Mechanism of worsening diabetic retinopathy with rapid lowering of blood glucose: the synergistic hypothesis

Abstract

Insulin treatment has been associated with a paradoxical worsening of diabetes retinopathy since many years in European cohorts. Recently, this issue has been stressed by some studies conducted in other parts of the world. However, the mechanism underlying such evolution is not well understood. An osmotic theory has been evocated but failed to explain the clinical features of the disease. Considering recent findings from basic and clinical research, we discuss the possibility of a synergistic hypothesis based on the simultaneous action of insulin and vascular endothelial growth factor on eye blood vessels. We postulate that exogenous insulin could act synergistically with the vascular endothelial growth factor expressed by ischemic retina so as to trigger vascular proliferation and the worsening of diabetes retinopathy.

Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review

“…Earlier, we described how rapid reductions in blood glucose affect osmotic pressure and the extracellular and intravascular areas. 27 There was a positive correlation between the magnitude of maximum hyperopic change and the daily rate of plasma glucose reduction over the first 7 days of treatment (P < 0.001), the number of days required for hyperopia to reach its peak (P < 0.001) and the number of days required for the development and resolution of hyperopic changes (P < 0.0001). 64 This correlation alone, however, is insufficient evidence for causation.…”

“…This causes water to move from high to low osmotic pressure levels, with vessels, such as small vessels in the eye, being low‐pressure areas that are particularly sensitive. However, this hypothesis is tentative and requires further investigation …”

“…Thus, changes in blood glucose concentrations can alter osmotic pressure, which in turn affects water retention. Earlier, we described how rapid reductions in blood glucose affect osmotic pressure and the extracellular and intravascular areas . Although evidence for this theory is limited, transient refractive error is associated with tight glycaemic control, relating to the rate of reduction in plasma blood glucose.…”

“…The synergistic hypothesis postulates that early worsening is caused by the synergistic action of insulin and VEGF on blood vessels in the retina, triggering vascular proliferation and, therefore, worsening DR. 27 In an in vitro study, insulin was found to increase reactive oxygen species (ROS) in bovine retinal endothelial cells. This increased insulin-induced ROS production and VEGF expression, in the presence of high glucose, may explain early worsening DR (Table 3).…”

Telemedicine Applications for Screening Diabetic Retinopathy

“…Therefore, the vascular permeability is increased, and vessels in the retina are abnormally proliferated in response to the lack of perfusion. 8 According to the WHO, the prevalence of diabetic retinopathy in the Eastern Mediterranean region is estimated to be in the range of 5% to 15%. 9 In the United States, about 28.5% of diabetic patients have diabetic retinopathy which is the main cause of severe and moderate loss of vision among adults at work age.…”