In vitro chronic glycation induces AGEs accumulation reducing insulin stimulated glucose uptake and increasing GLP1R in adipocytes

Glycation is one of the most important post-translational modifications in cells and tissues and gives rise to highly reactive species called advanced glycation end products (AGEs). AGEs exert their pathological effects through different ways and previous reports suggest that they may also affect adipose tissue function and insulin sensitivity. All the data belong only to short-term treatments; however, in vivo glycation is a continuous process. To fill this gap, our study investigated the effect of chronic pro-glycating conditions on adipogenesis and adipocyte's insulin responsiveness. Our results show that chronic pro-glycating treatments with methylglyoxal (MGO) and MGO modified-BSA (BSA-MGO) do not display cytotoxicity but modify gene expression without affect adipogenic differentiation. These treatments induce different levels of intracellular accumulation of AGEs which colocalize with the insulin-sensitive glucose transporter GLUT4 (solute carrier family 2 member 4- SLC2A4) in the cytoplasm; in particular, BSA-MGO reduces glucose uptake. Moreover, the adipocytes differentiated in pro-glycating conditions display an enhancement in the protein expression of the receptor for advanced glycation end products (RAGE) and glucagon-like peptide 1 receptor (GLP1R). These results suggest that intracellular AGEs could link alterations in GLP1 signaling and insulin resistance in adipose tissue, revealing that GLUT4 protein can be susceptible to glycation. Further studies are needed to clarify if this pathway could be targeted and if the reduction of AGEs accumulation in adipocytes can ameliorate insulin responsiveness.