INS and diabetes mellitus: During diabetes, however, certain anomalies in the metabolic pathways (i.e., prolonged activation and production of advanced glycation end-products and their receptors; AGE/RAGE system) may contribute to insulin resistance, which could ultimately impact the ECM architecture and reduce the insulin-stimulated VEGF expressions in the heart; thereby, possibly explaining the observed anti-angiogenic phenotype [33,34,35].