Skeletal muscle mitochondrial dysfunction in Type 2 diabetes

Modern living is closely associated with a rapid increase in the incidence of serious metabolic disease characterized by excess body fat and gradual and insidious elevations of blood glucose concentrations. In many regions of the world, up to 40% of the adult population is now overweight or obese, and the prevalence of Type 2 diabetes (both diagnosed and undiagnosed) is as high as 30%. These common metabolic diseases constitute an enormous burden on the affected individuals and on society as a whole. In light of the contemporary epidemic of obesity and the increasing prevalence of Type 2 diabetes [1,101], there is increasing interest in the contribution of abnormalities in skeletal muscle metabolism.

Type 2 diabetes is characterized by insulin resistance in several tissues, particularly skeletal muscle, liver and adipose tissue. Insulin resistance in skeletal muscle is associated with abnormalities in both glucose and lipid metabolism [2]. In relation to lipid metabolism, there is increased intramyocellular storage of triglycerides and other lipid intermediates and dys­regulation of the b-oxidation of fatty acids [3]. A number of mechanisms have been suggested that could explain an association between cytosolic lipid accumulation and insulin resistance in skeletal muscle. The accumulation of lipids in muscle tissue could result from increased fatty acid delivery, reduced utilization or the combination of both [4,5]. Skeletal muscle mitochondria could contribute to the pathogenesis of Type 2 diabetes, according to one hypothesis, if a primary defect in mitochondrial functional capacity could lead to an intramyocellular accumulation of ‘toxic’ lipid intermediates, which would then disrupt insulin signaling leading to insulin resistance [6,7]. However, it remains contentious whether altered mitochondrial biology itself contributes to insulin resistance or whether it merely reflects the consequence of other systemic factors and does not constitute a primary contributor to the pathophysiology of insulin resistance.

A number of studies using a variety of techniques have shown that the skeletal muscle of insulin-resistant, obese or Type 2 diabetes subjects have a reduced mitochondrial oxidative capacity compared with lean, healthy controls [8–16]. However, it has not been definitively established whether the reduced oxidative capacity present in insulin-resistant states is a result of reduced mitochondrial mass, deficiency in mitochondrial function or both. There is evidence that the mitochondrial dysfunction associated with insulin resistance actually precedes the development of obesity and diabetes. It has been shown that lean but insulin-resistant offspring of patients with Type 2 diabetes have increased intramyocellular lipid content, reduced baseline activity of mitochondrial oxidative phosphorylation and decreased skeletal muscle mitochondrial density and content [11,14,15]. These observations support the theory that skeletal muscle mitochondrial dysfunction is in fact heritable. Thus, mitochondrial dysfunction could contribute to the primary pathology underlying insulin ­resistance and the progression to diabetes.

Taken together, a number of studies of skeletal muscle from obese and Type 2 diabetes patients suggest a disruption in mitochondrial biology, as evidenced by reduced concentrations of oxidative enzymes [8,10,13,17], reduced mitochondrial size and altered mitochondrial morphology [8,18]. Studies of skeletal muscle mitochondrial respiration provide conflicting evidence. One study using high-resolution respirometry performed in isolated myofibrils suggests that the functioning of skeletal muscle mitochondria in Type 2 diabetes is normal, and that the reduced skeletal muscle oxidative capacity of these patients is due to a reduction in mitochondrial content [12]. Other studies provide evidence that at least some parts of the electron transport chain have decreased functional capacity, resulting in diminished mitochondrial respiration [19,20].

Mitochondrial biogenesis requires the concordant activation of both the mitochondrial and the nuclear genomes to generate electron transport chain subunits and other proteins that are necessary for mitochondrial function. Insulin resistance in muscle of individuals with obesity or Type 2 diabetes is associated with reduced expression of nuclear genes responsible for oxidative metabolism, such as PPAR-γ coactivator (PGC)-1a [21]. Remarkably, insulin-resistant muscle has been shown to display a coordinated reduction in the expression of a cluster of genes encoding proteins of the mitochondrial inner membranes, respiratory chain complexes, ATP synthesis, fatty acid oxidation, the Krebs cycle and pyruvate kinase [17]. The expression of the transcriptional co-activators PGC-1a and PGC-1b has been shown to be downregulated in nondiabetic individuals who have a positive family history of diabetes [17]. Proteomic studies have also recently demonstrated a reduction in mitochondrial proteins in insulin-resistant muscle [22]. In parallel, reduced expression of mitofusin-2, a key protein essential for mitochondrial fusion and the regulation of inner membrane potential, has been described in patients with Type 2 diabetes [23].

Lifestyle and behavioral interventions have the potential to affect both mitochondrial biogenesis and mitochondrial dysfunction. It has long been established that the content of the mitochondria in skeletal muscle depends directly on the level of physical activity and that skeletal muscles have metabolic plasticity and can enhance oxidative phosphorylation in response to exercise. Therefore, some researchers advocate that the reduced skeletal muscle oxidative phosphorylation in states of insulin resistance is a reflection of sedentary lifestyle leading to obesity and Type 2 diabetes. Several studies have investigated the effect of weight loss and exercise inter­ventions on mitochondrial function in obesity and Type 2 diabetes. These have shown that both mitochondrial content and electron transport chain activity improve in skeletal muscle in both obese and Type 2 diabetes patients in response to weight loss and exercise training [9,24,25]. This effect is paralleled by improvements in insulin sensitivity. Interestingly, although both are insulin-sensitizing interventions, exercise training results paradoxically in increased intra­myocellular lipid content, in contrast to the effect of diet-induced weight loss [9,25]. The net effect of combined dietary and exercise interventions might, therefore, be expected to result in an unchanged intramyocellular lipid content pre- and post-intervention. It has been shown that diet-induced weight loss has no effect on mitochondrial capacity despite reducing intramyocellular lipid content in subjects with Type 2 diabetes [9]. These observations suggest that interplay of muscle cytosolic lipid content and muscle mitochondrial function contribute to insulin sensitivity. Very recently, new data have been published suggesting that there are regional anatomical differences in skeletal muscle mitochondrial respiration, and that locomotor muscles play an important metabolic role [26].

Patients with different phenotypes of Type 2 diabetes may have different degrees of dysfunction in mitochondrial metabolism. Early-onset Type 2 diabetes is increasing in prevalence, in parallel with the rising rates of obesity. This subgroup of patients have a clinical profile broadly similar to the phenotype of Type 2 diabetes in older adults with a few important distinctions: more extreme insulin resistance, marked visceral obesity and, typically, a strong family history of diabetes [27,28]. Studies of skeletal muscle of patients with early-onset Type 2 diabetes have recently shown that these patients have comparable mitochondrial mass but reduced expression of electron transport chain proteins and mitofusin-2 compared with BMI- and age-matched obese individuals with normal glucose metabolism [29]. In addition, it has previously been shown that these patients demonstrate an incapacity to increase maximal oxygen consumption in response to 12 weeks of aerobic exercise training. At the molecular level, this is accompanied by failure to increase expression of PGC-1a and mitofusin-2 in the skeletal muscle – the physio­logical response observed in healthy controls. These mitochondrial abnormalities, both at baseline and following exercise intervention, are unlikely to represent primary defects alone, and are more likely to result from a combination of genetic predisposition, early-onset obesity (with poor diet) and a longstanding sedentary life style [29].

Thus, the role of mitochondrial dysfunction in the pathogenesis of Type 2 diabetes is not yet completely understood. Future studies will probably focus on identifying specific subphenotypes of patients with Type 2 diabetes who have distinct mitochondrial biology who have, accordingly, a lesser or greater potential to respond to lifestyle intervention. In parallel with efforts to improve the drug treatment of diabetes, this avenue of research supports the ultimate goal of personalized medicine and the design of a tailored approach to lifestyle interventions. In addition to this, the output from study of the molecular pathways leading to mitochondrial dysfunction may also facilitate the development of new pharmacotherapeutic ­interventions for this growing population of patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.