Insulin resistance, reduced β-cell mass, and hyperglucagonemia are consistent features in type 2 diabetes mellitus (T2DM). We used pancreas and islets from humans with T2DM to examine the regulation of insulin signaling and cell-cycle control of islet cells. We observed reduced β-cell mass and increased α-cell mass in the Type 2 diabetic pancreas. Confocal microscopy, real-time PCR and western blotting analyses revealed increased expression of PCNA and down-regulation of p27-Kip1 and altered expression of insulin receptors, insulin receptor substrate-2 and phosphorylated BAD. To investigate the mechanisms underlying these findings, we examined a mouse model of insulin resistance in β-cells--which also exhibits reduced β-cell mass, the β-cell-specific insulin receptor knockout (βIRKO). Freshly isolated islets and β-cell lines derived from βIRKO mice exhibited poor cell-cycle progression, nuclear restriction of FoxO1 and reduced expression of cell-cycle proteins favoring growth arrest. Re-expression of insulin receptors in βIRKO β-cells reversed the defects and promoted cell cycle progression and proliferation implying a role for insulin-signaling in β-cell growth. These data provide evidence that human β- and α-cells can enter the cell-cycle, but proliferation of β-cells in T2DM fails due to G1-to-S phase arrest secondary to defective insulin signaling. Activation of insulin signaling, FoxO1 and proteins in β-cell-cycle progression are attractive therapeutic targets to enhance β-cell regeneration in the treatment of T2DM.
Altered insulin receptor signalling and β-cell cycle dynamics in type 2 diabetes mellitus / F. Folli, T. Okada, C. Perego, J. Gunton, C.W. Liew, M. Akiyama, A. D'Amico, S. La Rosa, C. Placidi, R. Lupi, P. Marchetti, G. Sesti, M. Hellerstein, L. Perego, R.N. Kulkarni. - In: PLOS ONE. - ISSN 1932-6203. - 6:11(2011), pp. e28050.e28050-1-e28050.e28050-11.
|Titolo:||Altered insulin receptor signalling and β-cell cycle dynamics in type 2 diabetes mellitus|
PEREGO, LUCIA (Penultimo)
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
Settore MED/13 - Endocrinologia
|Data di pubblicazione:||2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1371/journal.pone.0028050|
|Appare nelle tipologie:||01 - Articolo su periodico|