Altered mitochondrial metabolism in the insulin-resistant heart.

Marina Makrecka‐Kuka,Maija Dambrova,Carlos M Palmeira,Kersti Tepp,Erkan Tuncay,Katie A O'Brien,Tuuli Käämbre,Marju Puurand,Edgars Liepinsh,Belma Turan,Woo H Han,Rob C I Wüst,Hélène Lemieux,Andrew J Murray,Yusuf Olgar,Paul De Goede,Terje S Larsen,Neoma T Boardman,Anabela P Rolo

doi:10.1111/apha.13430

Abstract

Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

Highlights

Type 2 diabetes mellitus (T2DM) has reached epidemic proportions; in 2014 around 422 million people had been diagnosed with T2DM, corresponding to about 8.5% of the global population of adults over 18 years of age.[1]
The authors further reported a normalization of mitochondrial respiratory function in the diet-induced obese heart following high-intensity interval training (HIIT), with increased oxidative phosphorylation (OXPHOS) capacity and improved efficiency in isolated cardiac mitochondria supplied with glutamate and malate as substrates for the N-Pathway via Complex I.19
The alterations in metabolism in insulin-resistant and T2DM hearts can be studied at various levels, from long-term treatment of cultured cells with high concentrations of glucose, through to studies of the whole heart or at the whole body level in diabetic animal or human subjects

Summary

Introduction

Type 2 diabetes mellitus (T2DM) has reached epidemic proportions; in 2014 around 422 million people had been diagnosed with T2DM, corresponding to about 8.5% of the global population of adults over 18 years of age.[1].

Results

Conclusion