Endocrine

, Volume 46, Issue 2, pp 209–214 | Cite as

Somatostatin and diabetic retinopathy: current concepts and new therapeutic perspectives

  • Cristina Hernández
  • Olga Simó-Servat
  • Rafael Simó
Mini Review

Abstract

Somatostatin (SST) is abundantly produced by the human retina, and the main source is the retinal pigment epithelium (RPE). SST exerts relevant functions in the retina (neuromodulation, angiostatic, and anti-permeability actions) by interacting with SST receptors (SSTR) that are also expressed in the retina. In the diabetic retina, a downregulation of SST production does exist. In this article, we give an overview of the mechanisms by which this deficit of SST participates in the main pathogenic mechanisms involved in diabetic retinopathy (DR): neurodegeneration, neovascularization, and vascular leakage. In view of the relevant SST functions in the retina and the reduction of SST production in the diabetic eye, SST replacement has been proposed as a new target for treatment of DR. This could be implemented by intravitreous injections of SST analogs or gene therapy, but this is an aggressive route for the early stages of DR. Since topical administration of SST has been effective in preventing retinal neurodegeneration in STZ-induced diabetic rats, it seems reasonable to test this new approach in humans. In this regard, the results of the ongoing clinical trial EUROCONDOR will provide useful information. In conclusion, SST is a natural neuroprotective and antiangiogenic factor synthesized by the retina which is downregulated in the diabetic eye and, therefore, its replacement seems a rational approach for treating DR. However, clinical trials will be needed to establish the exact position of targeting SST in the treatment of this disabling complication of diabetes.

Keywords

Diabetic retinopathy Retinal neurodegeneration Neovascularization Vascular leakage Somatostatin Somatostatin receptors Cortistatin Eye drops 

References

  1. 1.
    N. Cheung, P. Mitchell, T.Y. Wong, Diabetic retinopathy. Lancet 376, 124–136 (2010)PubMedCrossRefGoogle Scholar
  2. 2.
    J.W. Yau, S.L. Rogers, R. Kawasaki, E.L. Lamoureux, J.W. Kowalski, T. Bek, S.J. Chen, J.M. Dekker, A. Fletcher, J. Grauslund, S. Haffner, R.F. Hamman, M.K. Ikram, T. Kayama, B.E. Klein, R. Klein, S. Krishnaiah, K. Mayurasakorn, J.P. O’Hare, T.J. Orchard, M. Porta, M. Rema, M.S. Roy, T. Sharma, J. Shaw, H. Taylor, J.M. Tielsch, R. Varma, J.J. Wang, N. Wang, S. West, L. Xu, M. Yasuda, X. Zhang, P. Mitchell, T.Y. Wong, Meta-analysis for eye disease (META-EYE) study group, global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35, 556–564 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    L.J. Lee, A.P. Yu, K.E. Cahill, A.K. Oglesby, J. Tang, Y. Qiu, H.G. Birnbaum, Direct and indirect costs among employees with diabetic retinopathy in the United States. Curr. Med. Res. Opin. 24, 1549–1559 (2008)PubMedCrossRefGoogle Scholar
  4. 4.
    E.M. Pelletier, B. Shim, R. Ben-Joseph, J.J. Caro, Economic outcomes associated with microvascular complications of type 2 diabetes mellitus: results from a US claims data analysis. Pharmacoeconomics 27, 479–490 (2009)PubMedCrossRefGoogle Scholar
  5. 5.
    E. Heintz, A.B. Wiréhn, B.B. Peebo, U. Rosenqvist, L.A. Levin, Prevalence and healthcare costs of diabetic retinopathy: a population-based register study in Sweden. Diabetologia 53, 2147–2154 (2010)PubMedCrossRefGoogle Scholar
  6. 6.
    R. Simó, C. Hernández, European consortium for the early treatment of diabetic retinopathy (EUROCONDOR), neurodegeneration is an early event in diabetic retinopathy: therapeutic implications. Br. J. Ophthalmol. 96, 1285–1290 (2012)PubMedCrossRefGoogle Scholar
  7. 7.
    R. Simó, C. Hernández, Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol. Metab. 25(1), 23–33 (2013). doi:10.1016/j.tem.2013.09.005 PubMedCrossRefGoogle Scholar
  8. 8.
    P. Brazeau, W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, R. Guillemin, Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179(4068), 77–79 (1973)PubMedCrossRefGoogle Scholar
  9. 9.
    S. Krantic, I. Goddard, A. Saveanu, N. Giannetti, J. Fombonne, A. Cardoso, P. Jaquet, A. Enjalbert, Novel modalities of somatostatin actions. Eur. J. Endocrinol. 151(6), 643–655 (2004)PubMedCrossRefGoogle Scholar
  10. 10.
    D. Marshak, T. Yamada, Characterization of somatostatin-like immunoreactivity in vertebrate retinas. Invest. Ophthalmol. Vis. Sci. 25(1), 112–115 (1984)PubMedGoogle Scholar
  11. 11.
    T. Yamada, D. Marshak, S. Basinger, J. Walsh, J. Morley, W. Stell, Somatostatin-like immunoreactivity in the retina. Proc. Natl. Acad. Sci. U S A. 77(3), 1691–1695 (1980)PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    T. Yamada, S. Basinger, Biosynthesis of somatostatin-like immunoreactivity by frog retinas in vitro. J. Neurochem. 39(6), 1539–1546 (1982)PubMedCrossRefGoogle Scholar
  13. 13.
    Y.C. Patel, T. Wheatley, C. Ning, Multiple forms of immunoreactive somatostatin: comparison of distribution in neural and nonneural tissues and portal plasma of the rat. Endocrinology 109(6), 1943–1949 (1981)PubMedCrossRefGoogle Scholar
  14. 14.
    D.M. Ferreiro, V.A. Head, R.H. Edwards, S.M. Sagar, Somatostatin mRNA and molecular forms during development of the rat retina. Brain Res. Dev. Brain Res. 57(1), 15–19 (1990)CrossRefGoogle Scholar
  15. 15.
    S.M. Sagar, O.P. Rorstad, D.M. Landis, M.A. Arnold, J.B. Martin, Somatostatin-like immunoreactive material in the rabbit retina. Brain Res. 244(1), 91–99 (1982)PubMedCrossRefGoogle Scholar
  16. 16.
    A.W. Spira, Y. Shimizu, O.P. Rorstad, Localization, chromatographic characterization, and development of somatostatin-like immunoreactivity in the guinea pig retina. J. Neurosci. 4(12), 3069–3079 (1984)PubMedGoogle Scholar
  17. 17.
    D.W. Marshak, J.R. Reeve, J.E. Shively, D. Hawke, M.S. Takami, T. Yamada, Structure of somatostatin isolated from bovine retina. J. Neurochem. 41(3), 601–606 (1983)PubMedCrossRefGoogle Scholar
  18. 18.
    C. Hernández, E. Carrasco, R. Casamitjana, R. Deulofeu, J. García-Arumí, R. Simó, Somatostatin molecular variants in the vitreous fluid: a comparative study between diabetic patients with proliferative diabetic retinopathy and non-diabetic control subjects. Diabetes Care 28(8), 1941–1947 (2005)PubMedCrossRefGoogle Scholar
  19. 19.
    P.M. van Hagen, G.S. Baarsma, C.M. Mooy, E.M. Ercoskan, E. ter Averst, L.J. Hofland, S.W. Lamberts, R.W. Kuijpers, Somatostatin and somatostatin receptors in retinal diseases. Eur. J. Endocrinol. 143, S43–S51 (2000)PubMedCrossRefGoogle Scholar
  20. 20.
    A. Feigenspan, J. Bormann, Facilitation of GABAergic signalling in the retina by receptors stimulating adenylate cyclase. Proc. Natl. Acad. Sci. U.S.A. 91(23), 10893–10897 (1994)PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    E. Carrasco, C. Hernández, A. Miralles, P. Huguet, J. Farrés, R. Simó, Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. Diabetes Care 30(11), 2902–2908 (2007)PubMedCrossRefGoogle Scholar
  22. 22.
    R. Simó, A. Lecube, L. Sararols, J. García-Arumí, R.M. Segura, R. Casamitjana, C. Hernández, Deficit of somatostatin-like immunoreactivity in the vitreous fluid of diabetic patients: possible role in the development of proliferative diabetic retinopathy. Diabetes Care 25(12), 2282–2286 (2002)PubMedCrossRefGoogle Scholar
  23. 23.
    D. Hoyer, GI. Bell, M. Berelowitz, J. Epelbaum, W. Feniuk, P.P. Humphrey, A.M. O’Carroll, Y.C. Patel, A. Schonbrunn, J.E. Taylor, Classification and nomenclature of somatostatin receptors. Trends Pharmacol. Sci. 16(3), 86–88 (1995)PubMedCrossRefGoogle Scholar
  24. 24.
    A. Giustina, I. Karamouzis, I. Patelli, G. Mazziotti, Octreotide for acromegaly treatment: a reappraisal. Expert Opin. Pharmacother. 14(17), 2433–2447 (2013)PubMedCrossRefGoogle Scholar
  25. 25.
    U. Kumar, Cross-talk and modulation of signaling between somatostatin and growth factor receptors. Endocrine 40(2), 168–180 (2011)PubMedCrossRefGoogle Scholar
  26. 26.
    Y.C. Patel, C.B. Srikant, Subtype selectivity of peptide analogs for all five cloned human somatostatin receptors (hsstr 1–5). Endocrinology 135(6), 2814–2817 (1994)PubMedGoogle Scholar
  27. 27.
    Y.C. Patel, M. Greenwood, R. Panetta, N. Hukovic, S. Grigorakis, L.A. Robertson, C.B. Srikant, Molecular biology of somatostatin receptor subtypes. Metabolism 45(8), 31–38 (1996)PubMedCrossRefGoogle Scholar
  28. 28.
    L. de Lecea, J.R. Criado, O. Prospero-Garcia, K.M. Gautvik, P. Schweitzer, P.E. Danielson, C.L. Dunlop, G.R. Siggins, S.J. Henriksen, J.G. Sutcliffe, A cortical neuropeptide with neuronal depressant and sleep-modulating properties. Nature 381, 242–245 (1996)PubMedCrossRefGoogle Scholar
  29. 29.
    A.D. Spier, L. de Lecea, Cortistatin: a member of the somatostatin neuropeptide family with distinct physiological functions. Brain Res. Brain Res. Rev. 33, 228–241 (2000)PubMedCrossRefGoogle Scholar
  30. 30.
    E. Carrasco, C. Hernández, I. de Torres, J. Farrés, R. Simó, Lowered cortistatin expression is an early event in the human diabetic retina and is associated with apoptosis and glial activation. Mol. Vis 14, 1496–1502 (2008)PubMedCentralPubMedGoogle Scholar
  31. 31.
    A.J. Barber, E. Lieth, S.A. Khin, D.A. Antonetti, A.G. Buchanan, T.W. Gardner, Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J. Clin. Invest 102, 783–791 (1998)PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    T.S. Kern, A.J. Barber, Retinal ganglion cells in diabetes. J. Physiol. 586, 4401–4408 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    R. Simó, E. Carrasco, A. Fonollosa, J. García-Arumí, R. Casamitjana, C. Hernández, Deficit of somatostatin in the vitreous fluid of patients with diabetic macular edema. Diabetes Care 30(3), 725–727 (2007)PubMedCrossRefGoogle Scholar
  34. 34.
    E. Lieth, A.J. Barber, B. Xu, C. Dice, M.J. Ratz, D. Tanase, J.M. Strother, Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes 47(5), 815–820 (1988)CrossRefGoogle Scholar
  35. 35.
    E. Lieth, K.F. LaNoue, D.A. Antonetti, M. Ratz, Diabetes reduces glutamate oxidation and glutamine synthesis in the retina. The Penn State Retina Research Group. Exp. Eye 70(6), 723–730 (2000)CrossRefGoogle Scholar
  36. 36.
    R.A. Kowluru, R.L. Engerman, G.L. Case, T.S. Kern, Retinal glutamate in diabetes and effect of antioxidants. Neurochem. Int. 38(5), 385–390 (2001)PubMedCrossRefGoogle Scholar
  37. 37.
    J. Ambati, K.V. Chalam, D.K. Chawla, C.T. D’Angio, E.G. Guillet, S.J. Rose, R.E. Vanderlinde, B.K. Ambati, Elevated gamma-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch. Ophthalmol. 115(5), 1161–1166 (1997)PubMedCrossRefGoogle Scholar
  38. 38.
    J.E. Pulido, J.S. Pulido, J.C. Erie, J. Arroyo, K. Bertram, M.J. Lu, S.A. Shippy, A role for excitatory amino acids in diabetic eye disease. Exp. Diabetes Res. 2007, 36150 (2007)PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Y.K. Ng, X.X. Zeng, E.A. Ling, Expression of glutamate receptors and calcium-binding proteins in the retina of streptozotocin-induced diabetic rats. Brain Res. 1018(1), 66–72 (2004)PubMedCrossRefGoogle Scholar
  40. 40.
    A.R. Santiago, J.M. Gaspar, F.I. Baptista, A.J. Cristóvão, P.F. Santos, W. Kamphuis, A.F. Ambrósio, Diabetes changes the levels of ionotropic glutamate receptors in the rat retina. Mol. Vis 15, 1620–1630 (2009)PubMedCentralPubMedGoogle Scholar
  41. 41.
    C. Hernández, M. García-Ramírez, L. Corraliza, J. Fernández-Carneado, J. Farrera-Sinfreu, B. Ponsati, A. González-Rodríguez, A. Martínez-Valverde, R. Simó, Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes. Diabetes 62, 2569–2578 (2013)PubMedCrossRefGoogle Scholar
  42. 42.
    L. Wang, Q.Q. Deng, X.H. Wu, J. Yu, X.L. Yang, Y.M. Zhong, Upregulation of Glutamate-Aspartate Transporter by Glial Cell Line-Derived Neurotrophic Factor Ameliorates Cell Apoptosis in Neural Retina in Streptozotocin-Induced Diabetic Rats. CNS Neurosci. Ther. 19, 945–953 (2013)PubMedCrossRefGoogle Scholar
  43. 43.
    A. Bigiani, C. Petrucci, V. Ghiaroni, M. Dal, Monte, A. Cozzi, H.J. Kreienkamp, D. Richter, P. Bagnoli, Functional correlates of somatostatin receptor 2 overexpression in the retina of mice with genetic deletion of somatostatin receptor 1. Brain Res. 1025(1–2), 177–185 (2004)PubMedCrossRefGoogle Scholar
  44. 44.
    E. Catalani, D. Cervia, D. Martini, P. Bagnoli, E. Simonetti, A.M. Timperio, G. Casini, Changes in neuronal response to ischemia in retinas with genetic alterations of somatostatin receptor expression. Eur. J. Neurosci. 25(5), 1447–1459 (2007)PubMedCrossRefGoogle Scholar
  45. 45.
    A. Akopian, J. Johnson, R. Gabriel, N. Brecha, P. Witkovsky, Somatostatin modulates voltage-gated K(+) and Ca(2+) currents in rod and cone photoreceptors of the salamander retina. J. Neurosci. 20(3), 929–936 (2000)PubMedCentralPubMedGoogle Scholar
  46. 46.
    M. Dal Monte, C. Petrucci, A. Cozzi, J.P. Allen, P. Bagnoli, Somatostatin inhibits potassium-evoked glutamate release by activation of the sst(2) somatostatin receptor in the mouse retina. Naunyn Schmiedebergs Arch. Pharmacol. 367(2), 188–192 (2003)PubMedCrossRefGoogle Scholar
  47. 47.
    E. Kouvidi, Z. Papadopoulou-Daifoti, K. Thermos, Somatostatin modulates dopamine release in rat retina. Neurosci. Lett. 391(3), 82–86 (2006)PubMedCrossRefGoogle Scholar
  48. 48.
    N. Mastrodimou, A. Vasilaki, A. Papadioti, M.J. Low, D. Hoyer, K. Thermos, Somatostatin receptors in wildtype and somatostatin deficient mice and their involvement in nitric oxide physiology in the retina. Neuropeptides 40(5), 365–373 (2006)PubMedCrossRefGoogle Scholar
  49. 49.
    N. Mastrodimou, F. Kiagiadaki, M. Hodjarova, E. Karagianni, K. Thermos, Somatostatin receptors (sst2) regulate cGMP production in rat retina. Regul. Pept. 133(1–3), 41–46 (2006)PubMedCrossRefGoogle Scholar
  50. 50.
    F. Kiagiadaki, K. Thermos, Effect of intravitreal administration of somatostatin and sst2 analogs on AMPA-induced neurotoxicity in rat retina. Invest. Ophthalmol. Vis. Sci. 49(7), 3080–3089 (2008)PubMedCrossRefGoogle Scholar
  51. 51.
    N.N. Osborne, R.J. Casson, J.P. Wood, G. Chidlow, M. Graham, J. Melena, Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog. Retin. Eye. Res 23(1), 91–147 (2004)PubMedCrossRefGoogle Scholar
  52. 52.
    D. Kokona, N. Mastrodimou, I. Pediaditakis, I. Charalampopoulos, H.A. Schmid, K. Thermos, Pasireotide (SOM230) protects the retina in animal models of ischemia induced retinopathies. Exp. Eye Res. 103, 90–98 (2012)PubMedCrossRefGoogle Scholar
  53. 53.
    N. Mastrodimou, G.N. Lambrou, K. Thermos, Effect of somatostatin analogues on chemically induced ischaemia in the rat retina. Naunyn. Schmiedebergs. Arch. Pharmacol 371(1), 44–53 (2005)PubMedCrossRefGoogle Scholar
  54. 54.
    D. Cervia, D. Martini, C. Ristori, E. Catalani, A.M. Timperio, P. Bagnoli, G. Casini, Modulation of the neuronal response to ischaemia by somatostatin analogues in wild-type and knock-out mouse retinas. J. Neurochem. 106(5), 2224–2235 (2008)PubMedCrossRefGoogle Scholar
  55. 55.
    D. Cervia, E. Catalani, M. Dal Monte, G. Casini, Vascular endothelial growth factor in the ischemic retina and its regulation by somatostatin. J. Neurochem. 120(5), 818–829 (2012)PubMedCrossRefGoogle Scholar
  56. 56.
    F. Kiagiadaki, M. Savvaki, K. Thermos, Activation of somatostatin receptor (sst 5) protects the rat retina from AMPA-induced neurotoxicity. Neuropharmacology 58(1), 297–303 (2010)PubMedCrossRefGoogle Scholar
  57. 57.
    F. Schmitt, M. Ryan, G. Cooper, A brief review of the pharmacologic and therapeutic aspects of memantine in Alzheimer’s disease. Expert Opin. Drug. Metab. Toxicol. 3(1), 135–141 (2007)PubMedCrossRefGoogle Scholar
  58. 58.
    L.C. Lin, E. Sibille, Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target? Front. Pharmacol. 4, 110 (2013)PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    L.E. Smith, J.J. Kopchick, W. Chen, J. Knapp, F. Kinose, D. Daley, E. Foley, R.G. Smith, J.M. Schaeffer, Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 276(5319), 1706–1709 (1997)PubMedCrossRefGoogle Scholar
  60. 60.
    M.I. Davis, M.I. Wilson, M.B. Grant, The therapeutic problem of proliferative diabetic retinopathy: targeting somatostatin receptors. Horm. Metab. Res. 33(5), 295–299 (2001)PubMedCrossRefGoogle Scholar
  61. 61.
    S.H. Wilson, M.I. Davis, S. Caballero, M.B. Grant, Modulation of retinal endothelial cell behaviour by insulin-like growth factor I and somatostatin analogues: implications for diabetic retinopathy. Growth Horm. IGF Res. 11(Suppl A), S53–S59 (2001)PubMedCrossRefGoogle Scholar
  62. 62.
    A. Baldysiak-Figiel, G.K. Lang, J. Kampmeier, G.E. Lang, Octreotide prevents growth factor-induced proliferation of bovine retinal endothelial cells under hypoxia. J. Endocrinol. 180(3), 417–424 (2004)PubMedCrossRefGoogle Scholar
  63. 63.
    M. Mei, D. Cammalleri, G. Azara, P. Casini, M. Bagnoli, Dal Monte, Mechanisms underlying somatostatin receptor 2 down-regulation of vascular endothelial growth factor expression in response to hypoxia in mouse retinal explants. J. Pathol. 226(3), 519–533 (2012)PubMedCrossRefGoogle Scholar
  64. 64.
    M. Dal Monte, M. Cammalleri, D. Martini, G. Casini, P. Bagnoli, Antiangiogenic role of somatostatin receptor 2 in a model of hypoxia-induced neovascularization in the retina: results from transgenic mice. Invest. Ophthalmol.Vis. Sci. 48(8), 3480–3489 (2007)PubMedCrossRefGoogle Scholar
  65. 65.
    S.S. Palii, A. Afzal, L.C. Shaw, H. Pan, S. Caballero, R.C. Miller, S. Jurczyk, J.C. Reubi, Y. Tan, G. Hochhaus, H. Edelhauser, D. Geroski, G. Shapiro, M.B. Grant, Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor. Invest. Ophthalmol. Vis. Sci. 49(11), 5094–5102 (2008)PubMedCrossRefGoogle Scholar
  66. 66.
    D. Ramos, A. Carretero, M. Navarro, L. Mendes-Jorge, V. Nacher, A. Rodriguez-Baeza, J. Ruberte, Mimicking microvascular alterations of human diabetic retinopathy: a challenge for the mouse models. Curr. Med. Chem. 20(26), 3200–3217 (2013)PubMedCrossRefGoogle Scholar
  67. 67.
    U. Hesse, D. Ysebaert, B. de Hemptinne, Role of somatostatin-14 and its analogues in the management of gastrointestinal fistulae: clinical data. Gut 49(Suppl 4), iv11–iv21 (2001)PubMedCentralPubMedGoogle Scholar
  68. 68.
    C. Ray, S. Carney, T. Morgan, A. Gillies, Somatostatin as a modulator of distal nephron water permeability. Clin. Sci. (Lond) 84(4), 455–460 (1993)Google Scholar
  69. 69.
    A.C. Lambooij, R.W.A.M. Kuijpers, E.G. van Lichtenauer-Kaligis, M. Kliffen, G.S. Baarsma, P.M. van Hagen, C.M. Mooy, Somatostatin receptor 2A expression in choroidal neovascularization secondary to age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 41(8), 2329–2335 (2000)PubMedGoogle Scholar
  70. 70.
    L. Corraliza, M. García-Ramírez, V. Villarroel, A. Ciudin, C. Hernández, R. Simó, Somatostatin 28 (SST-28) prevents the breakdown of human retinal pigment epithelial cells induced by the diabetic milieu. Diabetologia 53(Suppl 1), A1191 (2010)Google Scholar
  71. 71.
    M.B. Grant, R.N. Mames, C. Fitzgerald, K.M. Hazariwala, R. Cooper-DeHoff, S. Caballero, K.S. Estes, The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care 23(4), 504–509 (2000)PubMedCrossRefGoogle Scholar
  72. 72.
    B.O. Boehm, G.K. Lang, P.M. Jehle, B. Feldman, G.E. Lang, Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm. Metab. Res. 33(5), 300–306 (2001)PubMedCrossRefGoogle Scholar
  73. 73.
    M.C. Hernaez-Ortega, E. Soto-Pedre, J.J. Martin, Sandostatin LAR for cystoid diabetic macular edema: a 1-year experience. Diabetes Res. Clin. Pract. 64(1), 71–72 (2004)PubMedCrossRefGoogle Scholar
  74. 74.
    M.C. Hernaez-Ortega, E. Soto-Pedre, J.A. Piniés, Lanreotide Autogel for persistent diabetic macular edema. Diabetes Res. Clin. Pract. 80(3), e8–e10 (2008)PubMedCrossRefGoogle Scholar
  75. 75.
    J. Janssen, S. Lamberts, Circulating IGF-1 and its protective role in the pathogenesis of diabetic angiopathy. Clin. Endocrinol. 52(1), 1–9 (2000)CrossRefGoogle Scholar
  76. 76.
    Q. Wang, D. Dills, R. Klein, B. Klein, S. Moss, Does insulin-like growth factor 1 predict incidence and progression of diabetic retinopathy? Diabetes 44(2), 161–164 (1995)PubMedCrossRefGoogle Scholar
  77. 77.
    S.S. Palii, S. Caballero, G. Shapiro, M.B. Grant, Medical treatment of diabetic retinopathy with somatostatin analogues. Expert Opin. Investig. Drugs 16(1), 73–82 (2007)PubMedCrossRefGoogle Scholar
  78. 78.
    C. Gerhardinger, K.D. McClure, G. Romeo, F. Podestà, M. Lorenzi, IGF-I mRNA and signaling in the diabetic retina. Diabetes 50(1), 175–183 (2000)CrossRefGoogle Scholar
  79. 79.
    R. Simó, C. Hernández, R.M. Segura, J. García-Arumí, L. Sararols, R. Burgos, A. Cantón, J. Mesa, Free insulin-like growth factor 1 in the vitreous fluid of diabetic patients with proliferative diabetic retinopathy: a case-control study. Clin Sci (Lond) 104(3), 223–230 (2003)CrossRefGoogle Scholar
  80. 80.
    C. Hernández, R. Simó, Strategies for blocking angiogenesis in diabetic retinopathy: from basic science to clinical practice. Expert Opin. Investig. Drugs 6(8), 1209–1226 (2007)CrossRefGoogle Scholar
  81. 81.
    L.P. Aiello, Targeting intraocular neovascularization and edema-one drop at a time. N. Engl. J. Med. 359(9), 967–969 (2008)PubMedCrossRefGoogle Scholar
  82. 82.
    N. Cheung, P. Mitchell, T.Y. Wong, Diabetic retinopathy. Lancet 376(9735), 124–136 (2010)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Cristina Hernández
    • 1
    • 2
  • Olga Simó-Servat
    • 1
  • Rafael Simó
    • 1
    • 2
  1. 1.Diabetes and Metabolism Research Unit, Vall d’Hebron Research InstituteUniversitat Autònoma de BarcelonaBarcelonaSpain
  2. 2.Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)Instituto de Salud Carlos III (ISCIII)MadridSpain

Personalised recommendations