After 1 year of Look AHEAD ILI (22
), participants with type 2 diabetes had greatly improved levels of peripheral insulin sensitivity, fasting glucose, and FFAs in parallel to significant weight and fat loss, improvement in adipose tissue distribution, and decrease in hepatic fat. The changes in the peripheral insulin sensitivity were best predicted by the overall change in weight and fat mass; the only regional fat measure independently predicting metabolic improvements was the decrease in hepatic fat.
Several studies have examined the effect of weight loss on adipose tissue distribution and organ fat infiltration in type 2 diabetes (11
). These studies varied in duration from a few weeks to up to 6 months and reported variable changes in adipose tissue distribution and organ fat depending on the measurements done and the nature of the intervention leading to the weight loss. Our study is unique in that we have studied the subjects after a 1-year intervention, have measured all aspects of adipose tissue distribution and organ fat infiltration, and enrolled a number of subjects sufficient for reporting results separately for both men and women. In general, significant loss of visceral and hepatic fat has consistently been reported, whereas a decrease in muscle fat has not been consistently observed (11
). In our study, muscle fat infiltration did not change; this could have been due to the CT measurement technique, which is less sensitive than intramyocellular lipid measurement by nuclear magnetic resonance (NMR) spectroscopy (magnetic resonance spectroscopy [MRS]), as well as to the duration and nature of the intervention. Previous studies have suggested that exercise may prevent the loss of intramyocellular lipid during weight loss induced by caloric restriction (13
). Thus, the exercise component of our intervention could have had a similar effect over the 1-year period.
We also found that men in our study, and to a lesser degree women, had favorable changes in adipose tissue distribution from the upper to the lower and from the deeper to the more superficial depots. Such changes have not previously been reported during weight loss by dieting in type 2 diabetes; the exercise component of the ILI could have played a role (35
). Changes in adipose tissue distribution could accompany significant improvements in the components of the metabolic syndrome in individuals with type 2 diabetes (35
); however, we did not find that the relationships specifically between improvements in the adipose tissue distribution and improvements in the peripheral insulin sensitivity were independent of the change in overall weight and adipose tissue mass. We therefore confirmed our original hypothesis that, with the exception of the decrease in hepatic fat, weight loss and overall adipose tissue mass reduction better predicted the improvement in peripheral insulin sensitivity than improvements in adipose tissue distribution. This finding is also in agreement with previous reports, of shorter duration, with smaller sample sizes and more homogenous weight loss (12
The decrease in insulin-suppressed FFA levels and the decrease in hepatic fat were also independent determinants of improved peripheral insulin sensitivity. The latter finding is new for type 2 diabetes to the best of our knowledge, although cross-sectional independent associations between hepatic fat and insulin sensitivity have previously been described (2
). The causative direction and the underlying pathophysiology of this association could not be determined from the present study. Changes in insulin, glucose, and FFA levels could all be potential mediators. The association between the decrease in the insulin-suppressed FFA levels and the improvement in peripheral insulin sensitivity has previously been described (12
), and the role of FFAs in the etiology of insulin resistance in type 2 diabetes has been stressed in both cross-sectional (4
) and weight loss (12
) studies. Both glucose phosphorylation and glucose transport in skeletal muscle are known to be affected by circulating FFA levels (21
) and, in turn, improve with weight loss in type 2 diabetes (39
). We also found that the change in peripheral insulin sensitivity was related to the relative improvement in superficial adipose tissue distribution and the decrease in this depot's mean fat cell size. These relationships were not independent of the change in body weight but are significant in that they point to the importance of the subcutaneous fat characteristics in the etiology of insulin resistance in type 2 diabetes (18
With regard to fasting glucose, our results are similar to those previously published (12
) in that the best predictor for the improvement in fasting glucose was the improvement in insulin sensitivity (GDR). The changes in VAT and hepatic fat were associated with the improvement in fasting glucose independent of changes in overall adipose tissue mass, but only the change in hepatic fat was related to the change in fasting glucose, independent of the change in GDR. We also report for the first time that the changes in insulin-suppressed FFAs were related to the change in hepatic fat. The importance of hepatic fat as a determinant of metabolic parameters in type 2 diabetes has been underscored by cross-sectional associations with hepatic insulin resistance (12
) and by associations with insulin requirements during insulin therapy in type 2 diabetes, independent of measured insulin action and FFA levels (40
). In our study, a decrease in hepatic fat was associated with improvements in all three key metabolic variables studied. The exact mechanism is not known; among other possibilities is improved insulin clearance after weight loss (8
), which in addition to the improved β-cell function, could result in a more physiologic insulin pattern and lower both plasma glucose and FFAs (7
). Thus, we conclude that changes in hepatic fat play a key role in the improvement of metabolic parameters with weight loss in type 2 diabetes.
The changes in the oral hypoglycemic agents that occurred over the 1-year intervention are a potential limitation for our study. We performed separate analyses excluding the two subjects who were on insulin-sensitizing agents at the 1-year testing and not at baseline and adding discontinuation of any oral agents at 1 year compared with baseline (yes or no) as a factor. Results were essentially unchanged with a notable exception: the sex differences in the overall weight or fat loss () were not significant anymore once the discontinuation of the oral agents was accounted for. The peripheral insulin sensitivity changes () and the adipose tissue distribution changes presented in were not affected. Therefore, we speculate that, since more men discontinued oral agents than women, this may have accounted for the sex differences in the overall weight and fat loss. The baseline menopausal status of our women and its change over time could also have potentially influenced our results. Four women changed menopausal status over the course of the study; none changed hormone-replacement therapy. Although we did not find interactions by menopausal status in our analyses (results not shown), the number of women in the different categories is too small to exclude a possible influence of baseline menopausal status on adipose tissue distribution changes over the 1 year of the study.
Finally, the Look-AHEAD trial participants had measurements of fitness at baseline and then yearly throughout the ILI, as previously described (24
). In our cohort, fitness improved by 40 ± 8 and by 31 ± 7% in men and women, respectively (P
< 0.0001). The difference in magnitude compared with the fitness improvement of the entire ILI arm (25 and 18% in men and women, respectively) (25
) could be due to the special selection criteria of our study. Just for the entire ILI group (25
), in our study the fitness improvement was significantly correlated with the degree of weight loss; in addition, it was significantly correlated with changes in FM, percent body fat, and GDR but not with changes in fasting glucose or FFA. The fitness improvement, however, did not predict changes in GDR independent of the overall weight or fat loss, which is consistent with results from other studies (42
In conclusion, patients with type 2 diabetes undergoing a 1-year lifestyle intervention of diet and exercise had significant improvements in adipose tissue distribution, insulin sensitivity, fasting glucose, and circulating FFAs. Changes in overall weight, adipose mass, and hepatic fat were the most important associates of metabolic improvements.