Pancreatic β cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene

Aims: Although accumulating evidence suggests the associations between sleep apnea syndrome (SAS) and type 2 diabetes, the direct effect of intermittent hypoxia (IH) on pancreatic beta cell proliferation remains a missing piece of the puzzle. Main methods: Rat RINm5F beta cells, hamster HIT-T15 beta cells, and human 1.184 beta cells were exposed to normoxia (21% O-2, 5% CO2, and balance N-2), to sustained hypoxia (SH: 1% O-2, 5% CO2, and balance N-2), or to intermittent hypoxia (IH: 64 cycles of 5 min SH and 10 min normoxia) for 24 h. After the treatment, cellular proliferation and apoptosis were measured by WST-8 assay and TUNEL method, respectively. The expression of regenerating gene (Reg) family, interleukin (IL)-6, and hepatocyte growth factor (HGF) was determined by real-time RT-PCR. Key findings: The cellular proliferation of HIT-T15, RINm5F and 1.1B4 cells by IH was significantly increased, whereas apoptosis of these cells was unchanged. Real-time RT-PCR revealed that the mRNA levels of Reg family genes, IL-6, a typical Reg family gene inducer, and HGF, an inhibitor of high-concentration of Reg protein-induced apoptosis, were increased in IH-treated cells. In addition, siRNAs against rat Reg family genes except for PAPI/Reg 2 attenuated IH-induced beta cell proliferation. Significance: IH stress stimulates pancreatic beta cell to induce IL-6 gene expression. By the IL-6 stimulation, beta cells over-express Reg family genes as well as HGF gene. Reg family proteins stimulate beta cell proliferation and HGF inhibits apoptosis of beta cells. As a result, beta cell numbers are increased by IH. (C) 2013 Elsevier Inc. All rights reserved.