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EDITORIAL |
1 From the Department of Medicine, University of California, Davis, Davis, CA, and the VA Northern California Health Care System, Sacramento, CA
See corresponding article on page 1210.
2 Address reprint requests to L Berglund, Department of Medicine, University of California, Davis, UCD Medical Center, CRISP, 2921 Stockton Boulevard, Suite 1400, Sacramento, CA 95817. E-mail: lars.berglund{at}ucdmc.ucdavis.edu.
The possibility that insensitivity, or resistance, to insulin could be a cause of diabetes mellitus has long been recognized (1). Since the term "syndrome X" was coined by Reaven (2) <20 y ago to characterize a cluster of metabolic abnormalities associated with insulin resistance, interest in this ever more commonly occurring syndrome has increased substantially. It is well recognized that the metabolic abnormalities present in syndrome X, such as high circulating triacylglycerols, low HDL cholesterol, hypertension, and glucose intolerance, are cardiovascular disease risk factors. The constellation of these metabolic abnormalities has also been called the metabolic syndrome (3). However, although insulin resistance is common in the metabolic syndrome, syndrome X and the metabolic syndrome do not entirely overlap. Despite the recognition of the relation between insulin resistance and the associated metabolic abnormalities, progress in understanding the molecular and mechanistic underpinnings of syndrome X or the metabolic syndrome has been slow and quite challenging. A growing body of studies has pointed to the presence of heterogeneity regarding insulin resistance and insulin sensitivity among different tissues (4). Thus, there are indications that, within a person, the lipolytic response of adipose tissue may maintain insulin responsiveness even as skeletal muscle insulin resistance is detectable. In recent years, several studies independently reported that intermuscular fat deposition as well as increased fat content of muscle cells is associated with insulin resistance (5). The previously held view of adipose tissue as a relatively passive, energy-storing organ has developed into an appreciation of the important role of this tissue in regulating energy metabolism and serving endocrine functions (6). In particular, a dissociation of fatty acid release from adipose tissue from energy requirements in other organs may lead to fat deposition in nonadipose tissue, including skeletal muscle and liver (7). Using elegant, nuclear magnetic resonance spectroscopy techniques, Shulman et al (8) conducted studies suggesting that skeletal muscle mitochondrial function may be increasingly impaired with age, resulting in insulin resistance. Their findings, published in a series of articles, point to the importance of linking adipose tissue, skeletal muscle, and pancreatic endocrine function in a systems biology approach.
In the current issue of the Journal, Albu et al (9) report on the association of insulin resistance with alterations in adipose tissue and skeletal muscle in nondiabetic African American and white women by using a physiologic whole-body approach. In addition to quantifying visceral and subcutaneous adipose tissue, they assessed skeletal muscle volume and the adipose tissue depot in muscle, ie, the intermuscular adipose tissue. Previous studies pointed to a higher prevalence of obesity and diabetes mellitus as well as a higher degree of insulin resistance among African Americans than among whites, but the reasons for this difference were not clear. Using state-of-the-art imaging techniques, the authors investigated whether these apparent ethnic differences might be explained by physiologic factors. They found a higher degree of insulin resistance among African American women, also after adjustment for BMI, visceral fat, subcutaneous fat, and intermuscular adipose tissue. The only variable that significantly affected these results was skeletal muscle volume, which increased with an increase in weight more rapidly in the African American than in the white women. The authors reported that, of the body compartments analyzed, intermuscular adipose tissue predicted insulin sensitivity and also skeletal muscle volume, findings that underscored a relation between these 2 variables. Notably, when both skeletal muscle volume and intermuscular adipose tissue were included in the model, ethnicity no longer independently predicted insulin sensitivity. However, the African American women had a greater acute insulin response to glucose than did the white women, and this difference could not be explained by any of the measured body-composition variables.
These results underscore the fact that predictors of insulin resistance include elements of adipose tissue and skeletal muscle, and they focus attention on the quality of skeletal muscle as well as on the amount of adipose tissue present either between muscle fibers or within myocytes. Clearly, there are numerous causes of insulin resistance, and multiple organs, including the liver, may contribute, which points to a heterogeneity among underlying mechanisms that could affect intervention strategies. Together with emerging data on the importance of muscle mitochondrial function for development of insulin resistance and diabetes mellitus, these results underscore the importance of taking multiple tissues into account and thus focusing on a systems biology approach. However, whereas physiologic assessment methods, as used in the study by Albu et al, may be helpful in identifying mechanisms that lead to insulin resistance, it is clear that we need to link these observations to specific molecular targets to fully understand the causes of the metabolic abnormalities associated with the metabolic syndrome.
ACKNOWLEDGMENTS
The author had no personal or financial conflict of interest related to the study by Albu et al or to the article about the study.
REFERENCES
Related articles in AJCN:
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