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

Glycation is one of the most important posttranslational 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 proglycating conditions on adipogenesis and adipocyte's insulin responsiveness. Our results show that chronic proglycating treatments with methylglyoxal (MGO) and MGO-modified BSA (BSA-MGO) do not display cytotoxicity but modify gene expression without affecting 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 proglycating 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. NEW & NOTEWORTHY Intracellular AGEs accumulation increases RAGE and GLP1R and reduces glucose uptake in adipocytes.

Automated summary

The accumulation of intracellular AGEs increases the expression of RAGE and GLP1R while reducing glucose uptake in adipocytes, suggesting a potential link between alterations in GLP1 signaling and insulin resistance. Further research is needed to clarify the role of this pathway and whether reducing AGEs accumulation in adipocytes can improve insulin responsiveness.