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 beta-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 beta-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 beta-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 beta-cells. Re-expression in RIN beta-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 beta-cell dysfunction caused by chronic hyperglycemia.

Hribal, M., Perego, L., Lovari, S., Andreozzi, F., Menghini, R., Perego, C., et al. (2003). Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans. THE FASEB JOURNAL, 17(10), 1340-1342 [10.1096/fj.02-0685fje].

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

MENGHINI, ROSSELLA;LAURO, DAVIDE;FEDERICI, MASSIMO;LAURO, RENATO;BRUNETTI, ADALBERTO;SESTI, GIORGIO
2003-07-01

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 beta-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 beta-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 beta-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 beta-cells. Re-expression in RIN beta-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 beta-cell dysfunction caused by chronic hyperglycemia.
lug-2003
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/13 - ENDOCRINOLOGIA
Settore MED/09 - MEDICINA INTERNA
Settore MED/49 - SCIENZE TECNICHE DIETETICHE APPLICATE
Settore MED/50 - SCIENZE TECNICHE MEDICHE APPLICATE
English
Con Impact Factor ISI
Ribosomal Protein S6 Kinases, 70-kDa; Carrier Proteins; Intracellular Signaling Peptides and Proteins; RNA Splicing; Pancreas; Humans; Glucose; HMGA1a Protein; Proto-Oncogene Proteins c-akt; Transcription, Genetic; Islets of Langerhans; Protein-Serine-Threonine Kinases; Insulin Receptor Substrate Proteins; Models, Biological; Protein Isoforms; Phosphatidylinositol 3-Kinases; Insulin; Proto-Oncogene Proteins; Phosphoproteins; Adaptor Proteins, Signal Transducing; Receptor, Insulin; Signal Transduction; Cell Line
Hribal, M., Perego, L., Lovari, S., Andreozzi, F., Menghini, R., Perego, C., et al. (2003). Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans. THE FASEB JOURNAL, 17(10), 1340-1342 [10.1096/fj.02-0685fje].
Hribal, M; Perego, L; Lovari, S; Andreozzi, F; Menghini, R; Perego, C; Finzi, G; Usellini, L; Placidi, C; Capella, C; Guzzi, V; Lauro, D; Bertuzzi, F; Davalli, A; Pozza, G; Pontiroli, A; Federici, M; Lauro, R; Brunetti, A; Folli, F; Sesti, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/53669
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