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

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.