The Glucose-dependent Insulinotropic Effects And Its Relevant Mechanism Of Telmisartan

Objective:Mounting evidences indicate that telmisartan provides beneficial effects in patients with type 2 diabetes（T2DM）.Telmisartan suppresses oxidative stress and inflammation responses resulting from the overactivity of the local renin–angiotensin system,thereby protectingβ-cells against dysfunction and improving insulin sensitivity to maintain euglycemia.Insufficient insulin secretion is a fundamental process which determines the onset and progression of T2DM.However,few studies have focused on the effect of telmisartan on insulin secretion.Therefore,the present study aimed to investigate the insulinotropic effect of telmisartan and the underlying electrophysiological mechanism.Methods:1.Islets isolated from Wistar rats were incubated with drugs under different glucose conditions for 30 minutes,then supernatant liquid was collected for insulin secretion.Intracellular Ca²⁺([Ca²⁺]_i)levels ofβ-cells were measured by calcium imaging technology.Patch-clamp technology was applied to detect effects on action potential duration（APD）,Voltage-dependent potassium（Kv）channels,and voltage-gated calcium channels（VGCC）.CHO-Kv2.1 cell line was constructed with lentivirus vector overexpressing Kv2.1 channel,which was main subtype in the regulation of insulin release onβ-cell.Then patch-clamp experiment was performed on CHO-Kv2.1 cell.2.We applied db/db mice as T2DM model mice to determine whether telmisartan induced hypoglycemic effects in vivo.Male mice were administered with telmisartan or vehicle once by gavage at the age of 8 and 11 weeks,then oral glucose tolerance test（OGTT）was performed to observe the effects of telmisartan on glucose response.3.At the end of the in vivo experiment,islets were isolated from db/db mice at the age of 11 weeks,and in vitro insulin secretion assay and patch-clamp experiments were performed to ascertain whether telmisartan still functioned on pathologic condition.Results:1.Not affecting insulin secretion under low glucose condition,telmisartan dose-dependently stimulated insulin secretion under high glucose condition,and stimulation was enhanced with increasing glucose concentration.2.Likewise,acute increases of[Ca²⁺]_i concentration were glucose-dependently elicited by telmisartan only under high glucose condition.3.Telmisartan-induced elevations of[Ca²⁺]_i level were reversed in absence of extracellu Lar calcium or with L-VGCC blocker azelnidipine added,although[Ca²⁺]_iconcentrations were significantly increased through intracellular Ca²⁺mobilization by thapsigargin.4.Telmisartan decreased current density of Kv channels,and prolonged APD ofβ-cells.5.Not only Kv channels are involved in mediating telmisartan-induced insulin secretion and increase of[Ca²⁺]_i levels,but telmisartan also increased L-type VGCC current density.6.GW9662,a PPARγblocker,did not influence effects of telmisartan on insu Lin secretion,[Ca²⁺]_i concentration and ion channels.And similar effects were not observed in other ARBs valsartan and irbesartan.7.CHO cells have no endogenous outward potassium currents,while Kv 2.1channels currents and its suppression by telmisartan were both detected on CHO-Kv2.1 cells.8.Telmisartan ameliorates hyperglycemia by increasing insulin secretion in vivo in8-week-old and 11-week-old db/db mice.9.Consistent with the results of in vivo studies,telmisartan treatment similarly enhanced glucose stimulated insulin secretion,and exert similar electrophysiological effects on Kv channels and VGCCs under pathological condition of diabetes.Conclusions:1.Telmisartan amplifies glucose-stimulated insulin secretion in rat islets owing to enhancing[Ca²⁺]_i levels ofβ-cells.The electrophysiological mechanism is that telmisartan inhibits kv channels to prolong duration of extracellu Lar Ca²⁺influx,and activates L-type VGCCs to promote extracellu Lar Ca²⁺influx.2.Neither AT-1 receptors nor PPARγwas involved in above effects,and telmisartan-induced effects were partly due to direct inhibition of kv2.1 channels.3.Under the pathological state of T2DM,telmisartan exerted similar electrophysiological effects onβ-cells in vitro,and lowered the plasma glucose levels by the increasing the insulin secretion.