Effects of different doses of exercise in adjunct to diet-induced weight loss on the AGE-RAGE axis in patients with short standing type 2 diabetes: Secondary analysis of the DOSE-EX multi-arm, parallel-group, randomised trial.

AIMS/HYPOTHESIS: These secondary analyses aimed to investigate the effects of different volumes of exercise in adjunct to diet-induced weight loss and standard care on advanced glycation end-products (AGEs) and receptor for AGE (RAGE). We hypothesized that exercise in adjunct to a diet-induced weight loss would dose-dependently increase the soluble decoy receptor for AGE (sRAGE) more than diet-induced weight loss and standard care alone. Secondarily, we expected changes in sRAGE to be associated with improved glycaemic control and inversely associated with low-grade inflammation. METHODS: The DOSE-EX study was a 16-week parallel-group, 4-arm, single-centre, assessor-blinded, randomised, controlled trial (NCT03769883). We included persons living with T2D, duration ≤7 years, BMI >27 kg/m2 and <40 kg/m2, without severe diabetic complications. Participants were randomised (1:1:1:1) to either 1) standard care as control (CON), 2) standard care + diet (DCON), 3) standard care + diet + moderate exercise dose (MED) or 4) standard care + diet + high exercise dose (HED). Standard care included algorithm-guided pharmacological treatment. The diet intervention aimed at 25% reduced energy intake. The supervised exercise sessions included two aerobic sessions + one combined (aerobic and resistance training) session per week for the MED group, and four aerobic sessions + two combined sessions per week for the HED group. Primary outcome was the change in sRAGE from baseline to 16-week follow-up. Secondary outcomes encompassed changes in advanced glycation endproducts (AGE), glycaemic control and markers of low-grade inflammation. RESULTS: A total of 80 participants (CON: n = 20, DCON: n = 19, MED: n = 20, HED: n = 21) were included in this secondary analysis. The mean age was 58.3 years (SD 9.9), 53% males, and median T2D duration was 4.1 years (IQR 2.0-5.5). No change in sRAGE was observed in any of the groups from baseline to follow-up (p > 0.05). CONCLUSION/INTERPRETATION: A 16-week intervention with either three or six exercise sessions per week in adjunct to diet-induced weight loss did not change the levels of sRAGE in persons living with well-regulated, short standing T2D.

Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial.

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 (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose-response relationship (P > 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).