Increased pancreatic islet mass is accompanied by activation of the insulin receptor substrate-2/serine-threonine kinase pathway and augmented cyclin D2 protein levels in insulin-resistant rats.
It is well known that glucocorticoids induce peripheral insulin resistance in rodents and humans. Here, we investigated the structural and ultrastructural modifications, as well as the proteins involved in beta-cell function and proliferation, in islets from insulin-resistant rats. Adult male Wistar rats were made insulin resistant by daily administration of dexamethasone (DEX; 1mg/kg, i.p.) for five consecutive days, whilst control (CTL) rats received saline alone. Structure analyses showed a marked hypertrophy of DEX islets with an increase of 1.7-fold in islet mass and of 1.6-fold in islet density compared with CTL islets (P < 0.05). Ultrastructural evaluation of islets revealed an increased amount of secreting organelles, such as endoplasmic reticulum and Golgi apparatus in DEX islets. Mitotic figures were observed in DEX islets at structural and ultrastructural levels. Beta-cell proliferation, evaluated at the immunohistochemical level using anti-PCNA (proliferating cell nuclear antigen), showed an increase in pancreatic beta-cell proliferation of 6.4-fold in DEX islets compared with CTL islets (P < 0.0001). Increases in insulin receptor substrate-2 (IRS-2), phosphorylated-serine-threonine kinase AKT (p-AKT), cyclin D(2) and a decrease in retinoblastoma protein (pRb) levels were observed in DEX islets compared with CTL islets (P < 0.05). Therefore, during the development of insulin resistance, the endocrine pancreas adapts itself increasing beta-cell mass and proliferation, resulting in an amelioration of the functions. The potential mechanisms that underlie these events involve the activation of the IRS-2/AKT pathway and activation of the cell cycle, mediated by cyclin D(2). These adaptations permit the maintenance of glycaemia at near-physiological ranges.
Rafacho
Alex
A
Department of Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), São Paulo, Brazil. rafacho@unicamp.br
Ribeiro
Daniele Lisboa
DL
Boschero
Antonio Carlos
AC
Taboga
Sebastião Roberto
SR
Bosqueiro
José Roberto
JR
D000818:Animals; D018797:Cell Cycle Proteins / Q000032:analysis; D049109:Cell Proliferation; D056742:Cyclin D2; D016213:Cyclins / Q000032:analysis* / Q000378:metabolism; D003907:Dexamethasone; D005934:Glucagon / Q000032:analysis; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000032:analysis; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
C486197:Ccnd2 protein, rat; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D016213:Cyclins; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D003907:Dexamethasone; D005934:Glucagon; D017346:Protein Serine-Threonine Kinases