Obesity, insulin resistance, metabolic syndrome and type 2 diabetes have reached epidemic proportions, from the term: diabesity. Vitamin A is delivered by a specific binding protein called retinol-binding protein 4 (RBP4) a soluble protein, emerging to have a role in insulin resistance, the major cause of diabetes is highly associated with adipose tissue inflammation and obesity with action. RBP4, interacts with two receptors, the Toll-like receptor 4 (TLR4) and the plasma membrane protein are stimulated by retinoic acid 6 (STRA6), leading to the activation of c-Jun N-terminal protein kinase (JNK) pathways and JAK2/STAT5 cascade, respectively. Both mechanisms sustain insulin resistance. Therefore, ablation of STRA6 protects mice from RBP4-induced suppression of insulin signaling. In addition, mice harboring deletion of a specific chaperon for retinol, show infiltration of α-cells in the core of pancreatic islets, where usually only β-cells reside, showing a pre-diabetic like phenotype. Not only proteins in vitamin A shuttle and signaling are emerging in diabesity, recently, the discovery of 9cis retinoic acid (9cRA) with effects on controlling glucose levels have opened a new scenario. So far, only pancreas β-cells have been shown to synthesize it, and high levels of 9cRA correlate with obesity mice models. In this article, we summarize the recent literature present on this topic raising the hypothesis.