Роль и регуляция индуцируемого гипоксией фактора транскрипции-1 и сукцинатного рецептора-1 при диабете типа 2: связь с сосудистыми осложнениями

Диабет 2 типа является основным метаболическим заболеванием, которое со временем приводит к серьезным осложнениям. Жесткий контроль уровней глюкозы в крови считается важной мерой, позволяющей предотвратить осложнения диабета. Однако рандомизированные клинические испытания, проведенные за последние десятилетия, не выявили существенной пользы гликемического контроля для предотвращения микро- и макрососудистых осложнений диабета, за исключением снижения риска нефатального инфаркта миокарда на 15%. В то же время появляются данные, что существует корреляция между возникновением сосудистых осложнений сахарного диабета и нарушениями в регуляции ангиогенеза управляемой индуцируемым гипоксией фактором 1 (HIF-1) и сукцинатным рецептором 1 (SUCNR1). Диабет 2 типа влияет на активность HIF-1 на нескольких уровнях, включая транскрипцию субъединицы HIF-1α, трансляцию мРНК в белок HIF-1α, деградацию белка HIF-1α и связывание белка HIF-1α с коактиваторами, что в итоге приводит к нарушению адаптивного ангиогенного ответа на гипоксию. Гипергликемия и инсулиновая резистентность участвуют в этих нарушениях. Кроме того, диабет влияет на передачу сигналов сукцинатного рецептора 1 тканеспецифическим образом. Перекрестное взаимодействие между HIF-1 и SUCNR1 объясняет, по крайней мере частично, парадоксальные тканеспецифические изменения ангиогенеза при диабетических микрососудистых осложнениях, а именно чрезмерное образование кровеносных сосудов в сетчатке и дефицит мелких кровеносных сосудов в периферических тканях, таких как кожа. В заключение, терапевтическое воздействие на сигнальные системы HIF-1 и SUCNR1 может стать новым многообещающим подходом к профилактике и лечению сосудистых осложнений диабета 2 типа.

сахарный диабет 2 типа, гипергликемия, инсулин, индуцируемый гипоксией фактор 1 (HIF-1), сукцинатный рецептор 1 (SUCNR1), микрососудистые осложнения, макрососудистые осложнения

1. World Health Organization. Global report on diabetes. Geneva: 2016. https://www.who.int/diabetes/globalreport/en/ (accessed Jan 15, 2019).

2. Diabetes Control and Complications Trial Research Group, Nathan D.M., Genuth S., Lachin J., Cleary P., Crofford O., Davis M., Rand L., Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 1993 Sep 30;329(14):977–86.

3. [No authors listed] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837–53.

4. Ismail-Beigi F., Craven T., Banerji M.A., Basile J., Calles J., Cohen R.M., Cuddihy R., Cushman W.C., Genuth S., Grimm R.H.Jr., Hamilton B.P., Hoogwerf B., Karl D., Katz L., Krikorian A., O’Connor P., Pop-Busui R., Schubart U., Simmons D., Taylor H., Thomas A., Weiss D., Hramiak I.; ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outc omes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010 Aug 7;376(9739):419–30.

5. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein H.C., Miller M.E., Byington R.P., Goff D.C. Jr., Bigger J.T., Buse J.B., Cushman W.C., Genuth S., Ismail-Beigi F., Grimm R.H. Jr., Probstfield J.L., Simons-Morton D.G., Friedewald W.T. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 2008 Jun 12;358(24):2545–59.

6. Rodríguez-Gutiérrez R., Montori V.M. Glycemic Control for Patients With Type 2 Diabetes Mellitus: Our Evolving Faith in the Face of Evidence. Circ Cardiovasc Qual Outcomes. 2016 Sep;9(5):504–12.

7. Semenza G.L., Nejfelt M.K., Chi S.M., Antonarakis S.E. Hypoxia-inducible nuclear factors bind to an enhancer element located 3ʹ to the human erythropoietin gene. Proc Natl Acad Sci USA. 1991;88:5680–4

8. Samanta D., Semenza G.L. Maintenance of redox homeostasis by hypoxia-inducible factors. Redox Biol. 2017 Oct;13:331–5.

9. Flamme I., Fröhlich T., von Reutern M., Kappel A., Damert A., Risau W. HRF, a putative basic helix-loophelix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech Dev. 1997 Apr;63(1):51–60.

10. Wiesener M.S., Turley H., Allen W.E., Willam C., Eckardt K.U., Talks K.L., Wood S.M., Gatter K.C., Harris A.L., Pugh C.W., Ratcliffe P.J., Maxwell P.H. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood. 1998 Oct 1;92(7):2260–8.

11. Ravenna L., Salvatori L., Russo M.A. HIF3α: the little we know. FEBS J. 2016 Mar;283(6):993–1003.

12. Semenza G.L. Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol. 2014;76:39–56.

13. Hellwig-Bürgel T., Stiehl D.P., Wagner A.E., Metzen E., Jelkmann W. Review: hypoxia-inducible factor-1 (HIF1): a novel transcription factor in immune reactions. J Interferon Cytokine Res. 2005 Jun;25(6):297–310.

14. Cormier-Regard S., Nguyen S.V., Claycomb W.C. Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J. Biol. Chem. 1998 Jul 10;273(28):17787–92.

15. Manalo D.J., Rowan A., Lavoie T., Natarajan L., KellyB.D., Ye S.Q., Garcia J.G., Semenza G.L. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood. 2005 Jan 15;105(2):659–69.

16. Bosch-Marce M., Okuyama H., Wesley J.B., Sarkar K., Kimura H., Liu Y.V., Zhang H., Strazza M., Rey S., Savino L., Zhou Y.F., McDonald K.R., Na Y., Vandiver S., Rabi A., Shaked Y., Kerbel R., Lavallee T., Semenza G.L. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res. 2007 Dec 7;101(12):1310–8.

17. Kelly B.D., Hackett S.F., Hirota K., Oshima Y., Cai Z., Berg-Dixon S., Rowan A., Yan Z., Campochiaro P.A., Semenza G.L. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res. 2003 Nov 28;93(11):1074–81.

18. Simon M.P., Tournaire R., Pouyssegur J. The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1. J Cell Physiol. 2008 Dec;217(3):809–18.

19. Eyries M., Siegfried G., Ciumas M., Montagne K., Agrapart M., Lebrin F., Soubrier F. Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circ Res. 2008 Aug 15;103(4):432–40.

20. Hu J., Discher D.J., Bishopric N.H., Webster K.A. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun. 1998 Apr 28;245(3):894–9.

21. Camenisch G., Stroka D.M., Gassmann M., Wenger R.H. Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression. Pflugers Arch. 2001 Nov;443(2):240–9.

22. Forsythe J.A., Jiang B.H., Iyer N.V., Agani F., Leung S.W., Koos R.D., Semenza G.L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996 Sep;16(9):4604–13.

23. Gerber H.P., Condorelli F., Park J., Ferrara N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J. Biol. Chem. 1997 Sep 19;272(38):23659–67.

24. Okuyama H., Krishnamachary B., Zhou Y.F., Nagasawa H., Bosch-Marce M., Semenza G.L. Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1. J. Biol. Chem. 2006 Jun 2;281(22):15554–63.

25. Zelzer E., Levy Y., Kahana C., Shilo B.Z., Rubinstein M., Cohen B. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J. 1998 Sep 1;17(17):5085–94.

26. Treins C., Giorgetti-Peraldi S., Murdaca J., Semenza G.L., Van Obberghen E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J. Biol. Chem. 2002 Aug 2;277(31):27975– 81.

27. Stiehl D.P., Jelkmann W., Wenger R.H., Hellwig-Bürgel T. Normoxic induction of the hypoxia-inducible factor 1alpha by insulin and interleukin-1beta involves the phosphatidylinositol 3-kinase pathway. FEBS Lett. 2002 Feb 13;512(1–3):157–62.

28. Feldser D., Agani F., Iyer N.V., Pak B., Ferreira G., Semenza G.L. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res. 1999 Aug 15;59(16):3915–8.

29. Jiang B.H., Jiang G., Zheng J.Z., Lu Z., Hunter T., Vogt P.K. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 2001 Jul;12(7):363–9.

30. Masoud G.N., Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015 Sep;5(5):378–89.

31. Salceda S., Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J. Biol. Chem. 1997 Sep 5;272(36):22642–7.

32. Hirsila M., Koivunen P., Gunzler V., Kivirikko K.I., Myllyharju J. 2003. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 278:30772–80.

33. Poellinger L., Johnson R.S. HIF-1 and hypoxic response: the plot thickens. Curr Opin Genet Dev. 2004 Feb;14(1):81–5.

34. Mahon P.C., Hirota K., Semenza G.L. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev (2001) 15:2675–86.

35. Lando D., Peet D.J., Whelan D.A., Gorman J.J., Whitelaw M.L. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science (2002) 295:858–61.

36. Appelhoff R.J., Tian Y.M., Raval R.R., Turley H., Harris A.L., Pugh C.W., Ratcliffe P.J., Gleadle J.M. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J. Biol. Chem. 2004 Sep 10;279(37):38458–65.

37. Wu S., Nishiyama N., Kano M.R., Morishita Y., Miyazono K., Itaka K., Chung U.I., Kataoka K. Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene. Mol Ther. 2008 Jul;16(7):1227–34.

38. Takeda K., Cowan A., Fong G.H. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation. 2007 Aug 14;116(7):774–81.

39. Koivunen P., Hirsilä M., Remes A.M., Hassinen I.E., Kivirikko K.I., Myllyharju J. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 2007 Feb 16;282(7):4524–32.

40. Komaromy-Hiller G., Sundquist P.D., Jacobsen L.J., Nuttall K.L. Serum succinate by capillary zone electrophoresis: marker candidate for hypoxia. Ann Clin Lab Sci. 1997 Mar–Apr;27(2):163–8.

41. Hochachka P.W., Dressendorfer R.H. Succinate accumulation in man during exercise. Eur. J. Appl. Physiol. Occup. Physiol. 1976 Sep 23;35(4):235–42.

42. Chouchani E.T., Pell V.R., Gaude E., Aksentijević D., Sundier S.Y., Robb E.L., Logan A., Nadtochiy S.M., Ord E.NJ., Smith A.C., Eyassu F., Shirley R., Hu C.H., Dare A.J., James A.M., Rogatti S., Hartley R.C, Eaton S., Costa A.S.H., Brookes P.S., Davidson S.M., Duchen M.R, Saeb-Parsy K., Shattock M.J., Robinson A.J., Work L.M, Frezza C., Krieg T., Murphy M.P. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014 Nov 20;515(7527):431–5.

43. Gilissen J., Jouret F., Pirotte B., Hanson J.. Insight into SUCNR1 (GPR91) structure and function. Pharmacol Ther. 2016 Mar;159:56–65.

44. Wittenberger T., Schaller H.C., Hellebrand S. An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors. J Mol Biol. 2001 Mar 30;307(3):799–813.

45. He W., Miao F.J., Lin D.C., Schwandner R.T., Wang Z., Gao J., Chen J.L., Tian H., Ling L. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004 May 13;429(6988):188–93.

46. Robben J.H., Fenton R.A., Vargas S.L., Schweer H., Peti-Peterdi J., Deen P.M., Milligan G. Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells. Kidney Int. 2009 Dec;76(12):1258–67.

47. Sundström L., Greasley P.J., Engberg S., Wallander M., Ryberg E. Succinate receptor GPR91, a Gα(i) coupled receptor that increases intracellular calcium concentrations through PLCβ. FEBS Lett. 2013 Aug 2;587(15):2399–404.

48. Trauelsen M., Rexen Ulven E., Hjorth S.A., Brvar M., Monaco C., Frimurer T.M., Schwartz T.W. Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91. Mol Metab. 2017 Dec;6(12):1585–96.

49. Hamel D., Sanchez M., Duhamel F., Roy O., Honoré J.C., Noueihed B., Zhou T., Nadeau-Vallée M., Hou X., Lavoie J.C., Mitchell G., Mamer O.A., Chemtob S. G-protein-coupled receptor 91 and succinate are key contributors in neonatal postcerebral hypoxia-ischemia recovery. Arterioscler Thromb Vasc Biol. 2014 Feb;34(2):285–93.

50. Regard J.B., Sato I.T., Coughlin S.R. Anatomical profiling of G protein-coupled receptor expression. Cell. 2008 Oct 31;135(3):561–71.

51. Diehl J., Gries B., Pfeil U., Goldenberg A., Mermer P., Kummer W., Paddenberg R. Expression and localization of GPR91 and GPR99 in murine organs. Cell Tissue Res. 2016 May;364(2):245–62.

52. Toma I., Kang J.J., Sipos A., Vargas S., Bansal E., Hanner F., Meer E., Peti-Peterdi J. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest. 2008 Jul;118(7):2526–34.

53. Correa P.R., Kruglov E.A., Thompson M., Leite M.F., Dranoff J.A., Nathanson M.H. Succinate is a paracrine signal for liver damage. J Hepatol. 2007 Aug;47(2):262–9.

54. Aguiar C.J., Andrade V.L., Gomes E.R., Alves M.N., Ladeira M.S., Pinheiro A.C., Gomes D.A., Almeida A.P., Goes A.M., Resende R.R., Guatimosim S., Leite M.F. Succinate modulates Ca(2+) transient and cardiomyocyte viability through PKA-dependent pathway. Cell Calcium. 2010 Jan;47(1):37–46.

55. Aguiar C.J., Rocha-Franco J.A., Sousa P.A., Santos A.K., Ladeira M., Rocha-Resende C., Ladeira L.O., Resende R.R., Botoni F.A., Barrouin Melo M., LimaC.X., Carballido J.M., Cunha T.M., Menezes G.B., Guatimosim S., Leite M.F. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Commun Signal. 2014 Dec 24;12:78.

56. Yang L., Yu D., Fan H.H., Feng Y., Hu L., Zhang W.Y., Zhou K., Mo X.M. Triggering the succinate receptor GPR91 enhances pressure overload-induced right ventricular hypertrophy. Int J Clin Exp Pathol. 2014 Aug 15;7(9):5415–28.

57. Sapieha P., Sirinyan M., Hamel D., Zaniolo K., JoyalJ.S., Cho J.H., Honoré J.C., Kermorvant-Duchemin E., Varma D.R., Tremblay S., Leduc M., Rihakova L., Hardy P., Klein W.H., Mu X., Mamer O., Lachapelle P., Di Polo A., Beauséjour C., Andelfinger G., Mitchell G., Sennlaub F., Chemtob S. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med. 2008 Oct;14(10):1067–76.

58. Peruzzotti-Jametti L., Bernstock J.D., Vicario N., Costa A.S.H., Kwok C.K., Leonardi T., Booty L.M., Bicci I., Balzarotti B., Volpe G., Mallucci G., Manferrari G., Donegà M., Iraci N., Braga A., Hallenbeck J.M., Murphy M.P., Edenhofer F., Frezza C., Pluchino S. Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation. Cell Stem Cell. 2018 Mar 1;22(3):355–368.e13.

59. Hakak Y., Lehmann-Bruinsma K., Phillips S., Le T., Liaw C., Connolly D.T., Behan D.P. The role of the GPR91 ligand succinate in hematopoiesis. J Leukoc Biol. 2009 May;85(5):837–43.

60. Högberg C., Gidlöf O., Tan C., Svensson S., Nilsson-Öhman J., Erlinge D., Olde B. Succinate independently stimulates full platelet activation via cAMP and phosphoinositide 3-kinase-β signaling. J Thromb Haemost. 2011 Feb;9(2):361–72.

61. Rubic T., Lametschwandtner G., Jost S., Hinteregger S., Kund J., Carballido-Perrig N., Schwärzler C., Junt T., Voshol H., Meingassner J.G., Mao X., Werner G., Rot A., Carballido J.M. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol. 2008 Nov;9(11):1261–9.

62. Macaulay I.C., Tijssen M.R., Thijssen-Timmer D.C., Gusnanto A., Steward M., Burns P., Langford C.F., Ellis P.D., Dudbridge F., Zwaginga J.J, Watkins N.A., van der Schoot C.E., Ouwehand W.H. Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Blood. 2007 Apr 15;109(8):3260–9.

63. Vempati P., Popel A.S., Mac Gabhann F. Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev. 2014 Feb;25(1):1–19.

64. Chou E., Suzuma I., Way K.J., Opland D., Clermont A.C., Naruse K., Suzuma K., Bowling N.L., Vlahos C.J., Aiello L.P., King G.L. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation. 2002 Jan 22;105(3):373–9.

65. Pappachan J.M., Varughese G.I., Sriraman R., Arunagirinathan G. Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management. World J Diabetes. 2013 Oct 15;4(5):177–89.

66. Abaci A., Oğuzhan A., Kahraman S., Eryol N.K., Unal S., Arinç H., Ergin A. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation. 1999 May 4;99(17):2239–42.

67. Rzeczuch K., Jagielski D., Kołodziej A., KaczmarekA., Mielnik M., Banasiak W., Ponikowski P. Coronary collateral circulation is less developed when ischaemic heart disease coexists with diabetes. Kardiol Pol. 2003 Feb;58(2):85–92.

68. Islam M.M., Ali A., Khan N.A., Rahman A., Majumder A.S., Chowdhury W.A., Faruque G.M., Faruque M., Jalaluddin M. Comparative study of coronary collaterals in diabetic and nondiabetic patients by angiography. Mymensingh Med J. 2006 Jul;15(2):170–5.

69. Marfella R., Esposito K., Nappo F., Siniscalchi M., Sasso F.C., Portoghese M., Di Marino M.P., Baldi A., Cuzzocrea S., Di Filippo C., Barboso G., Baldi F., Rossi F., D’Amico M., Giugliano D. Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. Diabetes. 2004 Sep;53(9):2383–91.

70. Huang Y, Hickey RP, Yeh JL, Liu D, Dadak A, Young LH, Johnson RS, Giordano FJ. Cardiac myo cyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. FASEB J. 2004 Jul;18(10):1138–40.

71. Wikenheiser J., Wolfram J.A., Gargesha M., Yang K., Karunamuni G., Wilson D.L., Semenza G.L., Agani F., Fisher S.A., Ward N., Watanabe M. Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn. 2009 Oct;238(10):2688–700.

72. Dodd M.S., Sousa Fialho M.D.L., Montes Aparicio C.N., Kerr M., Timm K.N., Griffin J.L., Luiken J.J.F.P., Glatz J.F.C., Tyler D.J., Heather L.C. Fatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes. JACC Basic Transl Sci. 2018 Aug 28;3(4):485–98.

73. Ramalho A.R., Toscano A., Pereira P., Girão H., Gonçalves L., Marques C. Hyperglycemia-induced degradation of HIF-1α contributes to impaired response of cardiomyocytes to hypoxia. Rev Port Cardiol. 2017 May;36(5):367–73.

74. Orchard T.J., Secrest A.M., Miller R.G., Costacou T. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia. 2010 Nov;53(11):2312–9.

75. Afkarian M., Sachs M.C., Kestenbaum B., Hirsch I.B., Tuttle K.R., Himmelfarb J., de Boer I.H. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013 Feb;24(2):302–8.

76. Takiyama Y., Haneda M. Hypoxia in diabetic kidneys. Biomed Res Int. 2014;2014:837421.

77. Schrijvers B.F., Flyvbjerg A., De Vriese A.S. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int. 2004 Jun;65(6):2003–17.

78. Makino H., Miyamoto Y., Sawai K., Mori K., Mukoyama M., Nakao K., Yoshimasa Y., Suga S. Altered gene expression related to glomerulogenesis and podocyte structure in early diabetic nephropathy of db/db mice and its restoration by pioglitazone. Diabetes. 2006 Oct;55(10):2747–56.

79. Isoe T., Makino Y., Mizumoto K., Sakagami H., Fujita Y., Honjo J., Takiyama Y., Itoh H., Haneda M. High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein. Kidney Int. 2010 Jul;78(1):48–59.

80. Persson P., Palm F. Hypoxia-inducible factor activation in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017 Sep;26(5):345–50.

81. Krishan P., Singh G., Bedi O. Carbohydrate restriction ameliorates nephropathy by reducing oxidative stress and upregulating HIF-1α levels in type-1 diabetic rats. J Diabetes Metab Disord. 2017 Dec 19;16:47.

82. Nordquist L., Friederich-Persson M., Fasching A., Liss P., Shoji K., Nangaku M., Hansell P., Palm F. Activation of hypoxia-inducible factors prevents diabetic nephropathy. J Am Soc Nephrol. 2015 Feb;26(2):328–38.

83. Bohuslavova R., Cerychova R., Nepomucka K., Pavlinkova G. Renal injury is accelerated by global hypoxia-inducible factor 1 alpha deficiency in a mouse model of STZ-induced diabetes. BMC Endocr Disord. 2017 Aug 3;17(1):48.

84. Yau J.W., Rogers S.L., Kawasaki R., Lamoureux E.L., Kowalski J.W., Bek T., Chen S.J., Dekker J.M., Fletcher A., Grauslund J., Haffner S., Hamman R.F., Ikram M.K., Kayama T., Klein B.E., Klein R., Krishnaiah S., Mayurasakorn K., O’Hare J.P., Orchard T.J., Porta M., Rema M., Roy M.S., Sharma T., Shaw J., Taylor H., Tielsch J.M., Varma R., Wang J.J., Wang N., West S., Xu L., Yasuda M., Zhang X., Mitchell P., Wong T.Y. Meta-Analysis for Eye Disease (METAEYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012 Mar;35(3):556–64.

85. Aiello L.P., Avery R.L., Arrigg P.G., Keyt B.A., Jampel H.D., Shah S.T., Pasquale L.R., Thieme H., Iwamoto M.A., Park J.E., et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 1994 Dec 1;331(22):1480–7.

86. Ajlan R.S., Silva P.S., Sun J.K. Vascular Endothelial Growth Factor and Diabetic Retinal Disease. Semin Ophthalmol. 2016;31(1–2):40–8.

87. Urias E.A., Urias G.A., Monickaraj F., McGuire P., DasA. Novel therapeutic targets in diabetic macular edema: Beyond VEGF. Vision Res. 2017 Oct;139:221–7.

88. Ozaki H., Yu A.Y., Della N., Ozaki K., Luna J.D., Yamada H., Hackett S.F., Okamoto N., Zack D.J., Semenza G.L., Campochiaro P.A. Hypoxia inducible factor-1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci. 1999 Jan;40(1):182–9.

89. Matsumoto M., Suzuma K., Maki T., Kinoshita H., Tsuiki E., Fujikawa A., Kitaoka T. Succinate increases in the vitreous fluid of patients with active proliferative diabetic retinopathy. Am J Ophthalmol. 2012 May;153(5):896–902.e1.

90. Hu J., Wu Q., Li T., Chen Y., Wang S. Inhibition of high glucose-induced VEGF release in retinal ganglion cells by RNA interference targeting G protein-coupled receptor 91. Exp Eye Res. 2013 Apr;109:31–9.

91. Hu J., Li T., Du X., Wu Q., Le Y.Z. G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases. Vision Res. 2017 Oct;139:59–64.

92. Jeffcoate W.J., Vileikyte L., Boyko E.J., ArmstrongD.G., Boulton A.J.M. Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers. Diabetes Care. 2018 Apr;41(4):645–52.

93. Knighton D.R., Silver I.A., Hunt T.K. Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration. Surgery. 1981 Aug;90(2):262–70.

94. Kalani M., Brismar K., Fagrell B., Ostergren J., Jörneskog G. Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers. Diabetes Care. 1999 Jan;22(1):147–51.

95. Catrina S.B., Okamoto K., Pereira T., Brismar K., Poellinger L. Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes. 2004 Dec;53(12):3226–32.

96. Lerman O.Z., Galiano R.D., Armour M., Levine J.P., Gurtner G.C. Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia. Am. J. Pathol. 2003 Jan;162(1):303–12.

97. Thangarajah H., Yao D., Chang E.I., Shi Y., Jazayeri L., Vial I.N., Galiano R.D., Du X.L., Grogan R., Galvez M.G., Januszyk M., Brownlee M., Gurtner G.C. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13505–10.

98. Thangarajah H., Vial I.N., Grogan R.H., Yao D., Shi Y., Januszyk M., Galiano R.D., Chang E.I, Galvez M.G., Glotzbach J.P., Wong V.W., Brownlee M., Gurtner G.C. HIF-1alpha dysfunction in diabetes. Cell Cycle. 2010 Jan 1;9(1):75–9.

99. Botusan I.R., Sunkari V.G., Savu O., Catrina A.I., Grünler J., Lindberg S., Pereira T., Ylä-Herttuala S., Poellinger L., Brismar K., Catrina S.B. 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.

100. Wetterau M., George F., Weinstein A., Nguyen P.D., Tutela J.P., Knobel D., Cohen Ba.O., Warren S.M., Saadeh P.B. Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure. Wound Repair Regen. 2011 Jul–Aug;19(4):481–6.

101. Ceradini D.J., Yao D., Grogan R.H., Callaghan M.J., Edelstein D., Brownlee M., Gurtner G.C. Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. J. Biol. Chem. 2008 Apr 18;283(16):10930–8.

102. Consensus Development Conference on Insulin Resistance: 5–6 november 1997. Diabetes Care 1998, 21(2):310–14.