Abstract
At present, obesity is one of the most important public health problems in the world because it causes several diseases and reduces life expectancy. Although it is well known that insulin resistance plays a pivotal role in the development of type 2 diabetes mellitus (the more frequent disease in obese people) the link between obesity and insulin resistance is yet a matter of debate. One of the most deleterious effects of obesity is the deposition of lipids in non-adipose tissues when the capacity of adipose tissue is overwhelmed. During the last decade, reduced mitochondrial function has been considered as an important contributor to 'toxic' lipid metabolite accumulation and consequent insulin resistance. More recent reports suggest that mitochondrial dysfunction is not an early event in the development of insulin resistance, but rather a complication of the hyperlipidemia-induced reactive oxygen species (ROS) production in skeletal muscle, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action. Here, we review the literature dealing with the mitochondria-centered mechanisms proposed to explain the onset of obesity-linked IR in skeletal muscle. We conclude that the different pathways leading to insulin resistance may act synergistically because ROS production by mitochondria and other sources can result in mitochondrial dysfunction, which in turn can further increase ROS production leading to the establishment of a harmful positive feedback loop.
Highlights
In recent years, the observation that insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are growing dramatically all over the world has stimulated the research on such metabolic disorders and their possible therapy
IR is a reduction of the responses of peripheral target tissues including muscle, adipose tissue and liver to a physiological concentration of insulin, so that IR is characterized by reduced tissue insulin sensitivity and reduced glucose, lipid and protein metabolism
Because of the importance of skeletal muscle in the development of IR, many researchers focused on this tissue, and the results of their works seem to indicate that the impaired glucose uptake that characterizes skeletal muscle IR results from impaired insulin receptor signaling (Goodyear et al 1995, Bjornholm et al 1997, Cusi et al 2000)
Summary
The observation that insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are growing dramatically all over the world has stimulated the research on such metabolic disorders and their possible therapy. The purpose of this review is to examine the literature examining how the mitochondria might act as a contributory factor to skeletal muscle IR describing possible cellular and molecular mechanisms Another not secondary purpose of the review is to find a way, if any, to reconcile the different views on the role of mitochondria in IR development. Adipose tissue does store energy and acts as an active endocrine and paracrine organ that plays a major role in the control of metabolism through secretion of a large number of biologically active molecules (Matsuzawa et al 1999), collectively known as adipocytokines or adipokines, including plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor α (TNF-α), resistin, leptin and adiponectin (Vettor et al 2005). Adiponectin is believed to activate the 5′-AMP activated protein kinase (AMPK), which seems to play a role in insulin-independent glucose uptake by the muscle (Yamauchi et al 2002)
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