P162Sitagliptin reduces fatty-acids uptake in detriment of glucose in experimental type-II diabetic hearts

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Objective: To study the effect of sitagliptin on glucose and fatty-acids uptake in the myocardium of type-II diabetic rats.

Background: The energy source in the heart shifts from fatty-acids to glucose after damage. However, fatty-acids are used as the only substrate available in the diabetic myocardium. Sitagliptin improves hyperglycemia and insulin resistance, but it is unknown whether it could influence the cellular transporters for both glucose and fatty-acids.

Methods: Non-obese, non-hypertensive type-II diabetic rats (Goto-Kakizaki; GK) were treated with sitagliptin (10 mg/kg/day) or vehicle. A group of wistar rats were used as control. (N=10 rats, each). After 20 weeks, cardiac structure and function were measured by Echo-Doppler, and glucose uptake was examined by positron emission tomography (PET). Then, hearts were isolated and processed for protein and RNA extracts. Plasmas were used to evaluate metabolic parameters.

Results: GK rats developed hyperglycemia (452 vs. 208 mg/dl, for GK and wistar, respectively. p<0.01), cardiac hypertrophy (0.22 vs. 0.19 mm left ventricular posterior wall thickness, for GK and wistar, respectively. p<0.05), and diastolic dysfunction (36.16 vs. 33.72 ms decceleration time, and 1.05 vs. 1.39 E/A ratio. p<0.05). GK exhibited also a reduction in the left ventricular diastolic diameter (LVDD; 0.61 vs. 0.8 mm. p<0.05), and left ventricular systolic diameter (LVSD; 0.28 vs. 0.53 mm. p<0.05), without significant changes in ejection fraction. In addition, GK rats showed a reduced myocardial glucose uptake (~30%) mainly in basal and middle regions of the heart, and the expression and translocation of Glut4 (a glucose transporter), in favor of FAT/CD36 (a fatty-acid transporter). Interestingly, sitagliptin treatment attenuated hyperglycemia (382 mg/dl), increased LVDD (0.73 mm) and LVSD (0.43 mm), reduced the decceleration time (31.1 ms), and elevated E/A ratio (1.2). Furthermore, sitagliptin increased glucose uptake and Glut4 translocation to the sarcolema (p<0.05).

Conclusions: Sitagliptin could improve cardiac function in type-II diabetes by increased glucose uptake and reduced fatty-acids uptake, and their respective cellular receptors.

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