Alpha cell receptor for advanced glycation end products associate with glucagon expression in type 1 diabetes

• Published in: Scientific reports 2023-08, Vol.13 (1), p.12948-12948, Article 12948
• Main Authors: Leung, Sherman S., Lenchik, Nataliya, Mathews, Clayton, Pugliese, Alberto, McCarthy, Domenica A., Le Bagge, Selena, Ewing, Adam, Harris, Mark, Radford, Kristen J., Borg, Danielle J., Gerling, Ivan, Forbes, Josephine M.
• Format: Article
• Language: English
• Subjects: 692/163/2743; 692/308/3187; 692/699/2743/137/138; 692/699/2743/137/1418; Advanced glycosylation end products; Bioinformatics; Confocal microscopy; Diabetes; Diabetes mellitus (insulin dependent); Generalized linear models; Glucagon; Glycosylation; Humanities and Social Sciences; Hypoglycemia; Ligands; multidisciplinary; Pancreas; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-39243-x

Hypoglycemia in type 1 diabetes associates with changes in the pancreatic islet α cells, where the receptor for advanced glycation end products (RAGE) is highly expressed. This study compared islet RAGE expression in donors without diabetes, those at risk of, and those with type 1 diabetes. Laser-dissected islets were subject to RNA bioinformatics and adjacent pancreatic tissue were assessed by confocal microscopy. We found that islets from type 1 diabetes donors had differential expression of the RAGE gene ( AGER ) and its correlated genes, based on glucagon expression. Random forest machine learning revealed that AGER was the most important predictor for islet glucagon levels. Conversely, a generalized linear model identified that glucagon expression could be predicted by expression of RAGE signaling molecules, its ligands and enzymes that create or clear RAGE ligands. Confocal imaging co-localized RAGE, its ligands and signaling molecules to the α cells. Half of the type 1 diabetes cohort comprised of adolescents and a patient with history of hypoglycemia—all showed an inverse relationship between glucagon and RAGE. These data confirm an association between glucagon and islet RAGE, its ligands and signaling pathways in type 1 diabetes, which warrants functional investigation into a role for RAGE in hypoglycemia.