A4800 Dipeptidyl peptidase-4 inhibition prevents increased hepatic triglyceride content in insulin-resistant female rats

Abstract

Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibition has been show to exert beneficial effects against insulin resistance (IR) and fatty liver disease. Combined oral contraceptive (COC) treatment has been shown to be associated with glucose deregulation and increased hepatic triglyceride (TG) levels, but the mechanisms are elusive. We therefore, hypothesized that DPP-4 inhibition (DPP-4i) will ameliorate COC-induced glucose dysregulation and hepatic TG accumulation through adenosine deaminase (ADA) /xanthine oxidase (XO) /uric acid-dependent pathway. Methods: Female Wistar rats received (po) vehicle and COC (1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel; po) with or without DPP-4 inhibitor (sitagliptin; 100 mg/kg; po) for 8 weeks (n = 6/group). Glucose dysmetabolism was accessed by elevated fasting blood glucose, impaired oral glucose tolerance test and homeostatic model assessment of insulin resistance. Results: Treatment with COC led to increased plasma fasting glucose, triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, IR and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic triglycerides (TG), TG/HDL-cholesterol ratio, malondialdehyde, uric acid, lactate dehydrogenase, DPP-4, ADA and XO activities. On the other hand, COC led to reduction in nitric oxide level. However, DPP-4i significantly ameliorated these alterations induced by COC treatment except plasma and hepatic XO activity. Conclusion: This demonstrates that increased uric acid, DPP-4 and ADA activities are involved in glucose dysregulation and hepatic TG accumulation induced by COC treatment. Therefore, DPP-4i would impact positively on cardiometabolic disorders, at least in part, through ADA and uric acid suppression.