Mitochondrial dysfunction as a central event for mechanisms underlying insulin resistance: the roles of long chain fatty acids.

Insulin resistance is characterized by hyperglycaemia, dyslipidaemia and oxidative stress prior to the development of type 2 diabetes mellitus. To date, a number of mechanisms have been proposed to link these syndromes together, but it remains unclear what the unifying condition that triggered these events in the progression of this metabolic disease. There have been a steady accumulation of data in numerous experimental studies showing the strong correlations between mitochondrial dysfunction, oxidative stress and insulin resistance. In addition, a growing number of studies suggest that the raised plasma free fatty acid level induced insulin resistance with the significant alteration of oxidative metabolism in various target tissues such as skeletal muscle, liver and adipose tissue. In this review, we herein propose the idea of long chain fatty acid-induced mitochondrial dysfunctions as one of the key events in the pathophysiological development of insulin resistance and type 2 diabetes. The accumulation of reactive oxygen species, lipotoxicity, inflammation-induced endoplasmic reticulum stress and alterations of mitochondrial gene subset expressions are the most detrimental that lead to the developments of aberrant intracellular insulin signalling activity in a number of peripheral tissues, thereby leading to insulin resistance and type 2 diabetes.

Metabolomic strategies to study lipotoxicity in cardiovascular disease.

Cardiovascular disease arises from a combination of dyslipidaemia and systemic inflammation in both humans and mouse models of the disease. Given the strong metabolic component and also the strong interaction between diet and disease, one would expect strategies based on the global profiling of metabolism should hold substantial promise in defining the mechanism involved in this collection of pathologies. This review examines how metabolomics is being used both as a research tool to understand mechanisms of pathology and as an approach for biomarker discovery in cardiovascular disease. While the lipid fraction of blood plasma has a profound influence on the development of cardiovascular disease, there is also a growing body of evidence that the aqueous fraction of metabolites also have a role in following the effects of myocardial infarction and monitoring the development of atherosclerosis. Metabolomics has also been used in conjunction with proteomics and transcriptomics as part of a systems biology description of cardiovascular disease and in high-throughput approaches to profile large numbers of patients as part of epidemiology studies to understand how the genome interacts with the development of atherosclerosis.