Telmisartan increases hepatic glucose production via protein kinase C ?-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 ? (G6Pase-?), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ? (PKC?) 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 ?M concentration without a change in G6Pase-? 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-PKC?-Thr410 which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative PKC? 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 ? (PPAR?) 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-PKC?-Thr410. Conclusion:These results suggest that telmisartan increases HGP by inducing p-PKC?-Thr410 that increases p-IRS-1-Ser302 and decreases p-IRS-1-Tyr632 in a PPAR?-independent manner.

SUBMITTER: Cho KW 

PROVIDER: S-EPMC6784617 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature