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Indexed/Abstracted in: EMBASE, PubMed/MEDLINE, Science Citation Index Expanded (SciSearch), Scopus
Impact Factor 1,118
Online ISSN 1827-1634
Bin LU, Ping GU, Yixin XU, Xiaozhen YE, Yingzhijie WANG, Hong DU, Jiaqing SHAO
Department of Endocrinology, School of Medicine, Nanjing University/Southern Medical University, Jinling Hospital, Nanjing, China
BACKGROUND: Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin signaling. We reported previously that impaired glucose-stimulated insulin secretion (GSIS) in rats fed high-fat diet was associated with higher PTP1B protein levels in islets. The aim of the present study was to investigate the effect of increasing PTP1B on insulin secretion in β-cells.
METHODS: INS-1 cells were transduced with recombinant adenoviruses containing human PTP1B cDNA (Ad-PTP1B), or no exogenous gene (Ad-ctrl). The expression levels of PTP1B, insulin receptor (IR), insulin receptor substrate-1(IRS-1), glucokinase and glucose transporter-2 were evaluated by Western blot. Then insulin-stimulated IR and IRS tyrosine phosphorylation, and Akt pathway activation were measured. GSIS was also performed to evaluate INS-1 cells function.
RESULTS: PTP1B expression level was increased 5.9-fold at 48h post-transduction. The overexpression of PTP1B had no effect on proliferation and apoptosis of INS-1 cells. Compared with control cells, INS-1 cells overexpressing PTP1B showed decrease in insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate-1(IRS-1) by 56.4% and 53.1%, respectively. In addition, Akt phosphorylation was reduced 59.6%. Moreover, in Ad-PTP1B-transduced cells, 16.7mM glucose caused a 1.6±0.2 fold increase (vs. 3.9±0.7 fold in nontransduced cells) in insulin secretion relative to secretion at 2.8mM glucose. Further analysis determined that overexpression of PTP1B induced down-regulated expression of glucokinase (42%) and glucose transporter-2 (48%).
CONCLUSIONS: Our findings suggested that overexpression of PTP1B can inhibit GSIS in INS-1 cells through negatively regulating insulin signaling.