Discussion
HED, obesityStill, reductions in visceral and ectopic fat, prediabetes, skeletal muscle microvascular blood flow, weight loss
SECONDARY, INCREASED INSULIN, INSULIN SENSITIVITY, PREDIABETES
One of our main findings is that all intervention groups improved beta-cell function, as expressed by late-phase DI, more than standard care. Furthermore, adding exercise to diet-induced weight loss improved beta-cell function more than diet-induced weight loss or standard care alone. This seemed to be achieved by additional increases in insulin sensitivity induced by exercise in a dose-dependent manner. However, the secondary and exploratory outcomes did not uniformly support the linear dose–response relationship observed for the primary outcome.There is a paucity of studies investigating the role of exercise and exercise volume in conjunction with diet-induced weight loss, but our observations are in line with previous findings suggesting that high volumes of exercise without a concomitant dietary intervention improve first-phase and/or late-phase DI in people with prediabetes and T2DAlthough we did not observe a difference in late-phase ISR with increased exercise volume compared with diet-induced weight loss alone, all intervention groups exhibited similar increases in late-phase ISR. Therefore, it could be speculated that diet-induced weight loss alone might explain this observation and that a weight loss of ~7.5% body weight may be sufficient to re-establish late-phase ISR in this study population. Supporting this, a previous study from our group, using the same intervention protocol as for HED, also increased DI. Consistent with our current findings, only the improvement in insulin sensitivity index, and not the small increase in insulin secretion, was associated with exercise volume in that studyIn this study, both late-phase DI and late-phase ISI increased linearly with increasing treatment intensity. However, a similar relationship was not observed during the MMTT nor in first-phase DI or the GLP-1 and arginine stimulations. Although speculative, this may relate to the route of glucose administration. Recently, it was described that the increased insulin secretion observed after oral administration of glucose compared with intravenous administration might be accompanied by a compensatory decrease in insulin sensitivityThese findings suggest that there is only a limited effect of increasing exercise volume from three to six sessions weekly in the context of diet-induced weight loss. Likewise, although weight loss was larger in both exercise groups compared with diet-induced weight loss alone, there was no apparent additional weight loss when doubling the exercise volume from three to six sessions per week. In contrast, the increase in both absolute and relative VOAlthough a weight loss of ≥5% may increase beta-cell function slightly, a weight loss of ≥11% may be necessary to maximize an increase in peripheral insulin sensitivity in people with obesityStill, diet-induced weight loss may primarily improve hepatic (central) insulin sensitivity and beta-cell insulin secretory capacity through reductions in visceral and ectopic fat (that is, in liver and pancreas) that confer a dose-dependent increase in beta-cell functionInterestingly, weight loss completely mediated the intervention effects in the oral DI and oral ISI, suggesting that weight loss becomes the most important signal in the context of an oral mixed meal and normal homeostatic postprandial regulation. Although speculative, this may relate not only to the complex neuronal and endocrine organ crosstalk, but also to the meal composition wherein certain amino acids and fatty acids regulate insulin secretion, as well as skeletal muscle microvascular blood flow.