Systemic metabolic markers and myocardial glucose uptake in type 2 diabetic and coronary artery disease patients treated for 16 weeks with rosiglitazone, a PPARγ agonist

Abstract

Introduction. Treatment with rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, in type 2 diabetic mellitus (T2DM) patients is under scrutiny because it affects adversely cardiovascular outcomes. In T2DM patients, with existing coronary heart disease, short-term treatment with rosiglitazone increases myocardial glucose uptake (MGU). Serum metabolic and lipoprotein subclass changes, which may be associated with this rosiglitazone-induced improvement, are unknown.

Methods. Patients with both T2DM and coronary heart disease were separated into placebo (n = 26) and treatment (rosiglitazone 4–8 mg; n = 25) groups. After 16 weeks of treatment, serum NMR metabolomics was used to measure circulating low-molecular-weight metabolites and lipoprotein subclasses and lipids that are associated with T2DM before and after the treatment. Significant metabolic measure changes after rosiglitazone treatment were correlated to MGU values assessed with [¹⁸F]fluorodeoxyglucose positron emission tomography.

Results. Compared to placebo, the treatment significantly increased circulating glutamine and decreased lactate concentrations. Circulating lactate concentrations showed a significant inverse association with MGU after rosiglitazone treatment.

Conclusion. In T2DM patients with existing coronary heart disease, short-term rosiglitazone treatment caused minor improvements in metabolism: serum lactate and glutamine concentrations changed, reflecting improvements in insulin sensitivity, and circulating lactate concentrations inversely correlated to increases in myocardial glucose uptake.

Key words::

• Glutamine
• lactate
• lipoprotein
• metabolomics
• myocardium
• NMR spectroscopy
• positron emission tomography
• type 2 diabetes mellitus
• rosiglitazone

Acknowledgements

Robert M. Badeau and Miikka-Juhani Honka contributed equally to the writing of the paper.

We appreciate the critical review by Dr Patricia Iozzo and the technical help received from the Turku PET Centre staff.

Declaration of interest: The study was conducted within the Centre of Excellence in Molecular Imaging in Cardiovascular and Metabolic Research, supported by the Academy of Finland, University of Turku, Turku University Hospital and Åbo Academy. This work was also supported by the Sigrid Jusélius Foundation, the Finnish Funding Agency for Technology and Innovation – TEKES, the Strategic Research Funding from the University of Oulu, the Turku University Foundation and the University of Turku Combined Research Fund. Dr Murray Stewart is an employee at GlaxoSmithKline, owner of rosiglitazone, the maker of Avandia, did not work with the data or limit the report. Therefore, his interest was limited and his role at GSK did not conflict with the interest of our research study.