Exercise can protect pancreatic beta cells in type 1 and type 2 diabetes

A new study, reported in Diabetologia, shows that vigorous exercise on a bike or using a home video helps protect pancreatic beta cells from apoptosis induced by endoplasmic reticulum-induced stress. The benefits were seen in people with or without type 1 or type 2 diabetes, shedding light on the role of physical activity in preventing or delaying the onset of the condition. Dr Susan Aldridge reports.

Loss of functional pancreatic beta cells drives the development and progression of diabetes. In type 1 diabetes, research into therapies has focused on the immune system. For instance, teplizumab, an anti-CD3 antibody recently approved by the Food and Drug Administration (FDA), significantly delays the onset of the condition in high-risk individuals, buying them precious time without the burden of diabetes. However, many treated with teplizumab will still go on to develop type 1 diabetes, so there is clearly a need for other therapies that can protect beta cells in both type 1 and type 2 diabetes.

Signals of endoplasmic reticulum (ER) stress are present in the beta cells of people with type 1 and type 2 diabetes. And several forms of monogenic diabetes are caused by mutations in genes involved in the response to ER stress. The underlying mechanism of ER stress involves accumulation of mis-or unfolded proteins in the ER lumen, which leads to beta cell apoptosis if it continues. ER stress can be reproduced in vitro by exposing human islets to proinflammatory cytokines and chemical ER stressors such as thapsigargin.

Therefore, agents that can restore normal ER function could perhaps provide a therapeutic strategy in diabetes. Tauroursodeoxycholic acid and imatinib are two compounds that have already been shown to reduce ER stress and protect beta cells in pre-clinical models of diabetes. Imatinib also showed modest but transient protection of beta cells in a clinical trial in people with recent-onset type 1 diabetes.

Physical exercise is an important non-pharmacological element in diabetes prevention and management. It improves glycaemic control in people with type 1 and type 2 diabetes by improving insulin sensitivity, stimulating glucose uptake by skeletal muscle cells and reducing weight. It also decreases circulating lipids, blood pressure and risk of cardiovascular complications. A combination of aerobic and resistance exercise is recommended, with interval aerobic training probably being more beneficial than continuous aerobic training.

Studies in animal models and human islets have also suggested that physical exercise has a direct effect upon beta cells. In an earlier study, Alexandra Coomans de Brachène of the Université Libre de Bruxelles, along with her colleagues, have shown that serum from eight healthy young male participants who performed moderate-intensity continuous exercise training for eight weeks protected beta cells from proinflammatory cytokines and thapsigargin. This protection was observed in primary human islets and the human beta cell line EndoC-βH1.

They have now extended this study to assess the impact of different forms of exercise on ER-stressed human beta cells in a larger cohort of individuals with and without diabetes.

Exercising to protect beta cells

Two separate groups of participants took part in this study – a group of healthy younger people and a mixed group of older people with or without type 1 or type 2 diabetes, and of different ancestral origins. All participants had VO_2peak, their maximal oxygen uptake (a measure of aerobic fitness), measured on an exercise bike at the start of the study. The 46 healthy participants – 26 female, 20 male – were assigned to one of four different physical exercise regimes carried out three times a week over an eight-week period.

Another five healthy participants acted as controls, doing their normal physical activity only. The intervention groups consisted of stationary bike high-intensity interval training (HIIT), adapted sprint interval training (aSIT), vigorous-intensity continuous training (VICT) or high-intensity functional training performed at home (HIFT). The three bike-training regimes were carried out in the authors’ laboratory and differed with respect to the proportion of VO_2peak worked at. The HIIT regime consisted of six bouts of two minutes at a load of 90% VO_2peak interspersed with two minutes active rest at 50% VO_2peak. The aSIT regime was 12 bouts at 30 seconds at 125%VO_2peak interspersed with two minutes of active rest. And the VICT regime was 28 continuous minutes at a load of 70% VO_2peak.

Meanwhile, the HIFT consisted of videos with four bouts of 30 seconds of whole-body exercises such as squats, lunges and jumping jacks, interspersed with 30 seconds of active rest. The difficulty and number of repetitions of the exercises increased from video one to video four, and the participants progressed through the series during the eight-week intervention period.

To evaluate the possible impacts of diabetes and ancestry on the beta cell-protective effects of exercise, 36 individuals who had type 1 or type 2 diabetes or no diabetes and were of Belgian origin (European ancestry) or were Belgians of Moroccan, Turkish or African origin (non-European ancestry) participated in the study.

For comparison, participants without diabetes were matched to those with type 1 and type 2 diabetes based on sex and similar age. They took part in training three times a week for 12 weeks, consisting of stationary bike HIIT training, similar to that described above, and strength-training exercises involving the four main muscle groups – namely, chest press, lateral pulldown, leg press and leg curl. They did three sets of 10 repetitions of these.

Blood was collected from all participants prior to the study and after four, eight and 12 weeks of training to obtain serum. Then EndoC-βH1 cells were treated with thapsigargin in the presence of serum to see if this ‘exercised serum’ protected the cells from ER stress. Thapsigargin alone would have triggered ER stress and beta cell apoptosis.

Fluorescence microscopy was then used to count apoptotic cells after staining them with a DNA-binding dye and RNA was extracted from the beta cells to assess any changes in gene expression from exposure to ‘exercised serum’.  

Positive findings

In the experiments involving the younger, healthy volunteers, there was significant protection against thapsigargin-induced beta cell apoptosis after four weeks of exercise for the three exercise bike regimes and after eight weeks for the home exercise. Since no major differences were found between the different types of exercise, the results were pooled and re-analysed according to sex.

There was significant exercise-mediated beta cell protection with a 29-32% reduction in apoptosis in women and 27-40% decrease among men. When pooling results for all 46 participants, there was a 28-35% decrease in apoptosis at four and eight weeks. Serum was also collected from 13 of the participants two months after the training and the protective effects were still seen. Sera from the control group did not confer any protection against thapsigargin, confirming the role of exercise.

When it came to participants with diabetes, they were older than the healthy participants, had a lower starting VO_2peak  and those with type 2 diabetes were obese. Serum from the individuals in this group who did not have diabetes significantly protected human beta cells from thapsigargin-induced apoptosis after four, eight and 12 weeks of training. Furthermore, ‘exercised serum’ from participants with type 1 or type 2 diabetes was also protective, reducing apoptosis by 45% and 26%, respectively, after 12 weeks of training.

Finally, to determine whether ancestry affected the response, data was pooled from the three groups and split into those of European and non-European origins. Again, serum conferred significant protection against apoptosis. Therefore, neither the presence of diabetes nor ancestral origin influence the protective effects of physical exercise against ER stress-induced beta cell apoptosis. 

How exercise might protect beta cells

What about the mechanism driving the beta cell protection conferred by exercise? RNA analysis of the beta cells exposed to ‘exercised serum’ showed reduction in expression of two pro-apoptosis genes, CHOP and DP5,and in the XBP1s gene, which is involved in ER stress. These changes are consistent with exercise conferring protection on beta cells via reduction in ER stress and apoptosis.

When exercised, skeletal muscle and other tissues release substances called exerkines into the bloodstream. A recent study showed that one exerkine, known as clusterin, protects rodent beta cells from metabolic stress. The authors therefore carried out an additional experiment to see if clusterin could reproduce the beneficial effects of ‘exercised serum’ in human beta cells. They found that clusterin reduced thapsigargin-induced cell death by 31-42% at two concentrations.

The mRNA expression of DP5 was also significantly reduced at the higher dose of clusterin. Taken together, these findings suggest that the mechanism of beta cell protection afforded by exercise involves muscle or multi-organ crosstalk with beta cells, mediated by circulating exerkines. Further experiments will help clarify the molecular pathways involved in this mechanism.

In practical terms, the finding that home-based exercise protected beta cells as well as gym-based exercise is important, as people can access these benefits via videos or apps rather than needing access to equipment. In the four training regimes, participants spent at least 50% of their time at their maximum heart rate. Whether beta cell protection would also result from mild to moderate exercise, such as brisk walking, remains to be determined.

In summary, serum from people with or without type 1 or type 2 diabetes after eight to 12 weeks of regular vigorous exercise confers beta cell protection against ER stress. The benefit also persists after the intervention. This shows the unexpected potential of exercise training in preserving beta cells.

Exercise training should therefore be tested in larger trials for its benefits as a non-pharmacological intervention in people who are at risk of either type 1 or type 2 diabetes. This could prove to be an effective way of preserving endogenous insulin secretion and beta cell health, as well as having cardiovascular and other health benefits. 

To read this paper, go to: Coomans de Brachène A, Scoubeau C, Musuaya E, Costa-Junior JM, Castela A, Carpentier J, Faoro V, Klass M, Cnop M, Eizirik D. Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes. Diabetologia 19 November 2022. https://doi.org/10.1007/s00125-022-05837-9

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.