Telmisartan is effective to ameliorate metabolic syndrome in rat model - a preclinical report

Abstract

Background: Metabolic syndrome (MS) is known to be associated with hypertension, insulin resistance, and dyslipidemia, and it raises the risk for cardiovascular diseases and diabetes mellitus. Telmisartan is used in clinic as an angiotensin II receptor blocker and it is also identified as activating peroxisome proliferator-activated receptors δ (PPARδ). Activation of PPARδ produced beneficial effects on fatty acid metabolism and glucose metabolism. This study aims to investigate the effects of telmisartan on the modulation of MS in rats fed a high-fat/high-sodium diet.

Methods: Rats were fed with a high-fat/high-sodium diet and received injections of streptozotocin at low dose to induce MS. Then, rats with MS were treated with telmisartan. The weight, glucose tolerance, and insulin sensitivity were measured. The lipid profiles were also obtained. The weights of retroperitoneal and epididymal fat pads were determined. The role of PPARδ in telmisartan treatment was identified in rats pretreated with the specific antagonist GSK0660.

Results: The results showed that telmisartan, but not losartan, significantly reduced plasma glucose and plasma insulin, and improved insulin resistance in rats with MS. Telmisartan also decreased blood pressure and lipids more significantly than losartan. Moreover, GSK0660 effectively reversed the effects of telmisartan in the MS rats. In the MS group, telmisartan activated PPARδ to enhance the levels of phosphorylated GLUT4 in muscle or the expression of phosphoenolpyruvate carboxykinase (PEPCK) in the liver, which was also abolished by GSK0660. Telmisartan is useful to ameliorate hypertension and insulin resistance in rats with MS. Telmisartan improves the insulin resistance through increased expression of GLUT4 and down-regulation of PEPCK via PPARδ-dependent mechanisms.

Conclusion: Telmisartan has been proven to ameliorate MS, particularly in the prediabetes state. Therefore, telmisartan is suitable to develop for the management of MS in clinics.

Keywords: GSK0660; PPARδ; diet; metabolic syndrome; telmisartan.

Figure 1

Effects of telmisartan or losartan on MS rats. Notes: The change in (A) blood glucose; (B) mean arterial blood pressure; (C) HOMA-IR; (D) AUC of HOMA-IR; and (E) ITT in normal rats and MS rats after 4 weeks of experimental period. Con (white column), SD rats fed normal chow diet; Con+Tel (white column), SD rats fed normal chow diet and administered with telmisartan (8mg/kg); Con+Los (white column), SD rats fed normal chow diet and administered with losartan (8mg/kg); Veh (black column), MS rats received with vehicle; Veh+Tel (black column), MS rats received administered with telmisartan (8mg/kg) for 4 weeks; Veh+Los (black column), MS rats received administered with losartan (8mg/kg) for 4 weeks. Data are expressed as mean ± SEM (n = 6). ^*P<0.05 vs Con; ^#P<0.05 vs Veh. Abbreviations: AUC, area under the curve; Con, control; HOMA-IR, homeostatic model assessment for insulin resistance; ITT, insulin tolerance test; Los, losartan; MS, metabolic syndrome; SD, Sprague Dawley; Veh, vehicle; Tel, telmisartan.

Figure 2

PPARδ antagonist GSK0660 inhibited the effects induced by chronic telmisartan treatment in MS rats. Notes: The changes in (A) blood glucose; (B) mean arterial blood pressure; (C) HOMA-IR; (D) AUC of HOMA-IR; and (E) ITT. Con (white column), SD rats fed normal diet; Con+Tel (white column), SD rats fed normal diet and administered with telmisartan (8mg/kg); Veh (black column), MS rats received telmisartan (8mg/kg) for 4 weeks and GSK0660 were pretreated 30 minutes before telmisartan treatment; Veh+GSK (black column) MS rats received administered with vehicle and GSK0660 for 4 weeks. Data are expressed as mean ± SEM (n = 6). ^*P<0.05 vs Con; ^#P<0.05 vs Veh. Abbreviations: AUC, area under the curve; Con, control; HOMA-IR, homeostatic model assessment; ITT, insulin tolerance test; MS, metabolic syndrome; PPARδ, peroxisome proliferator-activated receptor delta; SD, Sprague Dawley; Tel, telmisartan; Veh, vehicle.

Figure 3

Effects of telmisartan or losartan on PPARδ and related signal expression in skeletal muscle and liver. Notes: (A) Representative immunoblots are shown in the upper part of the figure, and the relative expression levels of GLUT4 and PPARδ expression in soleus muscle are indicated in the lower. (B) Representative immunoblots are shown in the upper part of the figure, and the relative expression levels of PEPCK and PPARδ in liver are indicated in the lower. Con (white column), SD rats fed normal diet; Con+Tel (white column), SD rats fed normal diet and administered with telmisartan (8mg/kg); Con+Los (white column), SD rats fed normal diet and administered with losartan (8mg/kg); Veh (black column), MS rats received with vehicle; Veh+Tel (black column), MS rats received administered with telmisartan (8mg/kg) for 4 weeks; Veh+Los (black column), MS rats received administered with losartan (8mg/kg) for 4 weeks. Data are expressed as mean ± SEM (n = 4). ^*P<0.05 vs Con; ^#P<0.05 vs Veh. Abbreviations: Con, control; PEPCK, phosphoenolpyruvate carboxykinase; PPARδ, peroxisome proliferator-activated receptor delta; Los, losartan; MS, metabolic syndrome; SD, Sprague Dawley; Tel, telmisartan; Veh, vehicle.

Figure 4

Effects of the PPARδ antagonist GSK0660 on expressions of PPARδ and related signals in skeletal muscle and liver isolated from the telmisartan-treated MS rats. Notes: (A) Representative immunoblots are shown in the upper part of the figure, and the relative expression levels of GLUT4 and PPARδ in soleus muscle are indicated in the lower. (B) Representative immunoblots are shown in the upper part of the figure and the relative expression levels of PEPCK and PPARδ in the liver are indicated in the lower. Con (white column), SD rats fed normal diet; Con+Tel (white column), SD rats fed normal diet and administered with telmisartan (8mg/kg); Veh (black column), MS rats received with vehicle; Veh+Tel (black column), MS rats received administered with telmisartan (8mg/kg) for 4 weeks; Veh+Tel+GSK (black column), MS rats received administered with telmisartan (8mg/kg) for 4 weeks and GSK0660 were pretreated 30 minutes before telmisartan treatment; Veh+GSK (black column) MS rats received administered with GSK0660 and vehicle for 4 weeks. Data are expressed as mean ± SEM (n = 4). ^*P<0.05 vs Con; ^#P<0.05 vs Veh. Abbreviations: Con, control; GSK, GSK0660; PEPCK, phosphoenolpyruvate carboxykinase; PPARδ, peroxisome proliferator-activated receptor delta; MS, metabolic syndrome; SD, Sprague Dawley; Tel, telmisartan; Veh, vehicle.