Combination of low-dose testosterone and vildagliptin confers cardioprotection in castrated obese rats

in Journal of Endocrinology
Correspondence should be addressed to N Chattipakorn: nchattip@gmail.com

*(A Arinno and N Apaijai contributed equally to this work)

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Although a physiological dose of testosterone replacement therapy (p-TRT) has been shown to improve left ventricular (LV) function, some studies reported that it increased the risk of myocardial infarction in testosterone-deprived men. We previously reported that vildagliptin might be used as an alternative to p-TRT. In this study, we hypothesized that a combined low-dose TRT with vildagliptin exerts greater efficacy than single regimen in improving cardiometabolic function in obese, insulin-resistant rats with testosterone deprivation. Male rats were fed on a normal diet or high-fat diet for 12 weeks. Then, they were divided into two subgroups, sham operation and orchiectomy (normal diet rats with orchiectomy (NDO), high-fat diet rats with orchiectomy (HFO)) and fed their diets for another 12 weeks. At week 25, orchiectomized rats were subdivided into four groups: vehicle, p-TRT, vildagliptin and combined drugs. At week 29, cardiometabolic and biochemical parameters were determined. HFO rats had obese insulin resistance with a worse LV dysfunction, compared with sham. Vildagliptin and combined drugs effectively reduced insulin resistance. All treatments reduced blood pressure, cardiac autonomic imbalance, LV dysfunction, mitochondrial dysfunction, apoptosis and increased mitochondrial fusion in NDO and HFO rats. However, p-TRT and combined drugs, but not vildagliptin, reduced mitochondrial fission in NDO and HFO rats. We concluded that combined low-dose TRT with vildagliptin mitigated LV function at a similar level to the p-TRT alone and vildagliptin via improving mitochondrial fusion, reducing mitochondrial dysfunction and apoptosis in testosterone-deprived rats. Our findings suggest that low-dose TRT combined with vildagliptin may be an alternative for p-TRT in conditions of obese insulin resistance with testosterone deprivation.

 

      Society for Endocrinology

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    Experimental protocol. BP, blood pressure; DPP-4, dipeptidyl peptidase 4; HFD, high-fat diet; HFO, high-fat diet rats with testosterone deprivation; HRV, heart rate variability; LV, left-ventricle; ND, normal diet; NDO, normal diet rats with testosterone deprivation; ORX, orchiectomy; T, physiological dose testosterone replacement therapy; V, vehicle; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    The effects of vildagliptin, a physiological dose TRT, and combined low-dose TRT with vildagliptin on metabolic parameters. (A) Body weight, (B) visceral fat weight, (C) plasma testosterone levels, (D) plasma glucose levels, (E) plasma insulin levels, (F) HOMA-IR index. *P < 0.05 vs NDS, P < 0.05 vs HFS, P < 0.05 vs orchiectomized rats treated with vehicle on the same diet. HFO, high-fat diet rats with orchiectomy; HFS, high-fat diet rats with sham operation; HOMA, homeostatic model assessment; NDO, normal diet rats with orchiectomy; NDS, normal diet rats with sham operation; T, physiological dose testosterone replacement therapy; V, vehicle; Vil, vildagliptin; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    The effects of vildagliptin, a physiological dose TRT, and combined low-dose TRT with vildagliptin on plasma lipid profiles. (A) Plasma total cholesterol levels, (B) plasma triglyceride levels, (C) plasma HDL-C levels, (D) plasma LDL-C levels. *P < 0.05 vs NDS, P < 0.05 vs HFS, P < 0.05 vs orchiectomized rats treated with vehicle on the same diet. HFO, high-fat diet rats with orchiectomy; HFS, high-fat diet rats with sham operation; NDO, normal diet rats with orchiectomy; NDS, normal diet rats with sham operation; T, physiological dose testosterone replacement therapy; V, vehicle; Vil, vildagliptin; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    The effects of vildagliptin, a physiological dose TRT, and combined low-dose TRT with vildagliptin on LV function, cardiac autonomic function, and blood pressure. (A) %LV EF prior to treatment, (B) LF/HF ratio prior to treatment, (C) SBP prior to treatment, (D) DBP prior to treatment, (E) %LV EF after treatment, (F) LF/HF ratio after treatment, (G) SBP after treatment, (H) DBP after treatment. *P < 0.05 vs NDS, P < 0.05 vs HFS, P < 0.05 vs orchiectomized rats treated with vehicle on the same diet. DBP, diastolic blood pressure; HFO, high-fat diet rats with orchiectomy; HFS, high-fat diet rats with sham operation; NDO, normal diet rats with orchiectomy; NDS, normal diet rats with sham operation; LF/HF ratio, low-frequency/high-frequency ratio; LV, left-ventricle; SBP, systolic blood pressure; T, physiological dose testosterone replacement therapy; V, vehicle; Vil, vildagliptin; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    The effects of vildagliptin, a physiological dose TRT, and combined low-dose TRT with vildagliptin on invasive LV function parameters. (A) HR, (B) ESP, (C) EDP, (D) dP/dt max, (E) dP/dt min, (F) SV. *P < 0.05 vs NDS, P < 0.05 vs HFS, P < 0.05 vs orchiectomized rats treated with vehicle on the same diet. EDP, end diastolic pressure; ESP, end-systolic pressure; HFO, high-fat diet rats with orchiectomy; HFS, high-fat diet rats with sham operation; HR, heart rate; NDO, normal diet rats with orchiectomy; NDS, normal diet rats with sham operation; SV, stroke volume; T, physiological dose testosterone replacement therapy; V, vehicle; Vil, vildagliptin; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    The effects of vildagliptin, a physiological dose TRT, and combined low-dose TRT with vildagliptin on cardiac mitochondrial function. (A) Respiratory control ratio, (B) mitochondrial ROS levels, (C) mitochondrial membrane potential changes, (D) mitochondrial swelling, (E) representative pictures of cardiac mitochondria. *P < 0.05 vs NDS, P < 0.05 vs HFS, P < 0.05 vs orchiectomized rats treated with vehicle on the same diet. HFO, high-fat diet rats with orchiectomy; HFS, high-fat diet rats with sham operation; NDO, normal diet rats with orchiectomy; NDS, normal diet rats with sham operation; ROS, reactive oxygen species; T, physiological dose testosterone replacement therapy; V, vehicle; Vil, vildagliptin; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    The effects of vildagliptin, a physiological dose TRT, and combined low-dose TRT with vildagliptin on cardiac mitochondrial biogenesis and dynamics. (A) PGC-1α protein expression, (B) CPT-1 protein expression, (C) p-Drp1ser616/Drp1 protein expression, (D) OPA-1 protein expression. *P < 0.05 vs NDS, P < 0.05 vs HFS, P < 0.05 vs orchiectomized rats treated with vehicle on the same diet. CPT-1, carnitine palmitoyl transferase 1; Drp1, dynamin-related protein 1; HFO, high-fat diet rats with orchiectomy; HFS, high-fat diet rats with sham operation; NDO, normal diet rats with orchiectomy; NDS, normal diet rats with sham operation; OPA-1, optic atrophy protein 1; PGC-1α, peroxisome proliferated receptor 1 gamma; T, physiological dose testosterone replacement therapy; V, vehicle; Vil, vildagliptin; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    The effects of vildagliptin, a physiological dose TRT, and combined low-dose TRT with vildagliptin on cardiac apoptosis. (A) Representative pictures of TUNEL, (B) TUNEL+ cells/DAPI. *P < 0.05 vs NDS, P < 0.05 vs HFS, P < 0.05 vs orchiectomized rats treated with vehicle on the same diet. HFO, high-fat diet rats with orchiectomy; HFS, high-fat diet rats with sham operation; NDO, normal diet rats with orchiectomy; NDS, normal diet rats with sham operation; T, physiological dose testosterone replacement therapy; V, vehicle; Vil, vildagliptin; VilT, combined low-dose testosterone replacement therapy with vildagliptin.

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    Summarized diagram of the effects of vildagliptin, physiological dose TRT, and combined low-dose TRT with vildagliptin on metabolic parameters, LV function, and mitochondrial function in obese, insulin-resistant rats with testosterone deprivation. The complete colored version of this figure is available at https://doi.org/10.1530/JOE-18-0673.

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