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Open Access 01-12-2018 | Original investigation

Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: role of GLP-1 isoforms in Glut4 receptor trafficking

Authors: E. Ramírez, B. Picatoste, A. González-Bris, M. Oteo, F. Cruz, A. Caro-Vadillo, J. Egido, J. Tuñón, M. A. Morcillo, Ó. Lorenzo

Published in: Cardiovascular Diabetology | Issue 1/2018

Abstract

Background

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 glucose homeostasis but it could also trigger direct cardioprotective actions, including regulation of energy substrate utilization.

Methods

Type-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.

Results

Untreated 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.

Conclusions

Besides 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.

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Title: Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: role of GLP-1 isoforms in Glut4 receptor trafficking
Authors: E. Ramírez
B. Picatoste
A. González-Bris
M. Oteo
F. Cruz
A. Caro-Vadillo
J. Egido
J. Tuñón
M. A. Morcillo
Ó. Lorenzo
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Cardiovascular Diabetology / Issue 1/2018
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-017-0643-2

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Results

Conclusions

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