The alarming increase in obesity and associated type 2 diabetes mellitus (T2DM) is a paramount public health concern in developing countries. Skeletal muscle insulin resistance is a hallmark characteristic of individuals with T2DM, most of whom are obese. In the classic sense, insulin resistance can be defined as an inability of target tissues to increase glucose uptake in response to insulin. Although the concept of insulin resistance can be expanded to include the reduced ability of insulin to suppress lipolysis in adipose tissue and glucose production by the liver, skeletal muscle insulin resistance is particularly relevant because it is the tissue responsible for the majority of whole-body insulin-stimulated glucose disposal. Insulin resistance in skeletal muscle is particularly germane to exercise because of its plasticity, that is, its response to exercise as well as physical inactivity. In particular, healthy exercise-trained muscle has an exceptional capacity to rapidly select its source of fuel, namely fat and carbohydrates, according to conditions of feeding, fasting, changing diet composition, and activity. By stark contrast, insulin-resistant muscle can be broadly characterized as having a reduced “metabolic flexibility.” Thus, the potential of exercise and other interventions designed to target skeletal muscle insulin resistance has obvious implications for prevention and treatment of obesity and T2DM.
It is known that insulin resistance is central to the development of T2DM in adults, and that appropriate lifestyle changes can delay or prevent the progression from impaired glucose tolerance, or “prediabetes,” to frank diabetes. Although a number of environmental and genetic factors are thought to contribute to the pathogenesis of insulin resistance in obesity and T2DM, this review focuses on the potential role of the content and metabolism of triglycerides within skeletal muscle as well as implications for exercise in the prevention and treatment of insulin resistance and T2DM.
REGIONAL BODY FAT DISTRIBUTION AND INSULIN RESISTANCE
Total body fat is associated with impaired glucose tolerance and insulin resistance. Although abdominal adiposity has received considerable attention in regard to insulin resistance, there is a substantial proportion of body fat in the legs, most of which comprises subcutaneous adipose tissue. Yet this fat depot is generally not related to insulin resistance. However, recent studies using computed tomography and magnetic resonance imaging have modified this perspective by demonstrating that the loss of adipose tissue located beneath the fascia lata as intermuscular adipose tissue is correlated with improved insulin sensitivity (3). Mechanisms that account for the association of intermuscular adipose tissue but not subcutaneous adipose tissue with insulin resistance are not well understood but may include fatty acids or paracrine factors (e.g., cytokines and adipokines) released by adipocytes immediately adjacent to muscle cells that impede insulin action within the myocytes. Accumulation of lipid within myocytes as triglycerides, referred to as intramuscular triglycerides or intramyocellular lipid, has also been linked to insulin resistance and T2DM.
MUSCLE TRIGLYCERIDE IS ASSOCIATED WITH INSULIN RESISTANCE
More than three decades after the first report of the existence of lipid storage in muscle, Pan et al. (10) determined that the triglyceride content of muscle biopsies was related to insulin resistance independent of total adiposity. As an alternative approach to biochemical extraction techniques for muscle triglyceride determination, lipid contained in muscle fibers can also be directly visualized with either histochemical staining (Fig. 1) or magnetic resonance spectroscopy, which reveals the distribution of lipids within myocytes. Using a quantitative imaging approach, the triglyceride content of myocytes has been found to be increased in obesity, particularly those obese subjects with T2DM (4).
The ability of magnetic resonance spectroscopy to distinguish the proton signal of intramyocellular lipids from that caused by lipids outside the muscle fibers has made this an attractive method for investigations involving humans. Perseghin et al. (12) reported that lipids contained within muscle fibers determined by magnetic resonance spectroscopy were strongly correlated with insulin resistance in adults. It was further observed in that study that intracellular lipid was increased among first-degree relatives of T2DM individuals and was related to insulin resistance in this high-risk group (12). Computed tomography imaging has also been used to reveal alterations in the attenuation values of muscle as a marker of higher lipid within muscle related to insulin resistance in obesity and T2DM.
Much of the evidence of an association between skeletal muscle triglyceride content and insulin resistance has emanated from cross-sectional comparisons and correlation studies. However, intervention studies designed to alter insulin resistance in humans and in animals have also provided strong support of this often-cited association. Diet-induced weight loss has been shown to improve insulin resistance concomitant with reduced muscle triglyceride content (4). The reverse is also true, that is, high-fat diets in animals can induce insulin resistance in parallel with an increased triglyceride content of muscle (15). Thus, the association between skeletal muscle triglyceride and insulin resistance has been consistently observed in a variety of models of obesity and diabetes using various methodologies for muscle lipid quantification. These observations have recently helped to rekindle a strong interest in the important interaction between fatty acid and glucose metabolism in T2DM.
SKELETAL MUSCLE TRIGLYCERIDE ACCUMULATION AND ITS ROLE IN TYPE 2 DIABETES
Lipid Metabolites and Insulin Action
Delineating mechanisms by which an increase in skeletal muscle lipid availability may confer insulin resistance in diabetes may help to identify specific target pathways, proteins, or genes involved in reduced insulin action. Certain lipid metabolites involved in the synthesis of muscle triglycerides or that are the result of triglyceride hydrolysis can directly act on signaling pathways known to be defective in T2DM (5,14). For example, excess triglyceride in insulin-resistant muscle might lead to elevated diacylglycerol concentrations. Diacylglycerol, in turn, activates protein kinase C, which can inhibit tyrosine kinase activity of the insulin receptor as well as tyrosine phosphorylation of insulin receptor substrate-1, leading to reduced insulin action (5). Ceramide, a derivative of fatty acids, has also been demonstrated to alter insulin signaling (14). The key point here, and one that will be raised again later in the review, is that these lipid metabolites, but not triglycerides themselves, have been shown to negatively affect insulin action.
Impaired Fatty Acid Metabolism in Insulin Resistance
Augmented lipid accumulation within skeletal muscle could occur primarily by either increased fatty acid uptake into muscle from the circulation or diminished fatty acid oxidation by muscle mitochondria. The prevailing plasma free fatty acid (FFA) concentration is an important determinant of FFA uptake by skeletal muscle, so that higher plasma FFA levels result in higher rates of uptake. However, there are several reasons to postulate that factors intrinsic to skeletal muscle also influence muscle lipid storage and accumulation. Patients with T2DM have reduced efficiency in the uptake of plasma FFA by skeletal muscle, indicating that plasma FFA availability is not the sole factor determining FFA entry into the myocyte and subsequent lipid accumulation. There are also potential mechanisms by which fatty acid transport proteins might contribute to increased storage of triglyceride and other skeletal muscle lipid metabolites in obese patients with T2DM. Recent studies in both animals (9) and humans (1) support the concept that increased delivery and/or transport of fatty acids in muscle may be related to lipid-induced or obesity-induced insulin resistance.
Several lines of inquiry suggest that a reduced capacity for fatty acid oxidation may contribute to elevated muscle triglyceride content in obesity and T2DM. In vitro (6,7) and in vivo (7) studies have provided evidence that defective fatty acid oxidation by skeletal muscle likely leads to altered lipid partitioning toward storage, potentially leading to insulin resistance. During resting postabsorptive conditions, less than half of fatty acid flux in the plasma pool is accounted for by oxidation, while the remaining is recycled into triglyceride, indicating a physiologic reserve that exceeds immediate tissue needs for oxidative substrates. The equilibrium between oxidation and re-esterification within muscle is paramount in determining lipid storage within muscle. After transport in the sarcoplasm, long-chain fatty acids must be translocated into mitochondria by the enzyme complex, carnitine palmitoyltransferase (CPT I and CPT II). The activity of CPT I is regarded as a key step in the regulation of fatty acid oxidation within muscle. CPT activity is reduced in skeletal muscle of insulin-resistant, obese subjects, consistent with an overall reduction in mitochondrial enzymes involved in oxidative metabolism and also with defects in skeletal muscle mitochondria in insulin resistance of obesity and T2DM (8). The biochemistry of skeletal muscle in obesity and T2DM suggest impairments that direct fatty acids toward storage rather than oxidation, thereby providing a mechanism for lipid accumulation within muscle.
EXERCISE, MUSCLE TRIGLYCERIDE, AND INSULIN RESISTANCE
Increased physical activity, along with weight loss, is often prescribed as a first-line therapy in the treatment of obesity and T2DM. Potential mechanisms by which exercise improves skeletal muscle insulin action include increases in GLUT4 protein and activities of hexokinase and glycogen synthase as well as increases in components of the insulin-signaling pathway. It is also known that improvements in fatty acid metabolism also accompany exercise training in nondiabetic subjects, although how these improvements might specifically predict improved insulin resistance are unclear.
Given the apparent association between higher muscle triglyceride and insulin resistance in sedentary individuals (Fig. 2), the periodic depletion of muscle lipid during exercise may be related to acutely improved insulin action. Skeletal muscle triglycerides provide substrate for oxidative energy metabolism during moderate-intensity physical activity. However, as depicted in Figure 2, endurance-trained athletes who are markedly insulin-sensitive have higher muscle triglyceride levels than lean sedentary subjects and, in fact, are quite similar to that of patients with T2DM (2). This apparent paradox is supported by studies demonstrating increased muscle triglycerides with exercise training in previously sedentary subjects (13). These observations appear at first to contradict the close association noted above between muscle triglyceride and insulin resistance. However, the explanation may lie in the exercise-enhanced capacity for triglyceride use within skeletal muscle.
In a trained individual, fatty acids derived from hydrolysis of intracellular triglyceride during periods of physical activity may be preferentially channeled toward the oxidative pathway. This is consistent with the notion that intramyocellular triglyceride per se is not the lipid entity that directly inhibits insulin action in muscle. Rather, triglyceride accumulation in obese/insulin-resistant muscle may merely be a marker for increased levels of other lipid molecules such as ceramide, diglyceride, or long-chain acyl-CoA that may interfere directly with the insulin-signaling pathway. With exercise training, and an increased tendency toward oxidation of fatty acids rather than synthesis of these metabolites, the potential harmful effects of lipid accumulation may be prevented. Interestingly, as Figure 3 illustrates, clinical interventions suggest that enhanced fatty acid oxidation resulting from increased physical activity predicts improvements in skeletal muscle insulin resistance, an association not observed with diet-induced weight loss (3). In addition, in a cultured cell model of lipid-induced insulin resistance, an elevated capacity for fatty acid oxidation appears to increase insulin sensitivity independent of changes in intracellular lipid (11). These intervention studies inducing changes in muscle lipid and the capacity for fatty acid oxidation have provided a valuable perspective into the role of muscle lipid in insulin resistance. Increased capacity for muscle fatty acid oxidation may therefore help to explain the beneficial effects of exercise and may also contribute to the insulin sensitizing properties of leptin, adiponectin, and the thiazolidinediones, agents that increase muscle fatty acid oxidation in addition to decreasing muscle lipid.
As summarized in Figure 4, the balance between use and storage of lipid within skeletal muscle likely plays a significant role in the development of insulin resistance and the subsequent development of T2DM. The accumulation of triglycerides within muscle cells is related to insulin resistance in sedentary subjects. Moreover, diet-induced weight loss results in reduced muscle triglycerides, concomitant with improved insulin sensitivity in obesity. An inverse relationship exists between insulin resistance and the capacity of muscle to oxidize fatty acids, providing further support of the notion that impaired capacity for fatty acid oxidation may lead to muscle triglyceride accumulation and, consequently, insulin resistance. However, several lines of evidence now support the notion that this association may be more complex than once thought.
Chronic exercise training actually appears to increase muscle triglyceride content, thus providing strong evidence for a paradox in the association between muscle triglyceride accumulation and insulin resistance. Healthy muscle is characterized by the capacity to use either lipid or carbohydrate fuels and to effectively transition between these fuels depending on the stimulus and the energy demand, reflecting a “metabolic flexibility.” The capacity for efficient fatty acid use may be related to insulin-stimulated glucose metabolism independent of muscle triglyceride content. It is apparent then that muscle triglycerides themselves do not confer insulin resistance but perhaps are a marker for other lipid metabolites known to negatively influence insulin action. The fatty acid composition or the subcellular localization of muscle triglycerides may also be important factors that influence insulin resistance. It is unknown whether exercise may modify the localization or fatty acid composition of muscle triglycerides or whether there may be favorable effects of exercise on other lipid metabolites. Further studies are critical to address these important questions, which may ultimately help define specific therapies in the prevention and treatment of insulin resistance and T2DM.
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