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).

Effects of an exercise-based lifestyle intervention on systemic markers of oxidative stress and advanced glycation endproducts in persons with type 2 diabetes: Secondary analysis of a randomised clinical trial.

AIMS/HYPOTHESIS: This secondary analysis aimed to investigate the effects of a 12 months intensive exercise-based lifestyle intervention on systemic markers of oxidative stress in persons with type 2 diabetes. We hypothesized lifestyle intervention to be superior to standard care in decreasing levels of oxidative stress. METHODS: The study was based on the single-centre, assessor-blinded, randomised, controlled U-turn trial (ClinicalTrial.gov NCT02417012). Persons with type 2 diabetes ˂ 10 years, ˂ 3 glucose lowering medications, no use of insulin, BMI 25-40 kg/m2 and no severe diabetic complications were included. Participants were randomised (2:1) to either intensive exercise-based lifestyle intervention and standard (n = 64) or standard care alone (n = 34). Standard care included individual education in diabetes management, advice on a healthy lifestyle and regulation of medication by a blinded endocrinologist. The lifestyle intervention included five to six aerobic exercise sessions per week, combined with resistance training two to three times per week and an adjunct dietary intervention aiming at reduction of ∼500 kcal/day (month 0-4). The diet was isocaloric from months 5-12. The primary outcome of this secondary analysis was change in oxidative stress measured by 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and secondarily in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), as markers of RNA and DNA oxidation, respectively, from baseline to 12-months follow-up. RESULTS: A total of 77 participants, 21 participants receiving standard care and 56 participants receiving the lifestyle intervention, were included in the analysis. Mean age at baseline was 54.1 years (SD 9.1), 41% were women and mean duration of type 2 diabetes was 5.0 years (SD 2.8). From baseline to follow-up the lifestyle group experienced a 7% decrease in 8-oxoGuo (-0.15 nmol/mmol creatinine [95% CI -0.27, -0.03]), whereas standard care conversely was associated with a 8.5% increase in 8-oxoGuo (0.19 nmol/mmol creatinine [95% CI 0.00, 0.40]). The between group difference in 8-oxoGuo was -0.35 nmol/mmol creatinine [95% CI -0.58, -0.12,], p = 0.003. No between group difference was observed in 8-oxodG. CONCLUSION/INTERPRETATION: A 12 months intensive exercise-based lifestyle intervention was associated with a decrease in RNA, but not DNA, oxidation in persons with type 2 diabetes.

The effects of different doses of exercise on pancreatic ß-cell function in patients with newly diagnosed type 2 diabetes: study protocol for and rationale behind the "DOSE-EX" multi-arm parallel-group randomised clinical trial.

BACKGROUND: Lifestyle intervention, i.e. diet and physical activity, forms the basis for care of type 2 diabetes (T2D). The current physical activity recommendation for T2D is aerobic training for 150 min/week of moderate to vigorous intensity, supplemented with resistance training 2-3 days/week, with no more than two consecutive days without physical activity. The rationale for the recommendations is based on studies showing a reduction in glycated haemoglobin (HbA1c). This reduction is supposed to be caused by increased insulin sensitivity in muscle and adipose tissue, whereas knowledge about effects on abnormalities in the liver and pancreas are scarce, with the majority of evidence stemming from in vitro and animal studies. The aim of this study is to investigate the role of the volume of exercise training as an adjunct to dietary therapy in order to improve the pancreatic ß-cell function in T2D patients less than 7 years from diagnosis. The objective of this protocol for the DOSE-EX trial is to describe the scientific rationale in detail and to provide explicit information about study procedures and planned analyses. METHODS/DESIGN: In a parallel-group, 4-arm assessor-blinded randomised clinical trial, 80 patients with T2D will be randomly allocated (1:1:1:1, stratified by sex) to 16 weeks in either of the following groups: (1) no intervention (CON), (2) dietary intervention (DCON), (3) dietary intervention and supervised moderate volume exercise (MED), or (4) dietary intervention and supervised high volume exercise (HED). Enrolment was initiated December 15th, 2018, and will continue until N = 80 or December 1st, 2021. Primary outcome is pancreatic beta-cell function assessed as change in late-phase disposition index (DI) from baseline to follow-up assessed by hyperglycaemic clamp. Secondary outcomes include measures of cardiometabolic risk factors and the effect on subsequent complications related to T2D. The study was approved by The Scientific Ethical Committee at the Capital Region of Denmark (H-18038298). TRIAL REGISTRATION: The Effects of Different Doses of Exercise on Pancreatic ß-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX), NCT03769883, registered 10 December 2018 https://clinicaltrials.gov/ct2/show/NCT03769883 ). Any modification to the protocol, study design, and changes in written participant information will be approved by The Scientific Ethical Committee at the Capital Region of Denmark before effectuation. DISCUSSION: The data from this study will add knowledge to which volume of exercise training in combination with a dietary intervention is needed to improve ß-cell function in T2D. Secondarily, our results will elucidate mechanisms of physical activity mitigating the development of micro- and macrovascular complications correlated with T2D.

The Impact of Physical Activity on Glycemic Variability Assessed by Continuous Glucose Monitoring in Patients With Type 2 Diabetes Mellitus: A Systematic Review.

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.