Telmisartan reverses antiretroviral-induced adipocyte toxicity and insulin resistance in vitro.

Sudeep P Pushpakom,David J Back,Gyanendra Tripathi,Antonysunil Adaikalakoteswari,Andrew Owen,Munir Pirmohamed,Sudhesh Kumar,Philip Mcternan

doi:10.1177/1479164118757924

Abstract

Background:Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose–response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects.Methods:Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively. Adipokine secretion and expression of insulin signalling mediators were evaluated using enzyme-linked immunosorbent assays.Results:Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAktSer473. The metabolic effects of telmisartan followed a non-monotonic response with the maximal effect observed at 5 µM in the primary human adipocyte model.Conclusion:Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviral-induced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial.

Highlights

Combination antiretroviral therapy is the mainstay of treatment in HIV
A similar result was observed in primary human adipocytes (LPV and RTV with 78% and 80% downregulation, respectively) which was partially reversed by 5 μM TEL (LPV + TEL, p = 0.03; RTV + TEL, p = 0.01; Figure 3(b))
A similar result was observed in primary human adipocytes (LPV, 88% reduction, p = 0.01; RTV, 73% reduction, p = 0.01; ATV, 7.5% reduction, NS); both TEL (5 μM) and ROSI (10 μM) were able to significantly reverse protease inhibitors (PIs)-induced downregulation of adiponectin (Figure 4(b))

Summary

Introduction

Combination antiretroviral therapy (cART) is the mainstay of treatment in HIV. It has improved the morbidity and mortality associated with HIV, turning it into a chronic disease. Insulin resistance (IR) is central to the development of cardiometabolic disease,[4] being present in 21% of HIV patients on antiretroviral (ARV) therapy.[5] In vitro as well as single-drug studies in both healthy[6] and HIV-infected patients[7] have shown that IR can be induced by both protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs). Results: Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAktSer[473]. Conclusion: Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviralinduced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial

Methods

Results

Discussion

Conclusion