Telmisartan increases hepatic glucose production via protein kinase C ζ-dependent insulin receptor substrate-1 phosphorylation in HepG2 cells and mouse liver

Abstract

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, telmis-artan increased phosphorylation of IRS-1 at Ser302 (p-IRS-1-Ser 302) and decreased p-IRS-1-Tyr 632 dose-dependently. Telmisartan dose-dependently increased p-PKCζ-Thr 410 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-Ser 302 and-inhibited p-IRS-1-Tyr 632. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible per-oxisome proliferator-activated receptor γ (PPARγ) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased p-IRS-1-Ser 302 and decreased p-IRS-1-Tyr 632 , which was accompanied by an increase in p-PKCζ-Thr 410. Conclusion: These results suggest that telmisartan increases HGP by inducing p-PKCζ-Thr 410 that increases p-IRS-1-Ser 302 and decreases p-IRS-1-Tyr 632 in a PPARγ-independent manner.