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Monoclonal antibody to six transmembrane epithelial antigen of prostate-4 influences insulin sensitivity by attenuating phosphorylation of P13K (P85) and Akt: Possible mitochondrial mechanism

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Abstract

We examined the effects of anti-six-transmembrane epithelial antigen of the prostate-4 (STEAP4) antibodies on glucose transport in mature adipocytes and determined the mechanism of insulin resistance in obesity. Western blotting was performed to determine STEAP4 expression, to assess translocation of insulin-sensitive glucose transporter 4 (GLUT4), and to measure phosphorylation and total protein content of insulin-signaling proteins. Confocal laser microscopy and flow cytometry were used to detect intracellular reactive oxygen species (ROS) and fluctuations in mitochondrial membrane potential (ΔΨ). ATP production was measured by using a luciferase-based luminescence assay kit. After the application of anti-STEAP4 antibodies at 0.002 mg/mL, adipocytes exhibited reduced insulin-stimulated glucose transport by attenuating the phosphorylation of IRS-1, PI3K (p85), and Akt. The antibodies also potentially increase the level of ROS and decrease cellular ATP production and ΔΨ. In conclusion, (i) STEAP4 regulates the function of IRS-1, PI3K, and Akt and decreases insulin-induced GLUT4 translocation and glucose uptake; (ii) ROS-related mitochondrial dysfunction may be related to a reduced IRS-1 correlation with the PI3K signaling pathway, leading to insulin resistance. These observations highlight the potential role of STEAP4 in glucose homeostasis and possibly in the pathophysiology of type 2 diabetes related to obesity and may provide new insights into the mechanisms of insulin resistance in obesity.

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Authors and Affiliations

  1. Department of Pediatrics, Nan**g Maternal and Child Health Hospital of Nan**g Medical University, No.123 Tianfei Road, Nan**g, 210004, China

    Da-ni Qin, **-gai Zhu, Chen-bo Ji,  Chunmei-Shi, Chun-zhao Kou, Guan-zhong Zhu, Chun-mei Zhang, Yan-** Wang & ** Wang & **-rong Guo

  2. Allele Biotechnology and Pharmaceuticals Inc, San Diego, CA, 92121, USA

    Yu-hui Ni

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  1. Da-ni Qin
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  2. **-gai Zhu
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  3. Chen-bo Ji
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  4. Chunmei-Shi
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  5. Chun-zhao Kou
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  6. Guan-zhong Zhu
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  7. Chun-mei Zhang
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  8. Yan-** Wang
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  9. Yu-hui Ni
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  10. **-rong Guo
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Corresponding authors

Correspondence to Yu-hui Ni or **-rong Guo.

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Dani Qin and **-gai Zhu contributed equally to this work

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Qin, Dn., Zhu, Jg., Ji, Cb. et al. Monoclonal antibody to six transmembrane epithelial antigen of prostate-4 influences insulin sensitivity by attenuating phosphorylation of P13K (P85) and Akt: Possible mitochondrial mechanism. J Bioenerg Biomembr 43, 247–255 (2011). https://doi.org/10.1007/s10863-011-9360-9

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  • DOI: https://doi.org/10.1007/s10863-011-9360-9

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