Endocrine Abstracts

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.