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Endocrine Abstracts (2018) 56 P345 | DOI: 10.1530/endoabs.56.P345

ECE2018 Poster Presentations: Diabetes, Obesity and Metabolism Diabetes (to include epidemiology, pathophysiology) (73 abstracts)

Telmisartan increases gluconeogenesis by inducing PKCζ-Thr410 phosphorylation in hyperglycemia-treated HepG2 cells and high-fat diet-fed mouse liver

Du-Hyong Cho 1 , Kae Won Cho 2 & Kee-Ho Song 3


1Department of Pharmacology, School of Medicine, Eulji University, Daejeon, Republic of Korea; 2Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Republic of Korea; 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea.


Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is widely prescribed for the treatment of hypertensive patients with simultaneous diabetes mellitus (DM). Unlike other ARBs, telmisartan is reported to have various ancillary effects as well as common blood pressure-lowering effect. In this regard, telmisartan improves endothelial dysfunction and cardiovascular complications in DM patients and is recently reported to reduce new-onset DM incidence. However, effects and mechanism of telmisartan on gluconeogenesis in hepatocytes and liver remain elusive. Here, we investigated effects and a molecular mechanism of telmisartan on gluconeogenesis in hyperglycemia-treated HepG2 cells and high-fat diet (HFD)-fed mouse liver. Telmisartan dose-dependently increased gluconeogenesis in hyperglycemia-treated HepG2 cells and accompanied an increase of phosphoenolpyruvate carboxykinase (PEPCK) expression without change of glucose-6-phosphatase (G6Pase) expression. Furthermore, telmisartan dose-dependently increased insulin receptor substrate-1 (IRS-1)-Ser302 phosphorylation and decreased IRS-1-Tyr632 phosphorylation, indicating that telmisartan impairs insulin action in HepG2 cells. Because protein kinase C ζ (PKCζ) is reported to reduce insulin action by inducing IRS-1 serine phosphorylations, we assessed its phosphorylation and found that telmisartan dose-dependently increased PKCζ-Thr410 phosphorylation. Ectopic expression of dominant-negative PKCζ constructs significantly attenuated the telmisartan-induced gluconeogenesis and the telmisartan-induced IRS-1-Ser302 phosphorylation and -inhibited IRS-1-Tyr632 phosphorylation, although it did not alter PEPCK expression, showing that gluconeogenesis, when insulin is acutely treated, is largely regulated by changes of IRS-1 phosphorylations. Among ARBs, including losartan and fimasartan, only telmisartan induced IRS-1-Ser302 phosphorylation and decreased IRS-1-Tyr632 phosphorylation. Furthermore, effects of telmisartan on IRS-1 phosphorylations were not altered by pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ antagonist. Finally, in the liver from HFD-fed mice, telmisartan increased PEPCK and G6Pase expressions and PKCζ-Thr410 phosphorylation, and accompanied an increase and a decrease of IRS-1-Ser302 and -Tyr632 phosphorylations, respectively. Taken together, our findings suggest that telmisartan increases gluconeogenesis by inducing PKCζ-Thr410 phosphorylation that leads to increased phosphorylation of IRS-1-Ser302 and decreased phosphorylation of IRS-1-Tyr632, and consequently impairs insulin action in hepatocytes.

Volume 56

20th European Congress of Endocrinology

Barcelona, Spain
19 May 2018 - 22 May 2018

European Society of Endocrinology 

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