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Telmisartan potentiates insulin secretion via ion channels, independent of the AT1 receptor and PPARγ

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

Posted 20 Sep 2020
bioRxiv DOI: 10.1101/2020.09.20.305334

Angiotensin II type 1 receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the effects of ARBs on insulin secretion remain unclear. Here, we investigated the insulinotropic effects of ARBs (telmisartan, valsartan, and irbesartan) and the underlying electrophysiological mechanism in rat islets. We found that only telmisartan among the three ARBs exhibited an insulin secretagogue role. Distinct from other ARBs, telmisartan exerted effects on ion channels including voltage-gated potassium (Kv) channels and voltage-gated Ca2+ channels to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. We observed that the peroxisome proliferator-activated receptor γ pathway was not involved in these telmisartan-induced effects. Furthermore, we identified that telmisartan at least directly inhibited Kv2.1 channel through construction of a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of type 2 diabetes model ( db / db ) mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in the oral glucose tolerance test. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from db / db mice. Collectively, our results establish an important function of telmisartan distinct from other ARBs in the treatment of diabetes.

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