Abstract
BackgroundThe distribution of glucose and fatty-acid transporters in the heart is crucial for energy consecution and myocardial function. In this sense, the glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, improves glucose homeostasis but it could also trigger direct cardioprotective actions, including regulation of energy substrate utilization.MethodsType-II diabetic GK (Goto-Kakizaki), sitagliptin-treated GK (10 mg/kg/day) and wistar rats (n = 10, each) underwent echocardiographic evaluation, and positron emission tomography scanning for [18F]-2-fluoro-2-deoxy-d-glucose (18FDG). Hearts and plasma were isolated for biochemical approaches. Cultured cardiomyocytes were examined for receptor distribution after incretin stimulation in high fatty acid or high glucose media.ResultsUntreated GK rats exhibited hyperglycemia, hyperlipidemia, insulin resistance, and plasma GLP-1 reduction. Moreover, GK myocardium decreased 18FDG assimilation and diastolic dysfunction. However, sitagliptin improved hyperglycemia, insulin resistance, and GLP-1 levels, and additionally, enhanced 18FDG uptake and diastolic function. Sitagliptin also stimulated the sarcolemmal translocation of the glucose transporter-4 (Glut4), in detriment of the fatty acyl translocase (FAT)/CD36. In fact, Glut4 mRNA expression and sarcolemmal translocation were also increased after GLP-1 stimulation in high-fatty acid incubated cardiomyocytes. PI3K/Akt and AMPKα were involved in this response. Intriguingly, the GLP-1 degradation metabolite, GLP-1(9-36), showed similar effects.ConclusionsBesides of its anti-hyperglycemic effect, sitagliptin-enhanced GLP-1 may ameliorate diastolic dysfunction in type-II diabetes by shifting fatty acid to glucose utilization in the cardiomyocyte, and thus, improving cardiac efficiency and reducing lipolysis.
Highlights
More than 300 million people worldwide currently suffer from type-II diabetes mellitus (T2DM) [1]
Sitagliptin attenuated hyperglycemia and insulin resistance in GK rats Compared to aged-matched wistar, GK rats exhibited a weight loss and elevation of circulating levels of glucose and lipids [triglycerides (TG), cholesterol (Ch), non-HDL Ch, high-density lipoproteins (HDL), and free FA (FFA)] (Fig. 1a)
After 15 min of oral glucose loading, GK rats did not respond by adequately increasing glucagon-like peptide-1 (GLP-1) and insulin (Fig. 1b, middle and bottom), leading to uncontrolled glycemia (Fig. 1b, top)
Summary
More than 300 million people worldwide currently suffer from type-II diabetes mellitus (T2DM) [1]. An oversupply of lipids can saturate mitochondria, producing toxic and oxidative metabolites, and cardiac dysfunction [4] In this regard, cardiac function has been improved described in patients with heart failure after balancing lipid degradation toward glucose oxidation [5]. Deletion of FA-translocase (FAT)/CD36 receptors prevented myocyte triacylglycerol accumulation, increased glucose utilization and ameliorated cardiac dysfunction in PPARα-overexpressed mice resembling T2DM [7]. The distribution of glucose and fatty-acid transporters in the heart is crucial for energy consecution and myocardial function. In this sense, the glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, improves glu‐ cose homeostasis but it could trigger direct cardioprotective actions, including regulation of energy substrate utilization
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
