Among adults with type 2 diabetes, 12 months of an intensive lifestyle intervention leading to 8% loss of body weight was successful in both reducing hepatic steatosis and decreasing the risk of incident NAFLD, compared with those in a control group Furthermore, a dose-response relationship was observed with weight loss, with the greatest reduction observed in those with the greatest weight loss (≥10%). Our findings therefore support the current recommendation for weight loss using lifestyle modification as the first step in the management of patients with NAFLD, including patients with type 2 diabetes and for those at risk for NAFLD.
We found that the decrease in steatosis was nearly double in the ILI group compared with that in the DSE group. In addition, as in the main Look AHEAD 1-year results (9
), the use of overall and specific medications such as thiazolidinedione and metformin tended to decrease more among the intervention arm. We would anticipate that these differences would then favor the control arm, leading to a more conservative estimate. These findings are important because NAFLD not only disproportionately affects individuals with type 2 diabetes but also because once NAFLD is present, the risk of developing more advanced forms of NAFLD, such as nonalcoholic steatohepatitis and hepatocellular carcinoma is higher in this group than in the general population (3
Our results are consistent and extend previous trials of weight loss for patients with NAFLD, suggesting improvement in hepatic steatosis. To our knowledge there have been a total of nine clinical studies of lifestyle intervention on hepatic steatosis measured by 1
H MRS (14
), and, of these, only two have been conducted among individuals with type 2 diabetes (17
). Petersen et al. (17
) treated eight individuals with obesity and diabetes with a 1,200-calorie liquid diet for 3–12 weeks to achieve 8% weight loss. Steatosis decreased on average 81% (from 12 to 2.2%). Tamura et al. (17
) randomly assigned 14 subjects to a controlled diet only (25–30 kcal/kg ideal body weight) or exercise and diet (same diet plus two or three 30-min sessions of walking 5–6 days/week) for 2 weeks. In this inpatient study, the mean decreases in hepatic steatosis were 25 and 28% for the diet only and diet plus exercise group, respectively (18
). Our study extends these findings in patients with type 2 diabetes by including a larger and diverse sample and a longer intervention.
Because most participants had normal liver enzymes at baseline, it is understandable that there was no significant change with weight loss and decrease in steatosis. However, consistent with other studies, our data show that normal liver test results are not good indicators of the presence or absence of hepatic steatosis.
Cytokines and adipokines have been posited to play an important role as mediators of improved hepatic insulin sensitivity with weight loss. In our study, changes in steatosis and adiposity were not associated with changes in IL-8, IL-10, TNF-α, adiponectin, ghrelin, or resistin. These results are consistent with two other previous studies (16
) and suggest that among individuals with type 2 diabetes these may not play a major role in changing insulin sensitivity in the liver.
Although a clinically meaningful change in steatosis remains to be defined, our results suggest that among patients with type 2 diabetes, reduction in hepatic steatosis is significantly associated with levels of A1C and triglycerides, both of which are important markers of disease risk and control (23
). Longer studies are needed to identify meaningful changes in liver fat, with respect to liver outcomes.
Our study has some limitations. First, we had no histopathological data to assess the effect of the intervention. Although 1
H MRS is an excellent method to quantify changes in steatosis because it is noninvasive and reliable, it cannot assess inflammation or fibrosis. Recently, Promrat et al. (24
) reported the results of an smaller trial of lifestyle intervention for 31 overweight patients with biopsy-proven nonalcoholic steatohepatitis, and their results are in agreement with our findings. In addition, our study included older individuals with type 2 diabetes and mostly with normal liver enzyme levels, probably reflecting a different spectrum of the disease. Second, even though this trial is by far is the largest of its kind, the study sample was not large enough to study participant subgroups (i.e., sex and race or to assess sex-treatment or race-treatment interactions). Third, we studied participants in a large randomized clinical trial who are likely to represent a very motivated group; however, although limiting generalizability, this setting is ideal to assess the efficacy of this intervention. Future studies will be needed to assess the effectiveness of this approach. Fourth, even though the parent study had a randomized design, our study groups were not comparable in all respects, probably because enrollment into this ancillary study occurred after randomization and by random chance. To address these imbalances we adjusted all our analyses by these baseline differences. Finally, because obesity hinders the successful acquisition of 1
H MRS, the results may be conservative.
In summary, in patients with type 2 diabetes, an intensive lifestyle intervention that produced 8% weight loss resulted in a significant, 25% greater reduction in hepatic steatosis and a substantially lower incidence of NAFLD compared with that of a comparison group after 12 months of the intervention. The long-term efficacy as well as the effectiveness of an intensive lifestyle intervention needs to be further established.