Insulin Signaling Via Retinal Pericytes, New Insights and Potential Implications in Diabetic Retinopathy.

Since the discovery of insulin 100 years ago, countless breakthroughs and discoveries in diabetes pathophysiology and therapeutics have been achieved, transforming the outlook for patients living with diabetes. However, several diabetes-related complications remain problematic, affecting the livelihood and quality of life of affected individuals. Understanding the pathophysiological processes leading to these complications is the foundational step for solution discovery.

Diabetic retinopathy (DR) represents a significant morbidity in people with diabetes, with nearly 35% being affected and ~12% reach vision-threatening advanced DR (1). These figures are more alarming when taking into consideration the accelerated rate of diabetes incidence around the world, estimated to reach 700 million by 2045 (1). Improvement in the standards of diabetes care including glucose, lipids, and blood pressure management result in reduction in macrovascular and microvascular complications including DR, whereas screening programs enable early detection and thus timely intervention and treatment (2, 3). Advancements in therapeutic interventions including laser therapy, intravitreal anti-vascular endothelial growth factor injections, and intraocular steroid implants have significantly improved the outcomes in many people affected by DR (4). However, despite these treatments, DR continues to be the leading cause for blindness in the working age people worldwide (1). A lot of progress has been made in understanding the pathophysiology of DR with several metabolic pathways being implicated including hexosamine pathway, protein kinase C pathway, and polyol pathways, in addition to accumulation of advanced glycation end-products and loss of pericytes in the retinal vasculature (4).

Pericytes play crucial role in vascular development, evidenced by embryonic fatality of a mouse model with near total pericyte depletion (5), whereas pericyte depletion in already formed vasculature in adults does not show such an effect (6). Several functions of pericytes have been elucidated including regulation of blood flow, maintenance of the blood–brain barrier, and control of vascular development and expansion (7), indicating the important role they play in vascular development and function. Although loss of pericytes is considered one of the hallmarks of DR (4), Warmke and colleagues sought to evaluate the effect of pericyte dysfunction, rather than depletion, on retinal vascular health when insulin signaling is disrupted in pericytes (8). To study this, the team used a novel pericyte insulin receptor knockout model termed PIRKO mice, with selective deletion of insulin receptor in pericytes using a cre-lox conditional deletion system in platelet-derived growth factor receptor-β expressing pericytes. In this PIRKO mouse model, Warmke and colleagues demonstrated several pathologies in the retina at an early stage of mouse development that resemble DR when compared with control mice. These changes included increase in retinal veins diameter, increase in capillary branching in retinal periphery, increased retinal venous plexus density, as well as increased vessel sprouting, whereas the retinal arterial plexus was unaffected. Moreover, there was evidence of reduced angiopoitin1-Tie2 signaling in the endothelium, with decrease in angiopoietin 1 expression and increase in angiopoietin 2 expression leading to increase in venous development. A concordant result was noted in human brain pericytes when partial silencing of insulin receptor was attained in vitro, which led to reduced secretion of angiopoietin 1 and reduced ability to activate Tie2 in human umbilical vein endothelial cell line (8). Interestingly, although glucose levels were not different in PIRKO mice in comparison to control mice, there was a significant increase in insulin level, indicating a state of insulin resistance, the cause of which was not clear. It was not clear whether this was a compensatory mechanism in an attempt to achieve adequate insulin signaling in affected pericytes or whether this represents a new mechanism for insulin resistance, a phenomenon that certainly merits further research because the conducted experiments by Warmke and colleagues were not designed to answer these questions.

Despite the debate regarding the presence of different pericyte phenotypes (6), these experiments demonstrated that disruption to insulin signaling in platelet-derived growth factor receptor-β + pericytes of normoglycemic mice at the embryonic stage results in capillary dysfunction and developmental anomalies that are similar to that in the retinae of people with DR. Although this does not confirm the presence of such pathophysiological processes in DR in humans, nor does it confirm similar effects will be seen in already developed retina; the findings presented by Warmke and colleagues open the door to a new avenue for research involving insulin receptor signaling and retinal pericyte activity, with promising possibilities of novel diagnostic and prognostic biomarkers and therapy approaches to DR. As Warmke and colleagues point out, it will be important to study role of insulin receptor in pericytes of animals with different stages of DR as well as evaluating insulin receptor role in pericytes in human retina with DR. These findings also raise questions regarding the role of insulin receptor dysfunction in pericytes in other tissues such as the kidneys, the nervous system, and the cardiovascular system and whether manipulation of insulin receptor can modify the pathophysiological process that leads to organ dysfunction. Moreover, the interesting observation of insulin resistance state with normoglycemia in the PIRKO mouse raises queries about the role of pericyte dysfunction in different states of insulin resistance, such as polycystic ovarian syndrome, metabolic syndrome, gestational diabetes, and type 2 diabetes. Finally, based on the reported findings by Warmke and colleagues in the retinal vasculature, selective insulin receptor manipulation in different cell phenotypes in different tissues would offer an exciting opportunity to gain a deeper understanding of the role of insulin signaling in these tissues and its role in organ pathophysiology, a knowledge that would be of great value for potential future therapy solutions.