Abstract
Advanced glycation end products (AGEs) might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs), in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2), glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS.
Highlights
Pancreatic beta cell dysfunction is a key pathophysiological target in diabetes mellitus [1,2,3]
It has been reported that both GSH synthesis and GSR expression are regulated by nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a basic leucine zipper transcription factor that in response to oxidative stress translocates to the nucleus
Since lower levels of GSH were found in mice lacking the transcriptional repressor Nrf2 [24], which is implicated in the regulation of detoxification enzymes [25], we investigated whether Nrf2 expression was affected by glycated serum (GS) and/or Glucagonlike peptide-1 (GLP-1). mRNA expression of Nrf2 was not affected by the incubation with GS in the presence or absence of GLP-1 (Figures 2(a) and 2(b))
Summary
Pancreatic beta cell dysfunction is a key pathophysiological target in diabetes mellitus [1,2,3]. It is well known that a long-lasting deleterious effect of hyperglycemia persists independently of the level of glucose [7,8,9]. This “memory” might be explained by the persistent overproduction of reactive oxygen species (ROS) directly induced by AGEs via the activation of their receptors [10]. The increase in pancreatic beta-cell responsiveness to oxidants [11, 12] might result in a decreased nuclear availability of the regulators of insulin promoters PDX-1 (pancreatic and duodenal homeobox-1) and MafA (v-maf musculoaponeurotic fibrosarcoma oncogene homologue A) [13,14,15,16]. It has been reported that both GSH synthesis and GSR expression are regulated by nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a basic leucine zipper transcription factor that in response to oxidative stress translocates to the nucleus
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