Berberine improves insulin-induced diabetic retinopathy through exclusively suppressing Akt/mTOR-mediated HIF-1α/VEGF activation in retina endothelial cells

Background: Insulin therapy is the major treatment of glycaemic control in type I diabetes mellitus (DM) and advanced type II DM patients who fail to respond to oral hypoglycemic agents. Nonetheless, insulin therapy is deemed unsuccessful in controlling the incidence of diabetic retinopathy (DR) and is likely a risk factor. Berberine, an isoquinoline alkaloid, has caught great attention towards its anti-diabetic mechanisms. This study aims to investigate the effect of berberine in decelerating DR progression in insulin-treated DM. Methods: To better understand the therapeutic potential of berberine in the presence of insulin, we elaborated the action of mechanism whether berberine inhibited retinal expression of HIF-1 alpha and VEGF through regulating AKT/mTOR pathway. Suppression of insulin-induced neovasculature of retina endothelial cells by berberine was also studied. Lastly, the in vivo efficacy and safety of berberine as adjuvant therapy for the treatment of DR were systemically investigated in experimental type I and type II DM mice with insulin treatment. Results: Among various types of retinal cells, the activity of HIF-1 alpha and VEGF in retinal endothelial cells could be particularly and exclusively stimulated by insulin intervention, which could be inhibited by berberine treatment in a dose- and time-dependent manner. Berberine suppressed Akt/mTOR activity in these cells, and restoration of Akt/mTOR signalling attenuated berberine's inhibition on HIF-1 alpha and VEGF expression. Berberine suppressed the progression of DR in experimental type I and type II diabetic mice receiving insulin therapy. Conclusion: Berberine improves insulin-induced diabetic retinopathy in type I and II diabetes through inhibiting insulin-induced activation of retinal endotheliocytes via Akt/mTOR/ HIF-1 alpha/VEGF pathway.