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Abstract
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.
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1 The University of Queensland (MRI-UQ), Glycation and Diabetes Complications, Mater Research Institute, Translational Research Institute (TRI), Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); The University of Queensland, Faculty of Medicine, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); Griffith University, School of Medicine and Dentistry, Brisbane, Australia (GRID:grid.1022.1) (ISNI:0000 0004 0437 5432); Wesley Research Institute, The Wesley Hospital, Brisbane, Australia (GRID:grid.417021.1) (ISNI:0000 0004 0627 7561)
2 University of Tennessee Health Science Center, Division of Endocrinology, Department of Medicine, Memphis, USA (GRID:grid.267301.1) (ISNI:0000 0004 0386 9246)
3 University of Miami, Division of Endocrinology, Department of Microbiology and Immunology, Department of Medicine, Diabetes Research Institute, Miller School of Medicine, Miami, USA (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606)
4 The University of Queensland (MRI-UQ), Glycation and Diabetes Complications, Mater Research Institute, Translational Research Institute (TRI), Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); The University of Queensland, Faculty of Medicine, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537)
5 The University of Queensland, Faculty of Medicine, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); MRI-UQ, TRI, Translational Bioinformatics Group, Brisbane, Australia (GRID:grid.489335.0) (ISNI:0000000406180938)
6 The University of Queensland, Faculty of Medicine, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); Mater Health Services, Queensland Diabetes Centre, Brisbane, Australia (GRID:grid.1491.d) (ISNI:0000 0004 0642 1746)
7 The University of Queensland, Faculty of Medicine, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); MRI-UQ, TRI, Cancer Immunotherapies Group, Brisbane, Australia (GRID:grid.489335.0) (ISNI:0000000406180938)