Telmisartan Potentiates Insulin Secretion via Ion Channels, Independent of the AT1 Receptor and PPARγ.

Tao Liu,Peifeng He,Min Zhang,Huan Xue,Linping Zhi,Yunfeng Liu,Mengmeng Liu,Yi Zhang,Qing Guo,Huanhuan Yang,Lijuan Cui,Xiaohua Yang,Zhihong Liu

doi:10.3389/fphar.2021.739637

Abstract

Angiotensin II type 1 (AT1) receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the direct effects of ARBs on insulin secretion remain unclear. In this study, we aimed to investigate the insulinotropic effect of ARBs and the underlying electrophysiological mechanism. We found that only telmisartan among the three ARBs (telmisartan, valsartan, and irbesartan) exhibited an insulin secretagogue role in rat islets. Independent of AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ), telmisartan exerted effects on ion channels including voltage-dependent potassium (Kv) channels and L-type voltage-gated calcium channels (VGCCs) to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. Furthermore, we identified that telmisartan directly inhibited Kv2.1 channel on a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of db/db mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in OGTT. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets or β-cells isolated from db/db mice. Collectively, our results establish an important insulinotropic function of telmisartan distinct from other ARBs in the treatment of diabetes.

Highlights

Diabetes and hypertension constitute common clinical conditions that are interlinked through numerous pathophysiological mechanisms (Deedwania, 2004; Ferrannini and Cushman, 2012)
Telmisartan, valsartan and irbesartan are clinically available ARBs owing to their high specificity for Angiotensin II type 1 (AT1) receptors (Michel et al, 2013), and the antihypertensive bioactivity of valsartan and irbesartan has been confirmed by us, our results suggested that telmisartan-mediated insulinotropic effect was independent of AT1 receptors
The results indicated that telmisartan inhibited Kv channels independent of the AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ)

Summary

Introduction

Diabetes and hypertension constitute common clinical conditions that are interlinked through numerous pathophysiological mechanisms (Deedwania, 2004; Ferrannini and Cushman, 2012). Telmisaratan Petentiates Insulin Secretion of both conditions significantly increases the risks of developing nephropathy, heart failure, and other cardiovascular disease, leading to high rates of mortality and morbidity (Deedwania, 2004; Ferrannini and Cushman, 2012). Growing evidence indicated that angiotensin II type 1 (AT1) receptor blockers (ARBs), an important drug class in the treatment of hypertension and heart failure, provided beneficial effects for patients with diabetes and prediabetes. Several clinical trials and retrospective-analyses have shown that ARBs reduce the incidence of new-onset diabetes among patients with hypertension and heart failure (Yusuf et al, 2005; Kjeldsen et al, 2006; McMurray et al, 2010). ARBs have been highly recommended in pharmacological therapy regimens for patients with both diabetes and hypertension by the American Diabetes Association (American Diabetes Association, 2015)

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