Background: Type 2 diabetes is associated with enhanced hepatic gluconeogenesis exacerbating hyperglycaemia as a result of increased production and release of glucagon by pancreatic alpha cells.  We recently identified a nuclear isoform of the receptor for advanced glycation end products (RAGE), which shows DNA regulatory capacity and can bind to consensus sequences in the promoter region of the  preproglucagon gene (in the promoter region or where?). Therefore the aim of this project was to investigate the role of RAGE in the transcriptional control of preproglucagon.

Method and Results: Male wild-type (WT) and RAGE deficient (RAGE-/-) mice were fed chow or a high fat diet for 16 weeks. RAGE-/- gained more body weight and % adipose tissue than corresponding WT groups (WT Control Δ 2.9 (± 2.1) vs RAGE-/- Control (Δ 8.3 (± 2.1) p<0.05, WT HFF Δ 11.0 (± 21.6) vs RAGE-/- HFF (Δ 15.4 (± 2.2) p<0.05,). Fasting plasma glucose and insulin concentrations were also increased in RAGE -/- mice and were exacerbated by obesity as a result of high fat feeding.  During insulin tolerance testing (ipITT) in the fasted state, RAGE -/- mice had increased plasma glucose concentrations.  Oral and intraperitoneal glucose tolerance testing revealed glucose intolerance and hyperinsulinaemia as well hyperglucagonemia  (AUC Glucagon, WT Control, 742.6 (± 0.78) v AUC RAGE-/- Control, 828.7 (± 0.74), p<0.01). Plasma lactate concentrations during i.pGTT were also elevated in RAGE-/- mice (AUC Lactate, WT Control, 41.9 (± 0.51) v AUC WT HFF 53.3 (± 0.67) p<0.05). RAGE expression in pancreatic islet alpha cells was also decreased in the context of obesity. Nuclear RAGE binding activity in the promoter region of the preproglucagon gene (via electro mobility shift assays (EMSA)) to various oligonucleotide consensus sequences and mutated counterparts was decreased with high fat feeding and obesity in the context of hyperglucagonaemia, suggesting negative regulation of the gene by RAGE. 

Conclusion: A loss of RAGE expression in pancreatic islet cells, may perturb hyperglucagonaemia in obesity by reducing the capacity to suppress preproglucagon expression.   Hence RAGE could be an important regulatory protein for alpha cell glucagon production and hepatic gluconeogenesis.