Ординатура / Офтальмология / Английские материалы / Diabetic Retinopathy_Lang_2007

Endothelial cells are surrounded by pericytes that regulate the function of the blood vessels. Regulation of the barrier function by endothelial cells is an intricate process, requiring coordination of a large number of complex signaling pathways. The breakdown of the blood-retinal barrier, resulting in leakage of plasma from small blood vessels in the macula, the central portion of the retina, is responsible for the major part of impaired visual function. Therefore, macular edema is a clinical correlate of a compromised barrier function [5, 6].

The development of pathological neovascularization is often associated with hypoxia/ischemia. Hypoxia and ischemia can be observed both in malignant tumors and in proliferative retinopathies, which includes diabetic retinopathy. Hypoxia is known to stimulate important angiogenic mediators including vascular endothelial growth factor (VEGF). This occurs through activation of hypoxia-inducible factor (HIF)-1 that increases VEGF expression [7, 8]. The concept that growth factors mediate retinal angiogenesis has been introduced in 1948 by Michaelson [9]. There is now ample evidence that the development of diabetic retinopathy is a multifactorial process in which growth factors, including growth hormone and insulin-like growth factor (IGF)-1, play an important role. The lack of inhibitory signals of growth has also been recently advocated [10–12]. The pathological neovascularization seen in patients with diabetes mellitus is the response to a rise in the local concentration of molecules that induce such angiogenesis, but it is also due to a fall in the levels of endogenous molecules inhibiting angiogenesis (fig. 1). One of the most potent endogenous regulators is pigment epithelium-derived factor (PEDF), which serves both as a survival factor for neuronal components of the eye as well as an essential inhibitor of the growth of ocular blood vessels. In the presence of a pathological/diabetic milieu, a reduced gene expression of PEDF resulting in a reduced antiangiogenic activity has been found [13, 14]. This suggests that an unbalanced expression of angiogenic mediators and antiangiogenic factors is involved in the development and progression of pathological neovascularization in the diabetic eye [15, 16]. PEDF may also act as an endogenous antiinflammatory factor in the eye. Therefore, decreased ocular PEDF levels may contribute to an ongoing low-grade inflammation and vascular leakage in diabetic retinopathy [17].

For an effective treatment of retinopathy in people with diabetes mellitus, one would recommend a concept leading to the downregulation of endogenous angiogenic stimulators and the upregulation of endogenous angiogenic inhibitors, resulting in a restoration of balance in angiogenic control [18, 19]. In this review, we will address the potential role of growth factor inhibitory substances, i.e. long-acting somatostatin analogues, in diabetic patients with proliferative retinopathy.

Quiescent vasculature

Fig. 1. Unbalanced expression of angiogenic mediators and antiangiogenic factors in the diabetic eye. GH Growth hormone; SMS somatostatin.

Diabetic Retinopathy

Diabetic retinopathy is the most severe of the several ocular complications of chromic hyperglycemia [20]. Diabetic retinopathy affects both type 1 and type 2 diabetic patients. Because diabetes is so common, although advances in treatment have greatly reduced the risk of blindness, retinopathy still remains a significant clinical problem in daily practice [20–22].

Current Approaches to Prevention and Treatment of

Diabetic Retinopathy

Without intervention, proliferative retinopathy will eventually develop in 60% of persons with diabetes, resulting in profound visual loss in almost half of them. Randomized, controlled clinical trials have shown that medical therapy providing glucose control at near-normal levels by use of intensive conventional therapy or continuous subcutaneous insulin infusion significantly retard development and progression of retinopathy in patients with type 1 diabetes [23]. Likewise, intensified treatment of type 2 diabetes mellitus will lower the risk of microvascular complications [24]. Blood glucose control and the control of lipids also delay progression [25–27].

There is no doubt that an intensified diabetes treatment is effective; however, in the Diabetes Control and Complications Trial, two rather unexpected observations were made, both of which are of considerable importance. First, the differences in progression between the group with ‘tight’ blood glucose control and the group with standard control did not appear until approximately 2.5 years after the

initiation of these treatment regimens. Second, about 10% of the patients with preexisting retinopathy had a transient worsening after the institution of tight blood glucose control [28]. Early worsening of their retinopathy was found to be related to increased systemic levels of IGF-1 plus the upregulation of the mitogenic cytokine VEGF and its receptor leading to an unbalanced increase in angiogenic mediators [29, 30]. In diabetic rats, acute intensive insulin therapy markedly increases VEGF mRNA and protein levels in the retinae. In this setting, retinal nuclear extracts revealed increased HIF-1 levels leading to an increased HIF- 1 -dependent binding to hypoxia-responsive elements in the VEGF promoter [31]. This suggest that a treatment of choice, i.e. intensified diabetes treatment, may also increase the likelihood of proliferative retinopathy in the short term.

Laser therapy, introduced during the 1960s, is the mainstay in the treatment of proliferative diabetic retinopathy and diabetic macular edema. However, it always has to be remembered that laser treatment is a destructive treatment [32, 33].

Novel Concepts – the Growth Factor Hypothesis

Knowledge of the major factors responsible for modulating neovascularization has had significant implications for the development of novel, nondestructive, pharmacologic treatment modalities [34–36]. Proliferative retinopathies could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycemia. The angiogenesis in proliferative diabetic retinopathy could also be treated via growth factor blockade by either upregulating endogenous angiogenic inhibitors or by pharmacological blocking. Targets could be VEGF and its corresponding receptor molecule, IGF-1, as well as the blockade of integrin molecules [35, 36].

Inhibitors of Growth Hormone Action

Inhibition of growth hormone action might be a potential pharmacological treatment for diabetic retinopathy. Interest in the field has emerged when the spontaneous resolution of proliferative diabetic retinopathy in a woman in whom acute panhypopituitarism had developed stimulated interest in pituitary ablation as a treatment for vision-threatening retinopathy [37–39]. Therefore, destruction of the pituitary by surgery or radiation has been used to treat proliferative retinopathy [40]. Long-term follow-up of patients who underwent pituitary ablation due to yttrium-90 implantation for treatment of proliferative diabetic retinopathy revealed either stabilization or improvement in visual acuity, including improvement in the grading of hard exudates, microaneurysms and hemorrhages [41–43].

Growth hormone action is mediated through the IGFs. Preclinical studies suggested that IGF-1 is not itself a vasoproliferative factor, but rather a strong permissive agent suggesting that neovascularization cannot occur in its absence but must be accompanied by other proangiogenic molecules such as VEGF to stimulate new vessel growth. These studies provide the rationale for the use of blockers of IGF-1 secretion, either by destroying the pituitary or by more specific inhibition of IGF-1 production [44, 45].

Long-Acting Somatostatin Analogue Treatment in

Diabetic Retinopathy

The peptide somatostatin was defined in the 1960s as a molecule that inhibits the release of growth hormone. The physiological actions of somatostatin are primarily inhibitory. It affects calcium and potassium ion channels, leads to tyrosine phosphatase activation, modulates secretion of neuroendocrine cells, and may also affect cell proliferation [46, 47]. Somatostatin regulates several organ systems, including the retina and vascular endothelial cells, acts as a classical hormone, a neurohormone, as a neurotransmitter, and exerts autocrine and paracrine functions.

The biological effects are mediated by 5 membrane-bound specific receptors, SSTR1–SSTR5. All receptors are G-protein-coupled receptors with 7 transmembrane-spanning domains linked to adenylate cyclase. SSTR genes are widely expressed in normal human eye tissues, with genes for SSTR1 and SSTR2 being the most widely expressed [48, 49]. SSTR2 and SSTR3 are the most important receptor subtypes mediating growth hormone secretion and endothelial cell cycle arrest, retinal endothelial cell apoptosis. SSTR expression suggests that somatostatin and its analogues will have a target in various compartments of the eye [50–53].

A number of uncontrolled clinical studies have used somatostatin analogue treatment in the context of diabetic retinopathy [for a summary, see ref. 54, 55]. Various dosages of the somatostatin analogues (minimal dosage per day 150 g, maximal dosage per day 500 g of SMS 201-995; 1,500 g/day of BMI23014) have been applied to patients with proliferative retinopathy [56–61] and cystoid macular edema [62]. The drugs were used for a variable length of time, ranging from 12 weeks up to a maximum of 12 months. Some studies reported effects on the suppression of growth hormone levels, stabilization of neovascularizations, resorption of hemorrhages, and reduction in the number of microaneurysms, respectively. In a case report, effective treatment of a macular edema was also found [62].

Two well-controlled trials have studied the delay to laser therapy and improvements in patients with persistence of proliferations following laser treatment [63, 64]. Grant et al. [63] have studied patients with severe nonproliferative diabetic retinopathy or early non-high-risk proliferative retinopathy. At this stage of diabetic retinopathy, the likelihood for the need of panretinal photocoagulation is high. The somatostatin analogue octreotide was titrated in 11 patients to the maximally tolerated dose for a 15-month period. From 200 up to 5,000 g/day octreotide was used. Only 1 of 22 eyes of octreotide-treated patients required panretinal photocoagulation, whereas 9 of 24 eyes in the control group had to be laser treated. The incidence of ocular disease progression was only 27% in patients treated with octreotide compared with 42% in patients with conventional management. This study provided the first clear evidence that octreotide treatment retarded progression of advanced retinopathy and delayed the time for laser photocoagulation.

Boehm et al. [64] reported the use of octreotide in a cohort of diabetic patients with a very advanced stage of proliferative diabetic retinopathy, i.e. the presence of active proliferations after full scatter laser treatment. Three hundred micrograms per day of octreotide was used in 9 patients, and 9 patients with standard diabetes management served as controls. The dose of 300 g/day is roughly equivalent to a 30-mg dose of the long-acting LAR formulation of octreotide. Ophthalmologists who defined end points of this intervention were masked throughout the study. The observation period was the longest ever reported in a trial using a somatostatin analogue for the treatment of diabetic complications. After 3 years of treatment, the incidence of vitreous hemorrhages was significantly lower in the octreotidetreated patients. Visual acuity was also preserved and significantly improved over time in the octreotide-treated group. Only in the group of patients with octreotide treatment, a regression of proliferations and fibrovascular changes, as defined by stereoscopic photography and fluorescein angiography, was found.

Mechanisms of Efficacy

The effects of octreotide on the progression of retinopathy may be explained by a least partial systemic suppression of a system overproduction of growth hormone and a partial correction of the associated imbalance of the IGF-1 system components. In addition, the recognition that SSTR subtypes are expressed at the retina provides evidence that a direct inhibition of locally produced growth factor molecules, including a direct inhibition of angiogenic response, and an antifibrotic action may also take place.

The expression pattern of both somatostatin and its receptors on various cellular components of the human eye makes it highly likely that somatostatin has

regulatory functions. The observed positive effects in cystic maculopathy and the positive case reports in patients with macular edema make it highly likely that somatostatin plays a direct role in fluid evasion or resorption. Most probably, the pigment epithelium cell is responsible for a favorable exchange of fluids.

This suggests that somatostatin may exert direct effects beyond a blockade of the IGF-1 system, since SSTR subtypes are expressed at various eye components, including the retina. This may also explain why the growth hormone receptor blocker pegvisomant was found ineffective in a recently published pilot trial [65]. In a 3-month, open-label study, pegvisomant did not cause regression of the new retinal vessels in patients with non-high-risk proliferative diabetic retinopathy, although plasma levels of IGF-1 decreased significantly by 50% [65].

Side Effects of Long-Acting Analogue Treatment

The side effect profile of long-acting analogue treatment includes the gut and hypoglycemic side effects. This side effect profile has been suggested to strongly argue against a clinical role for the current somatostatin analogues in the treatment of diabetes mellitus [66]. Since somatostatin can inhibit a large variety of physiological functions, including counterregulatory hormone response in the case of hypoglycemia, all trials (including the ongoing trails with octreotide LAR) have carefully monitored the safety of somatostatin use. In the Ulm trial, no severe hypoglycemic events, as defined by help needed from third parties or requirement of hospital admissions, did occur during an observational period of almost 3 years. Two patients complained of abdominal discomfort and increased bowel movements, which could be alleviated by use of an oral pancreatic enzyme supplementation. No gall bladder stones or sludges were noted on the routine ultrasound examinations of the abdomen. However, overall likelihood of gallstone formation is increased with long-acting somatostatin analogue treatment.

Long-acting somatostatin analogues can also decrease thyrotropin secretion. Therefore, follow-up procedures should include endocrine management with thyroid hormone replacement when appropriate [67]. Use of thyroid hormone supplementation in patients with diabetes mellitus will reduce the risk of hypoglycemia.

Perspective

Knowledge of the major factors responsible for modulating neovascularization has had significant implications for the development of novel, nondestructive, pharmacologic treatment modalities [67–69]. Substantial

efforts are under way to develop new therapies that do not result in tissue destruction inherent to laser treatment, including two large, randomized, phase III trials evaluating the efficacy and tolerability/safety of long-acting octreotide (Sandostatin LAR) in preparation for release of full trial results in 2007. Two phase III trials Sandostatin LAR (CSMS 802 trial: placebo vs. Sandostatin LAR® 20 and 30 mg and CSMS 804 trial: placebo vs. Sandostatin LAR® 30 mg) have reported a significant reduction in retinal bleeding. In both trials a risk reduction of vitreous hemorrhage of approximately 60% for octreotide compared to placebo was seen. In the 804 trial octreotide a delayed the time to progression of retinopathy as defined by ETDRS severity scale.

Future approaches might include the use of somatostatin analogues as a treatment option for reentry retinopathy and as an adjunct to an ongoing laser therapy, or even in vitreoretinal surgery [53, 54, 70–72]. Whether such a therapy may also prove effective for other retinal vascular proliferative diseases such as retinopathy of prematurity and age-related macular degeneration remains an open question that deserves attention, given our new understanding of the cellular and molecular mechanisms by which somatostatin may exert its antiangiogenic effects.

The use of long-acting analogues of the naturally occurring peptide, somatostatin, has evolved as a novel promising therapeutic option for retinopathy over the last decade. Current clinical evidence supports its use in diabetic retinopathy, but further clinical evidence from larger treatment groups of longer trial duration is required. Improved analogues may also help to make the use of somatostatin analogues an option far beyond the treatment of diabetes retinopathy [53, 54, 72].

References

1Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–1186.

2Bdolah Y, Sukhatme VP, Karumanchi SA: Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights. Semin Nephrol 2004;24:548–556.

3Chan-Ling T, McLeod DS, Hughes S, Baxter L, Chu Y, Hasegawa T, Lutty GA: Astrocyteendothelial cell relationships during human retinal vascular development. Invest Ophthalmol Vis Sci 2004;45:2020–2032.

4Grant MB, Afzal A, Spoerri P, Pan H, Shaw LC, Mames RN: The role of growth factors in the pathogenesis of diabetic retinopathy. Expert Opin Investig Drugs 2004;13:1275–1293.

5Tornquist P, Alm A, Bill A: Permeability of ocular vessels and transport across the blood-retinal- barrier. Eye 1990;4:303–309.

6Cunha-Vaz JG: The blood-retinal barriers system. Basic concepts and clinical evaluation. Exp Eye Res 2004;78:715–721.

7Ferrara N: Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581–611.

8Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS: Loss of HIF-1 in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis.

Cancer Cell 2004;6:485–495.

9Michaelson IC: The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK 1948;68:137–180.

10Spranger J, Osterhoff M, Reimann M, Mohlig M, Ristow M, Francis MK, Cristofalo V, Hammes HP, Smith G, Boulton M, Pfeiffer AF: Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease. Diabetes 2001;50:2641–2645.

11Boehm BO, Lang G, Volpert O, Jehle PM, Kurkhaus A, Rosinger S, Lang GK, Bouck N: Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy. Diabetologia 2003;46:394–400.

12Boehm BO, Lang G, Feldmann B, Kurkhaus A, Rosinger S, Volpert O, Lang GK, Bouck N: Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. A pilot study. Horm Metab Res 2003;35:382–386.

13Boehm BO, Schilling S, Rosinger S, Lang GE, Lang GK, Kientsch-Engel R, Stahl P: Elevated serum levels of N(epsilon)-carboxymethyl-lysine, an advanced glycation end product, are associated with proliferative diabetic retinopathy and macular oedema. Diabetologia 2004;47:1376–1379.

14Yamagishi S, Matsui T, Inoue H: Inhibition by advanced glycation end products (AGEs) of pigment epithelium-derived factor (PEDF) gene expression in microvascular endothelial cells. Drugs Exp Clin Res 2005;31:227–232.

15Bouck N: PEDF: anti-angiogenic guardian of ocular function. Trends Mol Med 2002;8:330–334.

16Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J: Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett 2001;489:270–276.

17Zhang SX, Wang JJ, Gao G, Shao C, Mott R, Ma JX: Pigment epithelium-derived factor (PEDF) is an endogenous antiinflammatory factor. FASEB J 2006;20:323–325.

18Gao G, Li Y, Gee S, Dudley A, Fant J, Crosson C, Ma JX: Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5. J Biol Chem 2002;277:9492–9497.

19Stellmach V, Crawford SE, Zhou W, Bouck N: Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor. Proc Natl Acad Sci USA 2001;98:2593–2597.

20Aiello LP, Gardner TW, King GL, et al: Diabetic retinopathy. Diabetes Care 1998;21:143–156.

21Frank RN: Diabetic retinopathy. N Engl J Med 2004;350:48–58.

22World Health Organization: Magnitude and causes of visual impairment. Accessed August 4, 2005, at http://www.who.int/mediacentre/factsheets/fs282/en.

23The Diabetes Control and Complications Trial Research Group. 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;329:977–986.

24UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853 (erratum published in Lancet 1999; 354:602).

25The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000;342:381–389.

26UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317: 703–713.

27Wilkinson-Berka JL, Kelly DJ, Gilbert RE: The interaction between the renin-angiotensin system and vascular endothelial growth factor in the pathogenesis of retinal neovascularization in diabetes. J Vasc Res 2001;38:527–535.

28Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998;116:874–886 (erratum published in Arch Ophthalmol 1998;116:1469).

29Lu M, Amano S, Miyamoto K, Garland R, Keough K, Qin W, Adamis AP: Insulin-induced vascular endothelial growth factor expression in retina. Invest Ophthalmol Vis Sci 1999;40:3281–3286.

30Punglia RS, Lu M, Hsu J, Kuroki M, Tolentino MJ, Keough K, Levy AP, Levy NS, Goldberg MA, D’Amato RJ, Adamis AP: Regulation of vascular endothelial growth factor expression by insulinlike growth factor I. Diabetes 1997;46:1619–1626.

31Poulaki V, Qin W, Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP: Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxiainducible factor-1 and VEGF. J Clin Invest 2002;109:805–815.

32Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796–1806.

33Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9. Ophthalmology 1991;98(suppl):766–785.

34Aiello LP: Clinical implications of vascular growth factors in proliferative retinopathies. Curr Opin Ophthalmol 1997;8:19–31.

35Duh E, Aiello LP: Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 1999;48:1899–1906.

36Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003;9:669–676.

37Poulsen JE: Recovery from retinopathy in a case of diabetes with Simmonds’ disease. Diabetes 1953;2:7–12.

38Poulsen JE: Diabetes and anterior pituitary insufficiency. Final course and postmortem study of a diabetic patient with Sheehan’s syndrome. Diabetes 1966;15:73–77.

39Pi-Sunyer FX, Cushman P Jr: Sheehan’s syndrome and diabetes mellitus: observations on the Houssay phenomenon in man. Am J Med Sci 1972;264:143–147.

40Lundbaek K, Malmros R, Andersen HC, et al: Hypophysectomy for diabetic angiopathy: a controlled clinical trial; in Goldberg MF, Fine SL (eds): Symposium on the Treatment of Diabetic Retinopathy. Washington, Government Printing Office (Public Health Service publication No 1890), 1968.

41Sharp PS, Fallon TJ, Brazier OJ, Sandler L, Joplin GF, Kohner EM: Long-term follow-up of patients who underwent yttrium-90 pituitary implantation for treatment of proliferative diabetic retinopathy. Diabetologia 1987;30:199–207.

42Hyer SL, Kohner EM: Aspects of growth hormone control in diabetes. Aust NZ J Ophthalmol 1990;18:33–39.

43Balodimos MC: Treatment of diabetic retinopathy: pituitary ablation and retinal photocoagulation. Med Clin North Am 1971;55:989–999.

44Smith LE, Shen W, Perruzzi C, et al: Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999;5:1390–1395.

45Smith LEH, Kopchick JJ, Chen W, et al: Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 1997;276:1706–1709.

46von Wichert G, Jehle PM, Hoeflich A, Koschnick S, Dralle H, Wolf E, Wiedenmann B, Boehm BO, Adler G, Seufferlein T: Insulin-like growth factor-I is an autocrine regulator of chromogranin. A secretion and growth in human neuroendocrine tumor cells. Cancer Res 2000;60: 4573–4581.

47von Wichert G, Haeussler U, Greten FR, Kliche S, Dralle H, Boehm BO, Adler G, Seufferlein T: Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells. Oncogene 2005;24:1284–1289.

48Klisovic DD, O’Dorisio MS, Katz SE, Sall JW, Balster D, O’Dorisio TM, Craig E, Lubow M: Somatostatin receptor gene expression in human ocular tissues: RT-PCR and immunohistochemical study. Invest Ophthalmol Vis Sci 2001;42:2193–2201.

49Patel YC: Somatostatin and its receptor family. Front Neuroendocrinol 1999;20:157–198.

50Baldysiak-Figiel A, Jong-Hesse YD, Lang GK, Lang GE: Octreotide inhibits growth factorinduced and basal proliferation of lens epithelial cells in vitro. J Cataract Refract Surg 2005;31: 1059–1064.

51Baldysiak-Figiel A, Lang GK, Kampmeier J, Lang GE: Octreotide prevents growth factor-induced proliferation of bovine retinal endothelial cells under hypoxia. J Endocrinol 2004;180:417–424.

52Sall JW, Klisovic DD, O’Dorisio MS, Katz SE: Somatostatin inhibits IGF-1 mediated induction of VEGF in human retinal pigment epithelial cells. Exp Eye Res 2004;79:465–476.

53Grant MB, Caballero S: Somatostatin analogues as drug therapies for retinopathies. Drugs Today (Barc) 2002;38:783–791.

54Boehm BO, Lustig RH: Use of somatostatin receptor ligands in obesity and diabetic complications. Best Pract Res Clin Gastroenterol 2002;16:493–509.