It is well-established that weight loss reduces risk of type 2 diabetes and improves glycemic control in men with established type 2 diabetes.13, 29, 30 For instance, meta-analyses have concluded that a weight loss of >5% at 12 months appears necessary for beneficial effects on glycemic control,30 and that every kilogram of weight lost is associated with an additional 7% decrease in risk of progression to type 2 diabetes.29 However, the T4DM trial shows that improvement in body composition may be of greater importance than weight loss per se.
In the T4DM trial, lifestyle intervention alone (placebo group) resulted in a weight loss of -3.53 kg (3.3%) while lifestyle intervention combined with testosterone treatment resulted in a 4.45 kg (4.2%) weight loss.11 The difference in weight loss between groups (-0.92 kg) did not reach statistical significance. Despite similar weight loss, the incidence of type 2 diabetes was nearly twice as high in the placebo group. This suggests that weight loss is not an accurate predictor of intervention effectiveness for diabetes prevention.
The reason for the lack of significant difference in weight loss between placebo and testosterone groups is that in the testosterone group, the reduction in total and abdominal fat mass was offset by an increase in muscle mass.11 Increased muscle mass is a well-documented effect of testosterone treatment,17, 31 and smaller studies have shown that testosterone treatment may attenuate weight loss-induced reduction in muscle mass.31, 32
The increase in muscle mass seen in testosterone treated men is particularly noteworthy, considering that a concern with traditional weight loss interventions is that they cause a significant loss of muscle mass.33 A decrease in muscle mass and concomitant decrease in strength, as seen in the placebo group in the T4DM trial, is a detrimental consequence of weight loss induced by lifestyle interventions, which can only be partly counteracted by an increase in physical activity.34 For instance, in the Look AHEAD trial, which is the longest duration intensive lifestyle intervention with body composition data, from baseline to year 1, men and women in the intervention group had a weight loss of 9.4 and 7.0 kg, of which 6.6 kg (70%) and 5.0 kg (71%) was body fat mass, respectively.35 In other words, lean mass made up 30% of the weight loss. From year 1 to 8, there was minimal change in lean mass; the weight gain was nearly exclusively body fat gain. In a sex-specific analysis, differences in fat mass among men in the intervention group and control group (standard diabetes education) were not significant at year 8, however, men in the intervention group had a significantly greater loss of lean mass at all time points.35
Preservation of lean (muscle) mass during weight loss is critical, as loss of muscle mass may increase risk for weight regain and increased fatness over time, by lowering maintenance energy requirement and triggering increased hunger/appetite.36 Furthermore, muscle tissue is important for maintenance of metabolic health,37 bone mass/skeletal integrity,38 as well as quality of life.39 Higher muscle mass is associated with a significantly reduced risk of the metabolic syndrome,40 nonalcoholic fatty liver disease 41 and, as shown in the T4DM trial, type 2 diabetes.42 Furthermore, higher muscle mass is associated with lower mortality risk, independently of body fat mass, cardiovascular and metabolic risk factors.43-46
It has been suggested that in healthy weight loss, the fraction of weight loss attributed to lean body mass should not exceed 25%.47 A meta-analysis of lifestyle interventions for weight loss (minimum intervention period including follow-up ≥12 months) found that 25% of weight loss commonly constitutes lean body mass.48 A systematic review found that the mean lean body mass loss as a percentage of weight loss after dietary and drug based weight loss interventions (resulting in a weight loss of >10 kg) is 27% and 31%, respectively.49 While the composition of weight loss is influenced by variables such as physical activity, diet composition, degree of caloric restriction, and - as shown in the T4DM trial - testosterone treatment, weight loss comprising less than 25% lean body mass may be a reasonable reference point for examination of the degree to which different weight loss interventions achieve preservation of muscle mass and healthy weight loss.
In the T4DM trial, loss of muscle mass in the placebo group was -37.4% (1.32/3.53 = 0.3739), which is alarmingly high.11 In contrast, in testosterone treated men, all weight loss was fat loss, which was accompanied by a small but significant increase in muscle mass. Hence, the T4DM trial provides evidence that testosterone therapy in conjunction with lifestyle intervention results in a significant improvement in body composition, which likely underlies the significantly larger reduction in incidence of type 2 diabetes, compared to men undergoing lifestyle intervention alone. Support for this comes from several studies showing that lower muscle mass is associated with higher fasting and postprandial blood glucose, as well as elevated insulin levels,50 and that higher muscle mass is associated with improved insulin sensitivity and reduced risk for prediabetes and type 2 diabetes.50, 51 After adjusting for age, ethnicity, sex, obesity and waist circumference, each 10% increase in muscle mass index (calculated as muscle mass divided by height squared) has been shown to be associated with 14% reduced insulin resistance and 23% reduced prediabetes risk 50. Muscle, together with the liver, is the main site for storage of glucose (as glycogen) after meals, and therefore plays a central role in glucose disposal.52 Therefore, it is crucial that future studies of interventions for type 2 diabetes prevention/reversal analyse not only weight loss, which can mask important changes in body composition, but also actual fat loss and change in muscle mass.