Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans.
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.
Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome-Tor Vergata, Rome, Italy.
Marta L
ML
Hribal
Lucia
L
Perego
Sarah
S
Lovari
Francesco
F
Andreozzi
Rossella
R
Menghini
Carla
C
Perego
Giovanna
G
Finzi
Luciana
L
Usellini
Claudia
C
Placidi
Carlo
C
Capella
Valeria
V
Guzzi
Davide
D
Lauro
Federico
F
Bertuzzi
Alberto
A
Davalli
Guido
G
Pozza
Antonio
A
Pontiroli
Massimo
M
Federici
Renato
R
Lauro
Antonio
A
Brunetti
Franco
F
Folli
Giorgio
G
Sesti
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D005947:Glucose / Q000494:pharmacology*; D025741:HMGA1a Protein / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D010179:Pancreas / Q000737:chemistry / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012326:RNA Splicing; D011972:Receptor, Insulin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005947:Glucose; D025741:HMGA1a Protein; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C087000:EIF4EBP1 protein, human; C526292:IRS1 protein, human; C526297:IRS2 protein, human; C494918:AKT1 protein, human