The Effect of Adding Different Doses of Exercise Training to a Diet-Induced Weight Loss on Beta-Cell Function in Persons with Newly Diagnosed Type 2 Diabetes: Primary Findings from the DOSE-EX Multi-Arm, Parallel-Group, Randomized Trial

Abstract Diet-induced weight loss improves beta-cell function in persons with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to a diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. In this four-armed randomized trial (Clinicaltrials.gov NCT03769883) 82 persons (35% females, mean age (SD) of 58.2 (9.8) years) with newly diagnosed T2D (<7 years) were randomly allocated to standard care (N=21), calorie restriction (25% energy reduction; N=20), calorie restriction and exercise 3 times per week (N=20) or calorie restriction and exercise 6 times per week (N=21) for 16 weeks. We determined beta-cell function by calculating the disposition index (insulin secretion multiplied by insulin sensitivity), during the first stage of a 3-stage hyperglycemic clamp technique (primary outcome) and based on a liquid mixed meal tolerance test (MMTT). Glucagon-like peptide-1 and arginine was infused during the 2nd and 3rd stage of the clamp, respectively. The beta-cell function during the clamp increased more in all three intervention groups compared to standard care (diet control group (DCON), 58%; 95% confidence intervals [CI] 16 to 116; moderate exercise dose group (MED) 105%; 95% CI, 49 to 182 and high exercise dose group (HED), 137%; 95% CI, 73 to 225) and followed a linear dose-response relationship (p<0.001 for trend). The beta-cell function during the MMTT also increased more in all three intervention groups compared to standard care (DCON, 87%; 95% CI 40 to 148; MED 133%; 95% CI, 73 to 213 and HED, 141%; 95% CI, 80 to 223) but with no linear dose-response improvement. Glucagon-like peptide-1 infusion increased insulin secretion more in all interventions (p≤0.001 for differences to CON) but only MED was associated with higher mean insulin secretion compared to DCON (p=0.045). Adding an exercise intervention to a diet-induced weight loss improves glucose stimulated beta-cell function in newly diagnosed persons with T2D in an exercise dose-dependent manner. However, when the beta-cell function was assessed during a MMTT, no consistent evidence of additional improvements in beta-cell function was observed when increasing exercise dose from 3 to 6 times per week.