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

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.