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JYMS : Journal of Yeungnam Medical Science

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Original article
Telmisartan increases hepatic glucose production via protein kinase C ζ-dependent insulin receptor substrate-1 phosphorylation in HepG2 cells and mouse liver
Kae Won Cho, Du-Hyong Cho
Yeungnam Univ J Med. 2019;36(1):26-35.   Published online December 20, 2018
DOI: https://doi.org/10.12701/yujm.2019.00059
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AbstractAbstract PDFSupplementary Material
Background
Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice.
Methods
Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase α (G6Pase-α), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ζ (PKCζ) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice.
Results
Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a 40 μM concentration without a change in G6Pase-α expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 (p-IRS-1-Ser302) and decreased p-IRS-1-Tyr632 dose-dependently. Telmisartan dose-dependently increased p-PKCζ-Thr410 which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative PKCζ significantly attenuated telmisartan-induced HGP and p-IRS-1-Ser302 and -inhibited p-IRS-1-Tyr632. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased p-IRS-1-Ser302 and decreased p-IRS-1-Tyr632, which was accompanied by an increase in p-PKCζ-Thr410.
Conclusion
These results suggest that telmisartan increases HGP by inducing p-PKCζ-Thr410 that increases p-IRS-1-Ser302 and decreases p-IRS-1-Tyr632 in a PPARγ-independent manner.

Citations

Citations to this article as recorded by  
  • HM-chromanone attenuates TNF-α-mediated inflammation and insulin resistance by controlling JNK activation and NF-κB pathway in 3T3-L1 adipocytes
    Jea Eun Park, Eunji Kang, Ji Sook Han
    European Journal of Pharmacology.2022; 921: 174884.     CrossRef
  • Label-free study of intracellular glycogen level in metformin and resveratrol-treated insulin-resistant HepG2 by live-cell FTIR spectroscopy
    Anchisa Poonprasartporn, K.L. Andrew Chan
    Biosensors and Bioelectronics.2022; 212: 114416.     CrossRef
  • Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats
    Jose A. Godoy-Lugo, Dora A. Mendez, Ruben Rodriguez, Akira Nishiyama, Daisuke Nakano, Jose G. Soñanez-Organis, Rudy M. Ortiz
    Molecular and Cellular Endocrinology.2022; 555: 111729.     CrossRef

JYMS : Journal of Yeungnam Medical Science