Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.

Diet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D ( 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).

Aim: Patients with Type 2 Diabetes Mellitus (T2DM) have increased risk of developing vascular complications due to chronic hyperglycemia. Glycemic variability (GV) has been suggested to play an even more important role in the risk of developing diabetic complications than sustained hyperglycemia. Physical activity (PA) has shown reducing effects on mean plasma glucose; however, the effect on GV in T2DM needs further description. The objective of this review is to evaluate the effect of PA on GV, assessed by continuous glucose monitoring (CGM) in people with T2DM. Methods: A systematic literature search was conducted on MEDLINE and Embase to find randomized controlled trials (RCTs) covering the aspects T2DM, PA, and CGM. Following eligibility screening, variables of population characteristics, PA interventions, and GV outcomes were extracted and processed through qualitative synthesis. Risk of bias (ROB) was assessed using Cochrane ROB tool v2.0. Results: Of 1,825 identified articles, 40 full texts were screened. In the ten included RCTs matching the eligibility criteria, sample sizes ranged from nine to 63, mean age from 51 (SD 11) to 65 (SD 2) years and mean T2DM duration from four (SD 3) to ten (SD 6) years. Eight RCTs examined GV following single bouts of exercise, while two RCTs examined GV following training interventions. One RCT applied parallel group design, while nine RCTs applied crossover design. Numeric reductions in GV following acute exercise were seen, with four RCTs reaching statistical significance. Numeric reductions in GV were seen following training interventions, with one RCT reaching statistical significance. Numeric reductions of GV after PA appeared independently of intensity and T2DM progression but higher in participants with high baseline HbA1c and GV than with low. 80% of the trials were evaluated as uncertain/high ROB. Conclusion: The systematic literature search revealed limited and biased evidence showing that acute PA numerically reduced GV in patients with T2DM. PA reduced GV independently of PA intensity and T2DM progression. Prolonged RCTs with low ROB are needed to confirm reducing effects of PA on GV and to assess the influence of patient- and intervention characteristics on the effect of PA on GV.

This study aimed to determine whether minimum recommended moderate-to-vigorous physical activity (MVPA; 30-min bout of continuous moderate-intensity walking) is sufficient to counteract the detrimental effects of prolonged sitting on postprandial metabolism and if there are any effects of breaking up sitting with intermittent standing when achieving minimum recommended MVPA. Fourteen (n = 14) physically inactive healthy adult males underwent four intrahospital 27-h interventions: 9-h continuous sitting (SIT), 15-min standing bouts every 30 min during the 9-h sitting (STAND), 30-min moderate-intensity walking bout followed by 8.5 h of sitting (MVPA), and 30-min moderate-intensity walking bout followed by 15-min standing bouts every 30 min during 8.5 h of sitting (MVPA + STAND). Three standardized meals on intervention day (day 1) and breakfast the following day (day 2) were served. Cumulative postprandial glucose response (incremental area under the curve) was lower in STAND versus SIT (↓27%, P = 0.04, effect size [ES] = −0.7) because of decreases in postprandial glucose after breakfast on day 1 (STAND vs SIT: ↓40%, P = 0.01, ES = −0.7) and day 2 (STAND vs SIT: ↓33%, P = 0.06, ES = −0.6). STAND did not affect postprandial insulin responses. Cumulative postprandial insulin response was lower in MVPA versus SIT (↓18%, P = 0.03, ES = −0.3) and MVPA + STAND versus SIT (↓26%, P = 0.02, ES = −0.4) because of expected exercise-induced decreases in postprandial insulin after breakfast on day 1 only (MVPA vs SIT: ↓36%, P = 0.003, ES = −0.7; MVPA + STAND vs SIT: ↓43%, P = 0.0001, ES = −0.8). Breaking up prolonged sitting with nonambulatory standing across 9 h acutely reduced postprandial glycemic response during and the day after the intervention independent of insulin levels, whereas a 30-min MVPA bout did not.