Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewThe role of mitochondria in the aetiology of insulin resistance and type 2 diabetes☆
Introduction
Type 2 diabetes has been labelled as one of the greatest challenges to human health of the 21st century [1]. At present, it is estimated that over 350 million people worldwide suffer from this disease [2]. Most alarmingly, this number is expected to rapidly increase in the future. This disease imparts a huge burden on patients, carers and health care systems and places enormous pressures on national and international economies [1]. Its associated comorbidities, which include cardiovascular disease, stroke, kidney disease and cancer, contribute to ~ 4 million deaths worldwide each year that are due to type 2 diabetes [3]. With the prevalence of chronic diseases such as type 2 diabetes rapidly increasing, it has been predicted that life expectancies will decline for the first time in over a century [4]. Historically, type 2 diabetes has been perceived as a problem that affects only developed and prospering nations, however new statistics reveal that 80% of people with type 2 diabetes now live in low and middle income countries [5]. These alarming statistics and the increasing prevalence of type 2 diabetes worldwide highlight that few effective treatment strategies exist to combat this disease. This is due, in part, to the fact that aspects of the biology underpinning this disease are poorly understood. Whilst it is known that resistance to the hormone insulin is central to the pathogenesis of type 2 diabetes, the mechanisms driving insulin resistance are not completely understood [6]. Perhaps one of the most contentious issues in the field is whether impaired mitochondrial function is involved in the development of insulin resistance [7], [8]. This review will provide an overview of the functional consequences of insulin resistance in various tissues and will examine the available evidence that describes the relationship between mitochondrial dysfunction and insulin action. This will be done in the context of the known roles of mitochondria in various cellular functions.
Insulin is a hormone released by β-cells of the pancreas in response to rising blood glucose levels. Insulin activates a canonical signalling pathway (see [9], [10] for reviews) that regulates numerous cellular effects in many different target tissues. A primary function of insulin is to facilitate nutrient uptake and storage in states of nutrient excess, such as after a meal [9]. Insulin is also able to control feeding behaviour and energy expenditure via specific brain centres [11]. These diverse functions make insulin critical for the integration of whole body metabolism with nutrient availability and demand.
Therefore, insulin resistance has numerous detrimental effects on metabolism that are the basis for a number of chronic diseases, including type 2 diabetes. Insulin resistance impairs glucose uptake into skeletal muscle, primarily due to the defective regulation of the facilitative glucose transporter isoform 4 (GLUT4) facilitative glucose transporter [12]. Insulin stimulation of skeletal muscle normally results in translocation of GLUT4 containing storage vesicles from intracellular sites to the sarcolemma, where the GLUT4 protein is then inserted into the membrane to facilitate glucose transport into the muscle cell [13]. Whilst the exact defect in this process in insulin resistant states has yet to be definitively established, and is likely to be multifaceted in heterogeneous forms of insulin resistance, impaired glucose uptake has significant effects on whole body glucose homeostasis. Indeed, skeletal muscle accounts for ~ 80% of post-prandial glucose disposal in healthy individuals [14]. In the liver, suppression of glucose output is impaired in the insulin resistant state, due to impaired suppression of gluconeogenesis and glycogenolysis [15]. Again, the exact mechanisms mediating this defect are not yet completely resolved, but are thought to include transcriptional dysregulation of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase; [16]). Whilst insulin resistance in skeletal muscle and the liver has negative effects on glucose homeostasis, the major impact of insulin resistance in adipose tissue is impaired suppression of lipolysis, which contributes to the hyperlipidaemia seen in insulin resistant states [17]. This is most detrimental in visceral adipose tissue and is also thought to alter the secreted adipokine profile to a pro-inflammatory state, which in turn has detrimental systemic effects on numerous metabolic tissues [18]. The heart is also susceptible to insulin resistance and this is associated with altered substrate metabolism, which similar to skeletal muscle, involves defective GLUT4 translocation to and/or insertion into the plasma membrane [19]. This results in a shift towards fatty acid oxidation at the expense of anaerobic and oxidative glucose metabolism, which can drive morphological and functional alterations in the heart [19]. Resistance to insulin can also occur in the satiety centres of the hypothalamus, such as the arcuate nucleus [20]. Insulin signalling in the arcuate increases proopiomelanocortin (POMC) expression, whilst reducing neuropeptide Y (NPY)/agouti related peptide (AgRP) expression, which via neuropeptide signalling to secondary neuronal nuclei, reduces food intake and enhances energy expenditure [20]. Insulin resistance in these centres, therefore, contributes to hyperphagia and reduces energy expenditure.
Together, these features of insulin resistance in multiple tissues are also hallmark features of type 2 diabetes. Indeed, the hyperglycaemia and hyperlipidaemia associated with insulin resistance are thought to be responsible for many of the co-morbidities associated with type 2 diabetes [21]. As insulin resistance appears central to the development of type 2 diabetes, intense research efforts have been dedicated to understanding its molecular mechanisms. This research effort suggests that the development of insulin resistance is multifactorial and involves complex interactions between the environment and genetic susceptibility [22]. At a mechanistic level, ectopic lipid accumulation in non-adipose tissues, chronic low grade systemic inflammation, endoplasmic reticulum stress and altered gut microbiome have all been implicated in the development of insulin resistance [23]. However, numerous associative studies have identified links between impaired function of mitochondria, the organelle responsible for the majority of cellular ATP production, and the development of insulin resistance in multiple tissues. The following sections will describe the role of mitochondria in normal cellular function and review the evidence that implicates mitochondrial dysfunction in the development of insulin resistance.
Section snippets
Major cellular processes regulated by mitochondria
Mitochondria regulate numerous cellular processes and are a critical contributor to cellular and organismal homeostasis. This section will review some of the major processes in which mitochondria are involved and will provide a superficial framework for understanding potential links between mitochondrial dysfunction and insulin resistance.
Associations between mitochondrial function and insulin resistance
Numerous observations have made an association between mitochondria, insulin resistance and type 2 diabetes, which have typically been centred on reductions in mitochondrial capacity and/or function in insulin resistant or diabetic patients and animal models. This section will review the evidence linking impaired mitochondrial capacity and/or function with insulin resistance in a number of key metabolic tissues.
Potential mechanisms linking impaired mitochondrial function and insulin resistance
The complex nature of mitochondrial function and the various putative defects in mitochondria in insulin resistant and diabetic states have led to the development of a number of theories describing the mechanisms linking mitochondria and insulin resistance. This section will discuss the most common theories posited to explain this relationship.
Speculative mechanisms potentially linking mitochondria and insulin action
Despite many years of intensive research, the previous sections highlight that controversies still exist regarding the involvement of mitochondrial dysfunction in the development of insulin resistance. A clear contributor to this controversy is deficiencies in our understanding of aspects of mitochondrial biology in the context of insulin action. For example, a common assumption in this debate is that all deficiencies in mitochondrial function equate to a homogenous, unified response on insulin
Summary
This review provides an overview of the hotly debated role of mitochondria in the development of insulin resistance and type 2 diabetes. Whilst there is no doubt of an association between impaired mitochondrial function and insulin resistance, the causality of this relationship remains controversial. This controversy is fuelled by our lack of understanding of some of the biological interactions between mitochondria and insulin regulated processes in the context of insults thought to induce
Acknowledgements
We apologise to those authors whose work we could not cite due to space constraints. The Metabolic Remodelling Laboratory is supported by Project Grants (APP1027227 and APP1027227) from the NHMRC, the Diabetes Australia Research Trust, the Central Research Grant Scheme of Deakin University and the Deakin University Molecular and Medical Research Strategic Research Centre. SLM is also supported by a Career Development Fellowship from the NHMRC (1030474).
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This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.