Hormetic modulation of hepatic insulin sensitivity by advanced glycation end products

- Despite inducing whole-body insulin resistance, chronic administration of AGEs increased insulin sensitivity in the liver.
- AGEs also decreased hepatic expression of pro-inflammatory and pro-oxidative genes.
- A mechanism that explains these findings is the activation of AKT and inactivation of GSK3β, which increased nuclear NRF2.
- AGEs were protective when given chronically, stimulating a pathway involved in both cellular defense and insulin sensitivity.

Because of the paucity of information regarding metabolic effects of advanced glycation end products (AGEs) on liver, we evaluated effects of AGEs chronic administration in (1) insulin sensitivity; (2) hepatic expression of genes involved in AGEs, glucose and fat metabolism, oxidative stress and inflammation and; (3) hepatic morphology and glycogen content. Rats received intraperitoneally albumin modified (AlbAGE) or not by advanced glycation for 12 weeks. AlbAGE induced whole-body insulin resistance concomitantly with increased hepatic insulin sensitivity, evidenced by activation of AKT, inactivation of GSK3, increased hepatic glycogen content, and decreased expression of gluconeogenesis genes. Additionally there was reduction in hepatic fat content, in expression of lipogenic, pro-inflamatory and pro-oxidative genes and increase in reactive oxygen species and in nuclear expression of NRF2, a transcription factor essential to cytoprotective response. Although considered toxic, AGEs become protective when administered chronically, stimulating AKT signaling, which is involved in cellular defense and insulin sensitivity.