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EDITORIAL |
1 From the Division of Endocrinology, Department of Internal Medicine, Central Arkansas Veterans Healthcare System, and the College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR
2 Reprints not available. Address correspondence to SC Elbein, Division of Endocrinology 111J/LR, Central Arkansas Veterans Healthcare System, 4300 West 7th Street, Little Rock, AR 72206. E-mail: elbeinstevenc{at}uams.edu.
See corresponding article on page 1590.
In this issue of the Journal, Miljkovic-Gacic et al (1) describe a cross-sectional study of 1249 Afro-Caribbean men from the Tobago Health Study, a study originally designed to examine prostate cancer (and thus limited to men 
40 y old). This population has a particularly high prevalence of type 2 diabetes—>20%—and nearly 70% of the population is either overweight or obese. Almost half of the men report a family history of type 2 diabetes. In this large and unique study, the investigators obtained quantitative computed tomography (QCT) measures of the lower calf, with quantitation of total muscle area and adipose tissue distribution of the calf. The authors report that, with aging, intermuscular adipose tissue (IMAT) increased, whereas subcutaneous adipose tissue and total muscle areas decreased. As in many previous studies, measures of obesity and family history were associated with type 2 diabetes, as was IMAT. Perhaps it is counterintuitive, but, as in at least one previous study (2), the amount of subcutaneous adipose tissue in the calf was inversely proportional to diabetes risk. In a logistic regression multivariate analysis, traditional risk factors of age and body mass index were most predictive, subcutaneous fat was protective, family history of diabetes was the most strongly predictive, and IMAT was modestly but significantly predictive of type 2 diabetes. Miljkovic-Gacic et al report that the positive association between fasting plasma glucose and IMAT was stronger in those persons with a family history of diabetes (P = 0.02 for the interaction), whereas no such association was observed for subcutaneous fat. This unexpected and provocative finding may suggest a gene x environment interaction. Alternatively, IMAT may be a better marker of diabetes risk in the presence of the multiple genetic determinants that characterize a strong family history of diabetes.
The strong association of various measures of intermuscular and intramuscular lipid accumulation with insulin resistance, obesity, and type 2 diabetes has been known for at least a decade and has been shown by multiple investigators using methods ranging from muscle biopsy with total lipid extraction to oil red O staining to computerized tomography to magnetic resonance spectroscopy and magnetic resonance imaging (3, 4). Each of these methods, although likely measuring different proportions of intramuscular and intermuscular fat, nonetheless showed a similar association with insulin resistance and diabetes. The study of Miljkovic-Gacic et al specifically measured intermuscular fat, which is the small adipose depot interspersed between muscle fibers. The authors do not provide measures, such as attenuation scores, that may reflect intramyocellular fat. Although it may seem easier to link intramyocellular fat than intermuscular fat to impaired insulin action in muscle, even that measure is but a marker of high triacylglycerols and low fat oxidation in sedentary persons. Paradoxically, endurance exercise training increases intramyocellular fat in persons who are lean, insulin sensitive, and at low risk of type 2 diabetes (5). Whether IMAT is similarly increased with exercise training or whether it, like visceral obesity, represents a redistribution of adipose to less healthy locations is not clear. Plausible hypotheses exist for why visceral fat can alter whole-body insulin action, but why IMAT would do so is unclear. Like intramyocellular fat, IMAT may be a marker of excess caloric intake, particularly fat intake, and of a sedentary lifestyle, rather than being causative of metabolic syndrome.
A key finding of the study of Miljkovic-Gacic et al was the interaction of family history and IMAT. That finding may point to a genetic interaction specific to this population that increases the risk of type 2 diabetes in persons with high IMAT, but many other explanations also are plausible. IMAT may be a marker of lipid partition away from subcutaneous depots such as hip and thigh, which appears to improve insulin sensitivity, and genetic factors may determine that distribution of fat. Alternatively, the interaction of family history and IMAT may be similar to the synergistic combination of obesity and family history, and IMAT may simply be a marker of caloric excess and a sedentary lifestyle, which, in the presence of a family history, are known to increase diabetes risk. Unfortunately, this cross-sectional epidemiology study provides few clues about diabetes pathogenesis in this very-high-risk cohort. Finally, whether the findings reported here are unique to this population or whether they, instead, reflect the high prevalence of obesity and the strong family history of diabetes in this older, male population is uncertain. To understand the interaction graphically, it would be helpful to see the IMAT by age curves according to family history.
Studies that have compared IMAT among ethnic groups are limited. Many studies suggest that African American persons are more insulin resistant than are whites. Although the current study proposes that greater IMAT may be causal, it may instead be a marker for lifestyle differences. It is interesting that Liska et al (6) recently reported that obese African American adolescents had less intramyocellular fat, as measured by magnetic resonance imaging, than did either white or Hispanic adolescents. In an examination of IMAT in elderly African American and white men and women, Goodpaster et al (7) reported findings similar to those of the study by Miljkovic-Gacic et al— ie, no difference by ethnicity in the effect of IMAT on metabolic syndrome. These studies raise questions about whether populations of African ancestry are indeed predisposed to a diabetogenic distribution of adipose as an explanation for their high diabetes prevalence.
From a physiologic standpoint, what do measures of intermuscular or intramyocellular fat mean? Although they are reproducible risk factors, neither depot appears to be the cause of insulin resistance. Considerable data suggest reduced oxidative phosphorylation in diabetic muscle, particularly resulting from pathways of peroxisome proliferator–activated receptor co-activator 1-
and nuclear respiratory factor 1 (8, 9). Similarly, mitochondrial activity is decreased in type 2 diabetes and with aging (10), which suggests decreased lipid oxidation in both conditions. These findings may explain the observations that IMAT correlates with age and type 2 diabetes. A recent study in whites (11) suggested that mitochondrial gene NDUFB6 expression was decreased with age in muscle. A common promoter variant was methylated in older but not younger persons, and thus expression decreased with age. Such studies suggest that increased intramyocellular fat or perhaps IMAT in the presence of a family history of diabetes and with increasing age may be a stronger marker of reduced oxidative phosphorylation and hence diabetes risk. Because of the greater genetic diversity in populations of African ancestry than in white populations, such genetic variation may account for the observations of the study by Miljkovic-Gacic et al.
Their rather large study adds one more piece of evidence that, in the setting of a high-risk population, IMAT along with intramyocellular lipid is another risk factor for type 2 diabetes. Whether this risk factor adds substantially to the more traditional, easily measured risk factors is not clear, and although the Tobago Health Study population is unusual, the reported findings are very similar to those reported in earlier studies. Increased IMAT and decreased calf subcutaneous fat may reflect a propensity to pathological partitioning of fat, such that, rather than fat residing in "healthy" depots (thigh and legs), caloric excess leads to triacylglycerol accumulation in pathological depots such as IMAT, intramyocellular triacylglycerol droplets, or fatty liver—ie, the "lipotoxicity" hypothesis. Whether IMAT in a very-high-risk, mostly obese Afro-Caribbean cohort represents a risk factor for diabetes such as a specific genetic propensity or instead reflects the high prevalence of obesity in a population selected for more advanced age remains to be determined.
ACKNOWLEDGMENTS
SCE had no personal or financial conflict of interest. NR has received investigator-initiated grants and honoraria for speaking engagements from the Takeda, Merck, and Abbott companies.
REFERENCES
Related articles in AJCN:
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