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).

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.

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (-2.7 ± 8.2% in the placebo vs. -20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

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.

Interleukin-6 May Not Affect Bone Resorption Marker CTX or Bone Formation Marker P1NP in Humans.

CONTEXT: Interleukin 6 (IL-6) contributes to bone remodeling in preclinical studies. Clinical trials investigating the role of IL-6 in bone remodeling are limited. OBJECTIVE: To investigate if IL-6 regulates bone remodeling in humans. DESIGN: Plasma concentrations of the bone resorption marker carboxy-terminal type I collagen crosslinks (CTX) and of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) were measured during a mixed-meal tolerance test (MMTT) in 3 placebo-controlled human studies. PARTICIPANTS: Five healthy individuals participated in study 1; 52 obese individuals, in study 2; and 10 healthy individuals, in study 3. INTERVENTIONS: Study 1 was a single-blinded crossover study consisting of a 1-h infusion of saline (placebo) or the IL-6 receptor antibody tocilizumab followed by an exercise bout. Study 2 was a randomized, double-blinded 12-week exercise training intervention study. Participants received infusions of saline or tocilizumab. Study 3 was a randomized, double-blinded, crossover study consisting of 30 min infusion of saline or IL-6. MAIN OUTCOMES MEASURES: Effect of IL-6 on CTX levels. RESULTS: CTX was significantly (P < 0.01) decreased during MMTTs in all 3 studies. Treatment with tocilizumab did not affect exercise or meal induced changes in plasma CTX or P1NP concentrations acutely (study 1) or after a 12-week treatment period (study 2). Exogenous IL-6 had no effect on CTX or P1NP plasma concentrations (study 3). CONCLUSIONS: IL-6 may not regulate bone remodeling in humans.

GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study.

AIMS/HYPOTHESIS: IL-6 is a cytokine with various effects on metabolism. In mice, IL-6 improved beta cell function and glucose homeostasis via upregulation of glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise potentiated this beneficial increase in GLP-1. This study aimed to identify whether exercise-induced IL-6 has a similar effect in humans. METHODS: In a multicentre, double-blind clinical trial, we randomly assigned patients with type 2 diabetes or obesity to intravenous tocilizumab (an IL-6 receptor antagonist) 8 mg/kg every 4 weeks, oral sitagliptin (a dipeptidyl peptidase-4 inhibitor) 100 mg daily or double placebos (a placebo saline infusion every 4 weeks and a placebo pill once daily) during a 12 week training intervention. The primary endpoints were the difference in change of active GLP-1 response to an acute exercise bout and change in the AUC for the concentration-time curve of active GLP-1 during mixed meal tolerance tests at baseline and after the training intervention. RESULTS: Nineteen patients were allocated to tocilizumab, 17 to sitagliptin and 16 to placebos. During the acute exercise bout active GLP-1 levels were 26% lower with tocilizumab (multiplicative effect: 0.74 [95% CI 0.56, 0.98], p = 0.034) and 53% higher with sitagliptin (1.53 [1.15, 2.03], p = 0.004) compared with placebo. After the 12 week training intervention, the active GLP-1 AUC with sitagliptin was about twofold that with placebo (2.03 [1.56, 2.62]; p < 0.001), while GLP-1 AUC values showed a small non-significant decrease of 13% at 4 weeks after the last tocilizumab infusion (0.87 [0.67, 1.12]; p = 0.261). CONCLUSIONS/INTERPRETATION: IL-6 is implicated in the regulation of GLP-1 in humans. IL-6 receptor blockade lowered active GLP-1 levels in response to a meal and an acute exercise bout in a reversible manner, without lasting effects beyond IL-6 receptor blockade. TRIAL REGISTRATION: Clinicaltrials.gov NCT01073826. FUNDING: Danish National Research Foundation. Danish Council for Independent Research. Novo Nordisk Foundation. Danish Centre for Strategic Research in Type 2 Diabetes. European Foundation for the Study of Diabetes. Swiss National Research Foundation.

Intermittent Standing but not a Moderate Exercise Bout Reduces Postprandial Glycemia.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.