On implications of somatostatin in diabetic retinopathy

Abstract

Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.

Figure 1

A simplified diagram illustrating the SST-involving pathogenesis of DR. Impairment of retinal neurovascular units, promoted by chronic hyperglycemia and metabolic disorders in the diabetic milieu, may be the onset event of DR. Under a combined hit of declined neuroprotection by peptides such as SST, glutamate excitotoxicity, oxidative damage, neuroinflammation and altered GH/IGF signaling, and diabetic retinal neurodegeneration occurs, characterized by glial activation and neuron death. Pericyte loss, BM thickening, endothelial cell junction breakdown, and hyperpermeability of the microvasculature collectively contribute to the disruption of the BRB. The resultant fluid leaking into the retina and depositing under the macula are manifestations of DMO. Increased release of inflammatory cytokines and pro-angiogenic factors such as VEGF stimulates neovascularization to compensate for retinal blood vessel damage. These immature, fragile, and permeable new vessels cause severe complications such as vitreous hemorrhage or tractional retinal detachment, which are features of PDR. Created with CorelDRAW. AGE: Advanced glycation end products; BM: basement membrane; BRB: blood-retinal barrier; DMO: diabetic macular edema; DR: diabetic retinopathy; EC: endothelial cells; GH: growth hormone; IGF: insulin-like growth factor; NPDR: non-proliferative DR; PDR: proliferative DR; rNVU: retinal neurovascular unit; ROS: reactive oxygen species; SST: somatostatin; VEGF: vascular endothelial growth factor.