Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes

Summary

The general aim of this study is to investigate the influence of systemic administration of Desferal (Deferoxamine \[DFO\]) on the response to hypoxic challenge in patients with diabetes mellitus (DM). The investigation will elucidate if DFO can restore: * the impaired angiogenetic response to hypoxia in patients with type 1 DM. * the disturbed respiratory and cardiovascular regulation in response to hypoxia in patients with DM type 1

Timeline

Start

2017-01-01

Primary completion

2023-12-12

Completion

2024-12-12

Publications

• Background Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc Ophthalmol. 2012 Feb;124(1):15-26. doi: 10.1007/s10633-011-9305-y.
• Background Schaper NC, Huijberts M, Pickwell K. Neurovascular control and neurogenic inflammation in diabetes. Diabetes Metab Res Rev. 2008 May-Jun;24 Suppl 1:S40-4. doi: 10.1002/dmrr.862.
• Background Flyvbjerg A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol. 2010 Feb;6(2):94-101. doi: 10.1038/nrendo.2009.266.
• Background Ruiter MS, van Golde JM, Schaper NC, Stehouwer CD, Huijberts MS. Diabetes impairs arteriogenesis in the peripheral circulation: review of molecular mechanisms. Clin Sci (Lond). 2010 Jun 8;119(6):225-38. doi: 10.1042/CS20100082.
• Background Friederich M, Fasching A, Hansell P, Nordquist L, Palm F. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):935-40. doi: 10.1016/j.bbabio.2008.03.030. Epub 2008 Apr 7.
• Background Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001 Apr 20;292(5516):464-8. doi: 10.1126/science.1059817. Epub 2001 Apr 5.
• Background Elson DA, Ryan HE, Snow JW, Johnson R, Arbeit JM. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 2000 Nov 1;60(21):6189-95.
• Background Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004 Aug;10(8):858-64. doi: 10.1038/nm1075. Epub 2004 Jul 4.
• Background Devlin C, Greco S, Martelli F, Ivan M. miR-210: More than a silent player in hypoxia. IUBMB Life. 2011 Feb;63(2):94-100. doi: 10.1002/iub.427. Epub 2011 Feb 24.
• Background Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54. doi: 10.1016/s0092-8674(01)00507-4.
• Background Mehrabani M, Najafi M, Kamarul T, Mansouri K, Iranpour M, Nematollahi MH, Ghazi-Khansari M, Sharifi AM. Deferoxamine preconditioning to restore impaired HIF-1alpha-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats. Cell Prolif. 2015 Oct;48(5):532-49. doi: 10.1111/cpr.12209.
• Background Weng R, Li Q, Li H, Yang M, Sheng L. Mimic hypoxia improves angiogenesis in ischaemic random flaps. J Plast Reconstr Aesthet Surg. 2010 Dec;63(12):2152-9. doi: 10.1016/j.bjps.2010.02.001. Epub 2010 Mar 31.
• Background Botusan IR, Sunkari VG, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Yla-Herttuala S, Poellinger L, Brismar K, Catrina SB. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19426-31. doi: 10.1073/pnas.0805230105. Epub 2008 Dec 4.
• Background Catrina SB. Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia. J Mol Med (Berl). 2014 Oct;92(10):1025-34. doi: 10.1007/s00109-014-1166-x. Epub 2014 Jun 12.
• Background Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Uttam Singh T, Rahal A, Kumar Tandan S, Kumar D. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015 Oct 5;764:9-21. doi: 10.1016/j.ejphar.2015.06.029. Epub 2015 Jun 19.
• Background Wang C, Cai Y, Zhang Y, Xiong Z, Li G, Cui L. Local injection of deferoxamine improves neovascularization in ischemic diabetic random flap by increasing HIF-1alpha and VEGF expression. PLoS One. 2014 Jun 25;9(6):e100818. doi: 10.1371/journal.pone.0100818. eCollection 2014.
• Background Hou Z, Nie C, Si Z, Ma Y. Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1alpha. Diabetes Res Clin Pract. 2013 Jul;101(1):62-71. doi: 10.1016/j.diabres.2013.04.012. Epub 2013 May 28.
• Background Smith TG, Balanos GM, Croft QP, Talbot NP, Dorrington KL, Ratcliffe PJ, Robbins PA. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol. 2008 Dec 15;586(24):5999-6005. doi: 10.1113/jphysiol.2008.160960. Epub 2008 Oct 27.
• Background Ren X, Dorrington KL, Maxwell PH, Robbins PA. Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans. J Appl Physiol (1985). 2000 Aug;89(2):680-6. doi: 10.1152/jappl.2000.89.2.680.
• Background Balanos GM, Dorrington KL, Robbins PA. Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1. J Appl Physiol (1985). 2002 Jun;92(6):2501-7. doi: 10.1152/japplphysiol.00965.2001.
• Background Duennwald T, Bernardi L, Gordin D, Sandelin A, Syreeni A, Fogarty C, Kyto JP, Gatterer H, Lehto M, Horkko S, Forsblom C, Burtscher M, Groop PH; FinnDiane Study Group. Effects of a single bout of interval hypoxia on cardiorespiratory control in patients with type 1 diabetes. Diabetes. 2013 Dec;62(12):4220-7. doi: 10.2337/db13-0167. Epub 2013 Jun 3.
• Background Duennwald T, Gatterer H, Groop PH, Burtscher M, Bernardi L. Effects of a single bout of interval hypoxia on cardiorespiratory control and blood glucose in patients with type 2 diabetes. Diabetes Care. 2013 Aug;36(8):2183-9. doi: 10.2337/dc12-2113. Epub 2013 Mar 27.
• Background Balczewska D, Ptaszynski P, Cygankiewicz I. [Baroreflex sensitivity: measurement and clinical aspects]. Przegl Lek. 2015;72(11):682-9. Polish.
• Background Svacinova J, Moudr J, Honzikova N. [Baroreflex sensitivity: diagnostic importance, methods of determination and a model of baroreflex blood-pressure regulation]. Cesk Fysiol. 2013;62(1):10-8. Czech.
• Background Collier DJ, Bernardi L, Angell-James JE, Caulfield MJ, Sleight P; Anglo-Scandinavian Cardiac Outcomes Trial. Baroreflex sensitivity and heart rate variability as predictors of cardiovascular outcome in hypertensive patients with multiple risk factors for coronary disease. J Hum Hypertens. 2001 Aug;15 Suppl 1:S57-60. doi: 10.1038/sj.jhh.1001077. No abstract available.
• Background La Rovere MT, Maestri R, Robbi E, Caporotondi A, Guazzotti G, Febo O, Pinna GD. Comparison of the prognostic values of invasive and noninvasive assessments of baroreflex sensitivity in heart failure. J Hypertens. 2011 Aug;29(8):1546-52. doi: 10.1097/HJH.0b013e3283487827.

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