Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN β‐cell line and human islets of Langerhans

• Published in: The FASEB journal 2003-07, Vol.17 (10), p.1340-1342
• Main Authors: Hribal, Marta L., Perego, Lucia, Lovari, Sarah, Andreozzi, Francesco, Menghini, Rossella, Perego, Carla, Finzi, Giovanna, Usellini, Luciana, Placidi, Claudia, Capella, Carlo, Guzzi, Valeria, Lauro, Davide, Bertuzzi, Federico, Davalli, Alberto, Pozza, Guido, Pontiroli, Antonio, Federici, Massimo, Lauro, Renato, Brunetti, Antonio, Folli, Franco, Sesti, Giorgio
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Carrier Proteins - metabolism; Cell Cycle Proteins; Cell Line; diabetes; Glucose - pharmacology; glucose toxicity; HMGA1a Protein - metabolism; Humans; Insulin - biosynthesis; Insulin - metabolism; Insulin Receptor Substrate Proteins; Insulin Secretion; Intracellular Signaling Peptides and Proteins; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Models, Biological; Pancreas - chemistry; Pancreas - ultrastructure; pancreatic islets; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptor, Insulin - analysis; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; RNA Splicing; Signal Transduction; Transcription, Genetic
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.02-0685fje

ABSTRACT Recent evidence suggests that insulin signaling through the insulin receptor A type (Ex11−), regulates insulin gene transcription. Because chronic hyperglycemia negatively affects insulin receptor function and regulates alternative splicing of the insulin receptor, we inquired whether chronic exposure of pancreatic β‐cells to high glucose results in alterations in insulin signaling due to changes in insulin receptor expression and relative abundance of its spliced isoforms. Our results demonstrate that the insulin receptor is localized in insulin secretory vescicles in human pancreatic β‐cells. Furthermore, we find that alterations in insulin expression and secretion caused by chronic exposure to high glucose are paralleled by decreased insulin receptor expression and increased relative abundance of the Ex11+ isoform in both human islets and RIN β‐cells. PDX‐1 and HMGI(Y) transcription factors are down‐regulated by high glucose. These changes are associated with defects in insulin signaling involving insulin receptor‐associated PI 3‐kinase/Akt/PHAS‐I pathway in RIN β‐cells. Re‐expression in RIN β‐cells chronically exposed to high glucose of the Ex11−, but not the Ex11+, isoform restored insulin mRNA expression. These data suggest that changes in early steps of insulin receptor signaling may play a role in determining β‐cell dysfunction caused by chronic hyperglycemia.