Somatostatin and diabetic retinopathy: current concepts and new therapeutic perspectives
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- Hernández, C., Simó-Servat, O. & Simó, R. Endocrine (2014) 46: 209. doi:10.1007/s12020-014-0232-z
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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.
KeywordsDiabetic retinopathyRetinal neurodegenerationNeovascularizationVascular leakageSomatostatinSomatostatin receptorsCortistatinEye drops
Diabetic retinopathy (DR) is the leading cause of visual impairment and preventable blindness [1, 2] and represents a significant socio-economic cost for healthcare systems worldwide [3–5]. Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina. However, there is growing evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR which participates in the microcirculatory abnormalities that occur in DR . The retina synthesizes neuroprotective factors which counteract the deleterious effects of neurotoxic factors involved in neurodegeneration . The loss of these neuroprotective factors or the reduction of their effectiveness is essential for the development of retinal neurodegeneration. Among the neuroprotective and neurotrophic factors, somatostatin (SST) is one of the most relevant.
The main aim of this article is to provide an overview of the role of SST in DR with especial emphasis in its potential therapeutic implications.
The somatostatinergic system in the retina and its role in the pathogenesis of DR
SST was isolated in 1973 as a tetradecapeptide from ovine hypothalamus and identified by its action as an inhibitor of GH release . However, it is now well known that SST is ubiquitously distributed and its diverse biological functions include neurotransmission, as well as antisecretory and antiproliferative activities . There are two predominantly biologically active forms of SST: SS-14 (1.6 kDa) and SST-28 (3.1 kDa). These two products are generated by endoproteolytic processing of the prohormone prosomatostatin, which, in turn, is generated from a precursor called preprosomatostatin .
Prosomatostatin is produced in the retina of all species studied, but a differential expression of SST-14 and SST-28 has been observed. Thus, whereas in chicken and hog, the relative distribution of the two molecular forms has been reported similar  in other species such as in goldfish , frogs , rats [13, 14], and rabbits  SST-14 seems the predominant molecular form synthesized by the retina. By contrast, SST-28 is the major form in the guinea pig , bovine , and human retina . In the mammalian retina, SST immunoreactivity has been reported in the neuroretina, mainly in GABAergic amacrine cells [19, 20]. However, we have found that SST expression is higher in the retinal pigment epithelium (RPE) than in the neuroretina from human eye donors . The amount of SST produced by the human retina is significant as is reflected by the strikingly high levels found in the vitreous fluid. Remarkably, intravitreal SST levels are four-fold higher than plasma levels in non-diabetic subjects [18, 22], suggesting that SST exerts an important role in retinal homeostasis.
The physiological actions of SST are mediated by five high-affinity membrane-bound G-protein-coupled receptors (SSTR-1 to SSTR-5). SSTR can be divided into two groups according to their structural and functional characteristics (SSTRs 1 and SSTRs 2). SSTRs 1 (which comprise SSTR-2, SSTR-3 and SSTR-5) and SSTRs 2 (which comprise SSTR-1 and SSTR-4) differ in their selectivity of binding of short synthetic SST analogs, as well as on the basis of amino acid homologies [23–25]. SST-14 and SST-28 interact with SSTR1-4 with similar affinity. However, this is not the case with SSTR-5 which displays up to a 10-fold higher affinity for SST-28 [26, 27].
Cortistatin (CST) is a recently discovered neuropeptide that shows a remarkable sequential resemblance to SST but is encoded by a different gene . CST binds to SSTRs and, consequently, shares several pharmacological and functional properties with SST .
In the diabetic retina, there is a downregulation of SST  and CST . The reason why a reduced production of SST and CST exists in the diabetic eye remains to be elucidated, but it seems reasonable to postulate that it occurs as a consequence of neuroretinal damage induced by the diabetic milieu. In fact, a loss of SST immunoreactivity occurs after degeneration of the retinal ganglion cell layer (GCL) . In this regard, it should be mentioned that GCL is the layer with the highest rate of apoptosis in the retinas from diabetic murine models as well as in diabetic subjects [21, 31, 32]. The lower production of SST in the retina is associated with a dramatic decrease of intravitreal SST levels in both diabetic patients with proliferative diabetic retinopathy (PDR) [18, 22] and with diabetic macular edema (DME) .
There is mounting evidence suggesting that SST could play a key role in preventing the main pathogenic mechanisms involved in DR: neurodegeneration, neovascularization, and vascular leakage.
Glutamate is the major excitatory neurotransmitter in the retina, and it has been found elevated in the extracellular space in experimental models of diabetes [34–36], as well as in the vitreous fluid of diabetic patients with PDR [37, 38]. This extracellular and synaptic excess of glutamate leads to overactivation of ionotropic glutamate receptors, mainly alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-d-aspartame (NMDA) receptors, which results in an uncontrolled intracellular calcium response in postsynaptic neurons and cell death [39, 40]. This deleterious effect of glutamate on retinal neurons is known as “excitotoxicity.” Glutamate transporters are essential for keeping the extracellular glutamate concentration below neurotoxic levels . In this regard, the expression of the glutamate/aspartate transporter (GLAST), the main glutamate transporter of the mammalian retina, is downregulated in rat retinas with diabetes induced by STZ [41, 42], thus favoring glutamate-mediated excitotoxicity.
Notably, SST reduces glutamate release through inhibition of neuronal Ca2+ currents in rods and bipolar cells [43–45]. However, SST elevates rather than inhibits Ca2+ currents in cones . On the other hand, it has been reported that SST inhibits potassium-evoked glutamate release without affecting basal glutamate release . Moreover, activation of SSTRs influences glutamate levels indirectly via the regulation of other neurotransmitter systems found in the retina, such as dopamine  and nitric oxide (NO) . Furthermore, SST increases cGMP which is an important regulator of retinal physiology, via the NO mechanism . Alternatively, dopamine receptor activation and nitrinergic agents regulate SST levels in the retina .
Retinal ischemia, the main condition for the initiation of PDR, is a major cause of neuronal death . There is experimental evidence suggesting that SST and its analogs, mainly acting through SSTR-2, exert potent neuroprotective effect from ischemic damage [43, 52–54]. In addition, it has been reported that the activation of SSTR-2 limits VEGF release under ischemic conditions . Finally, it should be noted that SST analogs administered intravitreally protect the retina from AMPA-induced neurotoxicity .
Recently, we found that topical treatment with SST eye drops prevents neurodegeneration in diabetic rats . One of the main mechanisms involved in this effect was the reduction of glutamate accumulation by upregulation of the GLAST.
The study of the molecular mechanisms by which SST induces a neuroprotective effect could also be transferred to other neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson disease. Retinal neurodegeneration in the setting of DR shares common pathogenic mechanisms with AD. For instance, excitotoxicity by glutamate via NMDA receptors is a neurotoxic mechanism involved in AD . Furthermore, the brain’s production of SST is also decreased in neurodegenerative disorders such as AD and Parkinson’s disease .
SST and its analogs may reduce endothelial cell proliferation and neovascularization by multiple mechanisms including the inhibition of postreceptor signaling events of peptide growth factors such as IGF-I, VEGF, epidermal growth factor, bFGF, and PDGF [59–62]. Moreover, using mouse retinal explants, it has also been demonstrated that octreotide (a SST analog) prevents hypoxia-induced activation of STAT3 and HIF-1 and the downstream increase in VEGF expression .
It has been demonstrated that SSTR-2 activation may protect against angiogenesis using transgenic mice . In addition, intravitreal administration of non-peptide imidazolidine-2,4-dione somatostatin receptor agonists (NISAs) inhibited retinal neovascularization in the laser model of choroidal neovascularization . The antiangiogenic effect of SST on DR models has not been investigated. In this regard, it must be stressed that murine diabetic models do not reproduce retinal neovascularization in a consistent manner. For this reason, other non-diabetic models that mimic the neovascularization are commonly used to study the pathogenesis of proliferative DR and potential treatments .
Regulation of water and ions transport
SST and SST analogs have been largely used due to their inhibitory effects on gastrointestinal secretions . In addition, it has been reported that SST regulates water permeability in the kidney . However, the potential anti-permeability effect of SST in the retina has been little studied. Various ion/water transport systems are located on the apical side of the RPE adjacent to the subretinal space, and a high expression of SST-2 has been shown in this apical membrane of the RPE . Therefore, SST could play a role in preventing DME. In this regard, it has been demonstrated that SST has a significant protective effect on RPE disruption (which constitutes the outer blood retinal barrier), caused by conditions mimicking the diabetic milieu .
Somatostatin for treatment of diabetic retinopathy: clinical studies
Pilot studies using SST analogs administered intramuscularly in patients with early PDR and severe NPDR have revealed a decreased incidence of progression to PDR requiring panretinal laser treatment  or vitreo-retinal surgery . In addition, some reports have suggested that SST analogs could also be beneficial in DME treatment [73, 74]. The rationale for using SST in these studies was based on the SST inhibition of circulating IGF-1. However, the role of serum IGF-1 in the development of DR is controversial and this concept has not been supported by clinical intervention trials [75, 76]. A Phase III clinical trial using long-acting octreotide given intramuscularly every 4 weeks in moderate-to-severe NPDR to low-risk PDR was conducted to shed light on this issue , and the results revealed a lack of effectiveness in arresting DR progression. The reasons behind the lack of success of this clinical trial could be: (1) Regional IGF-1 concentrations in the retina may be more important than systemic levels. However, both mRNA and protein levels of IGF-1 have been found lower in the retinas of diabetic donors in comparison with age-matched non-diabetic donors [78, 79], which means that intraocular production of IGF-1 can hardly be involved in the development of DR. (2) The effects of SST synthesized by the retina involve SSTR subtypes other than SSTR2 for which latter octreotide has a very high affinity. (3) Octreotide does not cross the BRB and has access to the retina only when and where there is a breakdown of the BRB, thus limiting the amount of the drug reaching the retinal target tissues. For all these reasons, a replacement treatment with SST or SST analogs locally administered has been proposed as a new therapeutic approach in DR .
Since SST analogs may have inadequate penetration of the BRB barrier after systemic administration and poor tissue distribution in the retina, local delivery of SST or SST agonists might be a rational approach to DR treatment . Moreover, intraocular delivery has the added benefit of providing less systemic exposure and thus potentially fewer side effects. However, when the early stages of DR are the therapeutic target, it would be inconceivable that an aggressive treatment such as intravitreous injections be recommended. To date, the use of eye drops has not been considered a good route for the administration of drugs addressed to preventing or arresting DR. This is because it is generally assumed that they do not reach the posterior chamber of the eye (i.e., the vitreous and the retina). However, this is a misleading concept and there is emerging experimental evidence that eye drops are useful in several diseases of the retina including DR . In this regard, we have recently demonstrated that SST reaches the vitreous and the retina after topical administration and prevents retinal neurodegeneration in diabetic rats .
A multicentric, phase II-III, randomized controlled clinical trial (EUROCONDOR-278040) to assess the efficacy of brimonidine and SST administered topically (eye drops) to prevent or arrest retinal neurodegeneration and its effect on the development and progression of microvascular impairment was approved by the European Commission in the setting of the FP7-HEALTH.2011. This trial started in February 2013, and recruitment finished in November 2013. The final results should be available in 2016.
SST has significant neuroprotective and anti-angiogenic actions in the retina. In view of these relevant SST functions in the retina and the reduction of SST production in the diabetic eye, the treatment of DR with SST should be contemplated as a replacement treatment rather than a therapy focused on the lowering of systemic IGF-1. For this purpose, intraocular administration of SST might be a good approach. However, clinical trials on this issue are still required. In addition, intraocular injection is a too much 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 should provide useful information.
In summary, 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 effectiveness and safety of targeting SST in the treatment of this disabling complication of diabetes.
This study was supported by Grants from 7th Framework Program (EUROCONDOR. FP7-278040), from the Spanish Ministerio de Economía y Competitividad (SAF2012-35562), and from the Generalitat de Catalunya (2009SGR-739).
Conflicts of interest
The authors declare that they have no conflict of interest.