Medical doctor and PhD student Mark Lyngbæk of Trygfondens Centre for Physical Activity Research, Rigshospitalet, and his team have put themselves into a straitjacket before setting out to investigate which dose of exercise training improves pancreatic β-cell function in patients with newly diagnosed type 2 diabetes: they have published a protocol article in Trials.

Mark Lyngbæk says that in the past decade it has become more popular to publish protocol articles for randomised controlled trials.  ‘They contribute to high-quality research, which is what the Danish Diabetes Academy and our research centre strive for’, he says.

Background
He points out that, historically, T2D has been regarded as a treatable, yet chronic, condition. ‘Diet and physical activity are a cornerstone of T2D care. The current physical activity recommendation for T2D is aerobic training of moderate intensity for 150 min/week, supplemented with resistance training 2–3 days/week. The rationale for the recommendations is primarily based on reductions in glycated haemoglobin (HbA1c), whereas evidence supporting an effect on central T2D pathophysiological mechanisms such as pancreatic β-cell function is scarce, with the majority of evidence stemming from animal and in vitro studies’, Mark Lyngbæk says.

The physical activity recommendations for T2D rely on the consistent observations supporting the efficacy of 150 min/week of exercise in reducing HbA1c in T2D patients, with even higher volumes of exercise providing more health benefits. This reduction is thought to be caused by increased insulin sensitivity in muscle and adipose tissue, whereas knowledge of effects on abnormalities in the liver and pancreas is more limited. However, more evidence is suggesting the possibility of T2D remission in which a person with T2D can achieve adequate glucose control with non-pharmacological treatment. This has been shown to be possible if the person still has β-cell function remaining. The Direct trial demonstrated that a diet-induced weight loss intervention could induce T2D remission, and this beneficial effect on β-cell health may be mediated indirectly by β-cell rest, while other studies suggest that exercise may be directly beneficial to β-cell health. It is thus clinically relevant to investigate the effect on β-cell function of the recommended 150 min/week and higher volume of exercise in addition to a diet-induced weight loss.

Methods/design of the Dose-Ex Trial
The group’s plan is that, in a parallel-group 4-arm assessor-blinded randomised clinical trial, at least 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, (2) dietary intervention, (3) dietary intervention and supervised moderate-volume exercise (150 minutes/week), or (4) dietary intervention and supervised high-volume exercise (300 minutes/week). Enrolment was initiated on 15 December  2018 and will continue until at least N = 80 or 1 December 2021. Primary outcome is pancreatic β-cell function assessed as change in late-phase disposition index (DI) from baseline to follow-up by a hyperglycaemic clamp. Secondary outcomes include measures of cardiometabolic risk factors related to T2D. We currently expect the last participant to complete by the end of September 2021.

‘Protocol publications are considered beneficial because they enhance research transparency, reduce publication bias and help to prevent selective reporting outcomes. They also help colleagues, patients and the general public know what trials are currently being conducted.’

Why is this study important?
Data from this study will help to clarify what volume of exercise training in combination with a diet-induced weight loss is needed to improve β-cell function in persons with newly diagnosed T2D. Secondarily, the data may elucidate mechanisms by which physical activity in combination with a diet-induced weight loss may mitigate the development of microvascular, macrovascular and muscular complications associated with T2D.  In addition to the above, the study will generate data enabling us to explore body composition, plasma, urine, hepatic and peripheral insulin sensitivity, systemic oxidative stress, gastric emptying, satiety and incretin response; other data will include 3-day home blood pressure measurements throughout the study, maximal oxygen consumption and maximal muscular strength, activity monitors, glycaemic variability, quantification of organ-specific (i.e. visceral, hepatic and pancreatic) fat, fat and muscle tissue and isolated adipocytes and muscle progenitor cells, clinical organ markers and a well-controlled pharmacological treatment of hypertension, dysglycaemia and dyslipidemia and adjacent adherence. These data, together with Centre for Physical Activity Research’s vast Biobank, may provide data for exploratory and hypothesis-generating studies.

CONTACT
Mark Preben Printz Lyngbæk MD, PhD student
Centre for Physical Activity Research, Rigshospitalet
E-mail: mark.lyngbaek@regionh.dk
Phone +45 20443304
/Photo: Nils Meilvang

READ THE ARTICLE HERE
Trials: DOI: 10.1186/s13063-021-05207-7
Published: 1 April 2021

The effects of different doses of exercise on pancreatic β-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. Mark P P Lyngbaek ^#, Grit E Legaard ^#, Sebastian L Bennetsen, Camilla S Feineis, Villads Rasmussen, Nana Moegelberg, Cecilie F Brinkløv, Anette B Nielsen, Katja S Kofoed, Carsten A Lauridsen, Caroline Ewertsen, Henrik E Poulsen, Robin Christensen, Gerrit Van Hall, Kristian Karstoft, Thomas P J Solomon, Helga Ellingsgaard, Thomas P Almdal , Bente K Pedersen, Mathias Ried-Larsen.
^#Shared first authorship