PhD Student and Danish Diabetes Academy grantee Mark P.P. Lyngbæk shares his insights from a study recently published in Nature Metabolism.

People with type 2 diabetes benefit greatly from both exercising and dietary weight loss. It may help them reduce or even discontinue their medication. And a little goes a long way – exercising just 3 days a week even while also dieting can make a big difference for people living with type 2 diabetes.

These are some of the results of a Danish study on exercise, weight loss, and beta-cell function published in Nature Metabolism this month.

The study 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 has Danish Diabetes Academy grant recipient Mark P.P. Lyngbæk listed as the shared first author.

We asked Mark a few questions about the study.  

Can you tell us a little about the background of this study?

Mark P.P. Lyngbæk: The study is based on a study that examined the effects of a 12-months intervention consisting of exercising six times per week combined with dietary weight loss on HbA1c. In that study, it was observed that around half of the participants in the intervention groups were able to discontinue their antidiabetic medication – in addition, a secondary analysis suggested that the improved beta-cell function – defined as the beta-cell disposition index (insulin sensitivity x insulin secretion) – was explained mainly by an increase in insulin sensitivity and not insulin secretion and that there may be a dose-response effect of exercise. In contrast, other data suggest that insulin secretion is mainly increased with exercise. Also, The European Association for the Study of Diabetes (EASD)’s current guidelines for the management of hyperglycemia recommend a weight loss of 5-15% as a treatment target. And since exercise is also recommended for people with type 2 diabetes, exercise ought to be investigated in the context of weight loss to make the research as clinically relevant as possible. Reconciling the inconsistencies in whether exercise improves beta-cell function via insulin secretion or insulin sensitivity, and a potential dose-response relationship of effect, plus the EASD recommendations for weight loss, led us to ask the questions: Does exercise improve beta-cell function as an adjunct to a diet-induced weight loss? And is the effect dose-depended?

How was the study conducted?

Mark P.P. Lyngbæk: We carried out a four-armed randomized trial, with a total of 82 persons (35% females, mean age (SD) of 58.2 (9.8) years) with newly diagnosed type 2 diabetes (<7 years). Participants 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. 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 insulin sensitivity from the hyperglycemic clamp, and insulin sensitivity and insulin secretion indices derived from a liquid mixed meal tolerance test. The hyperglycemic clamp is the gold standard for assessing beta-cell function, i.e., the beta-cell disposition index, but although the method is accurate and tightly controlled, it is not physiological. On the other hand, the liquid mixed meal tolerance test is physiological with calorie content resembling a full meal, a mix of nutrients, and involves the entire postprandial state; however, the liquid mixed meal tolerance test is not as controlled or accurate as the hyperglycemic clamp. By using both methods, we could evaluate and compare both methods to get a nuanced picture of the beta-cell function. For those interested, a thorough walk-through of all the methods has been published.

What were the most significant results of the study?

Mark P.P. Lyngbæk: The main findings include that all intervention groups improved beta-cell function, as expressed by the late-phase disposition index, more than standard care. Furthermore, adding either 6 or 3 times exercise per week to a diet-induced weight loss improved beta-cell function more than diet-induced weight loss or standard care alone. The improvements in the beta-cell disposition index seemed to be explained by additional increases in insulin sensitivity induced by exercise in a dose-dependent manner, while diet-induced weight loss alone mainly improved in beta-cell disposition index via increases in insulin secretion. This suggests that diet-induced weight loss and exercise may act differently but synergistically in improving beta-cell function. However, the secondary and exploratory outcomes, especially from the mixed meal tolerance test, did not uniformly support the linear dose-response relationship of exercise observed from the hyperglycemic clamp outcomes. In fact, there appear to be diminishing returns of benefit when exercising more than 3 times per week.

Generally, we learn that the more exercise, the better, but what are some of the benefits of exercising 3 times per week?

Mark P.P. Lyngbæk: As you said, our data do support that exercising 6 times per week is superior to exercising 3 times per week in improving beta-cell function indices while undergoing a diet-induced weight loss across 16 weeks. And exercising 3 timers or 6 times per week was generally also superior to diet-induced weight loss alone. However, the benefits of exercising 3 times per week compared to exercising 6 times per week were not substantial in terms of beta-cell function indices and there were little to no difference in reductions in cardiometabolic markers between the intervention groups. These results may be used in shared decision-making with people living with type 2 diabetes regarding what average results from a lifestyle intervention may entail when considering the dose-response effects of adding exercise to a diet. However, it is important to underline that in terms of cardiorespiratory fitness (which is a strong predictor for mortality and morbidity), there was a clear dose-response effect of exercise.

How can this study impact future research?

Mark P.P. Lyngbæk: Firstly, the results from the study may set new grounds for investigating the heterogeneity of the effects of different doses of exercise on beta-cell function indices when exercise is combined with dietary weight loss. This is apparent when looking at individual data points in our results; however, the results may indicate that individual variations diminish with increasing doses of exercise.

Secondly, although there were no differences in cardiometabolic markers between the intervention groups there were improvements in beta-cell function with adding exercise, and hypothetically adding exercise protects the beta-cell beyond a daily 25% caloric restriction weight loss by inducing more beta-cell rest via increasing insulin sensitivity. It is important to understand whether an intervention improves glycemic control and beta-cell function via insulin secretion or insulin sensitivity as this may have a role in preserving the beta-cells. Therefore, future research may consider adding some version of beta-cell function measurement when investigating glycemic control in type 2 diabetes and not solely focusing on e.g., HbA1c or fasting glucose.

Thirdly, given that there were notable discrepancies when comparing the hyperglycemic clamp (gold standard) and the liquid mixed meal tolerance test when assessing the beta-cell function, it may be worth considering implementing both measurements in future research studies, if the study results are aimed at being translated into a physiological/real life/clinical setting.

Fourthly, the study was 16 weeks long, and perhaps the intervention groups may have differed more if the intervention continued for an extended period – therefore, longer controlled trials with high intervention adherence are warranted despite their laborious nature for participants and researchers.

And finally, we used a treat-to-target pharmacological approach which meant that the better glycemic control the participants were getting, the more medication was reduced or discontinued during the intervention. So perhaps future research studies will find different results in beta-cell function if the intervention groups can achieve even better glycemic control by continuing their antidiabetic medication, even if the glycemic control measurements fall below type 2 diabetes diagnostic thresholds and approaches normoglycemia.

Mark P.P. Lyngbæk is a physician, currently in an introduction position at the Department of Rheumatology and Intern Medicine 2 at Holbæk Hospital, and also a PhD student at the Centre for Physical Activity Research at Rigshospitalet. He is supported by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation (grant number NNF17SA0031406).

The Centre for Physical Activity Research is supported by TrygFonden (grants ID 101390, ID 20045, and ID 125132).

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 – Nature Metabolism, May 2023 (DOI: https://doi.org/10.1038/s42255-023-00799-7)

Grit E. Legaard*, Mark P.P. Lyngbæk*, Thomas P. Almdal, Kristian Karstof, Sebastian L. Bennetsen, Camilla S. Feineis, Nina S. Nielsen, Cody G. Durrer, Benedikte Liebtrau, Ulrikke Nystrup, Martin Østergaard, Katja Thomsen, Beckey Trinh, Thomas P.J. Solomon, Gerrit Van Hall, Jan Christian Brønd, Jens J. Holst, Bolette Hartmann, Robin Christensen, Bente K. Pedersen & Mathias Ried-Larsen.

*Shared first author.

Contact information

Mark P.P. Lyngbæk
PhD student, University of Copenhagen
marklyngbaek@gmail.com