Diabetic retinopathy (DR) is the most common cause of blindness in working-age humans, and numbers are rising due to increased cases of type 2 diabetes (T2D). T2D is associated with increased obesity and dyslipidaemia, which is a major risk factor for DR. Adipocytes secrete several factors that affect the immune system and these molecules known as adipokines are now widely studies. Angiopoietin-like protein-4 (ANGPTL-4) is an adipokine that the authors have previously shown correlated with angiogenesis in patients with DR. ANGPTL4 is induced under hypoxic conditions and Peroxisome Proliferator Activated receptors, and acts as an endogenous inhibitor of lipoprotein lipase and its regulation by fatty acids. In this study diabetic (streptozocin treated Sprague-Dawley) or control rats were challenged with doxorubicin or shRNA to inhibit HIF-1α Human retinal microvascular endothelial cells were treated with normal or high glucose, and with or without blockade of several molecules in the ANGPTL-4 pathway. The results showed that levels of ANGPTL-4, profilin-1, HIF-1α and VEGF mRNA and protein were significantly raised in diabetic rats and human cells treated with high glucose. Hyperglycaemia induced increased expression of several inflammatory factors including IL-1β IL-6 and ICAM-1, which correlated with increased expression of ANGPTL4. Inhibition of ANGPTL-4 led to significant reduction of these inflammatory molecules. These results show that high glucose levels induce increased HIF-1α expression, and in turn ANGPTL-4 production. Inhibition of this pathway reduced inflammation in diabetic rats and human retinal cells and may be a therapeutic target to control DR.