. Diabetes 1990;39:1057–1063.
White KE, Bilous RW: Type 2 diabetic patients with nephropathy show structural-functional relationships that are similar to type 1 disease. J Am Soc Nephrol 2000;11:1667–1643.
Ellis EN, Steffes MW, Goetz FC, Sutherland DER, Mauer SM: Glomerular filtration surface area in type 1 diabetes mellitus. Kidney Int 1986;29:889–894.
Fioretto P, Steffes MW, Mauer M: Glomerular structure in non-proteinuric IDDM patients with various levels of albuminuria. Diabetes 1994;43:1358–1364.
Sawicki PT, Berger M: Measuring progression of diabetic nephropathy. Eur J Clin Invest 1994;24:651–655.
DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus. N Engl Med 1993;329:977–986.
Hostetter TH: Prevention of end-stage renal disease due to type 2 diabetes. N Engl J Med 2001;354:910–911.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: A clinical trial of angiotensin-converting enzyme inhibitors in the nephropathy of insulin-dependent diabetes. N Engl J Med 1993;329:1456–1463.
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860.
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870–878.
Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J: Angiotensin receptor blockade versus converting enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952–1961.
Cohen MP, Ziyadeh FN, Hong SW, Shearman CW, Hud E, Lautenslager GT, Iglesias-de la Cruz C, Chen C: Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1. Kidney Int 2002;61:2025–2032.
Chen S, Cohen MP, Lautenslager GT, Shearman CW, Ziyadeh FN: Glycated albumin stimulates TGF-β1 production and protein kinase C activity in glomerular endothelial cells. Kidney Int 2001;59:673–681.
Cohen M, Ziyadeh FN, Lautenslager GT, Cohen JA, Shearman CW: Glycated albumin stimulation of PKC-β activity is linked to increased collagen IV production in mesangial cells. Am J Physiol Renal Physiol 1999;276:F684–F690.
Cohen M, Shea E, Shearman CW: ERK mediates effects of glycated albumin in mesangial cells. Biochem Biophys Res Commun 2001;283:641–643.
Doublier S, Salvidio G, Lupia E, Ruotsalainen V, Verzola D, Deferrari G, Camussi G: Nephrin expression is reduced in human diabetic nephropathy. Evidence for a distinct role for glycated albumin and angiotensin II. Diabetes 2003;52:1023–1030.
Cohen MP, Ziyadeh FN: Amadori glucose adducts modulate mesangial cell growth and collagen gene expression Kidney Int 1994;45:475–484.
Ziyadeh FN, Han D, Cohen JA, Guo J, Cohen, MP: Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-β system. Kidney Int 1998;53:631–638.
Schalkwijk CG, Chaturvedi N, Twaalfhoven H, van Hinsbergh VW, Stehouwer CD: Amadori albumin correlates with macrovascular complications and precedes diabetic nephropathy in type 1 diabetic patients. Eur J Clin Invest 2002;32:500–506.
Schalkwijk CG, Ligtvoet N, Twaalfhoven H, Jager A, Blaauwgeers HG, Schlingeman RO, Tamow L, Parving HH, Stehouwer CD, van Hinsbergh VW: Amadori albumin in type 1 diabetic patients. Diabetes 1999;48:2446–2453.
Sakai H, Jinde K, Suzuki D, Yagame M, Nomoto Y: Localization of glycated proteins in the glomeruli of patients with diabetic nephropathy. Nephrol Dial Transplant 1996;11(suppl 5):66–71.
Cohen MP, Chen S, Ziyadeh FN, Shea E, Hud EA, Lautenslager GT, Shearman CW: Evidence linking glycated albumin to altered glomerular nephrin and VEGF expression and proteinuria in diabetes. Kidney Int 2005;68:1554–1561.
Cohen MP, Lautenslager GT, Hud E, Shea E, Wang A, Chen S, Shearman CW: Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency. Am J Physiol Renal Physiol 2007;292:F789–F795.
Warram JH, Gearin G, Laffel L, Krolewski AS: Effect of duration of type 1 diabetes on the prevalence of stages in diabetic nephropathy defined by urinary albumin/creatinine ratio. J Am Soc Nephrol 1996;7:930–937.
Baynes JW, Thorpe S, Murtiashaw MH: Nonenzymatic glycosylation of lysine residues in albumin. Meth Enzymol 1985;106:88–98.
Persson F, Rossing P, Schjoedt KJ, Juhl T, Tarnow L, Stehouwer CDA: Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int 2008;73:1419–1425.
Pagtalunan ME, Miller PL, Jumping-Eagle SD, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW: Podocyte loss and progressive glomerular injury in type 2 diabetes. J Clin Invest 1997;99:342–348.
Benigni A, Gagliardini E, Tomasoni S, Abbate M, Ruggenenti P, Kalluri R, Remuzzi G: Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy. Kidney Int 2004;65:2193–2200.
Langham RG, Kelly DJ, Cox AJ, Thomson NM, Holthofer H, Zaoui P, Pinel N, Cordonnier DJ, Gilbert RE: Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition. Diabetologia 2002;45:1572–1576.
Patari A, Forsblom C, Havana M, Taipale H, Groop PH, Holthofer H: Nephrinuria in diabetic nephropathy of type 1 diabetes. Diabetes 2003;52:2969–2974.
Steffes MW, Schmidt D, McCrery R, Basgen JM: Glomerular cell number in normal subjects and type 1 diabetic patients. Kidney Int 2001;59:2104–2113.
Toyoda M, Suzuki D, Umezono T, Uehara G, Maruyama M, Honma M, Sakai T, Sakai H: Expression of human nephrin mRNA in diabetic nephropathy. Nephrol Dial Transplant 2004;19:380–385.
Parving HH, Chaturvedi N, Viberti GC, Mogensen CE: Does microalbuminuria predict diabetic nephropathy? Diabetes Care 2002;25:406–407.
Tsalamandris C, Allen TJ, Gilbert RE, Sinha A, Panagiotopoulos S, Cooper ME, Jerums G: Progressive decline in renal function in diabetic patients with and without albuminuria. Diabetes 1994;43:649–655.
Perkins BA, Ficociello L, Silva, KH, Finkelstein DM, Warram JH, Krolewski AS: Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285–2293.
Ahmad J, Siddiqui MA, Ahmad H: Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care 1997;20:1576–1581.
Chaturvedi N, and The Euclid Study Group: Randomized placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997;349:1787–1792.
Laffel LM, McGill JB, Gans DJ: The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria: the North American Microalbuminuria Study Group. Am J Med 1995;99:497–504.
Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK: Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358:2433–2446.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.