Effectiveness of exercise to prevent and mitigate diabetes: An important role of the gut microbiota

Effectiveness of exercise to prevent and mitigate diabetes: An important role of the gut microbiota

OVERVIEW

  • In overweight, prediabetic and sedentary men, exercise induced changes in the gut microbiota that are correlated with improvements in blood sugar control and insulin sensitivity.
  • The microbiota of the participants who are “responders” to exercise had a greater ability to produce short chain fatty acids (SCFAs) and to eliminate branched-chain amino acids (BCAAs). Conversely, the microbiota of non-responders was characterized by an increased production of metabolically harmful compounds.
  • Transplantation of the fecal microbiota of responders into obese mice produced roughly the same beneficial effects of exercise on insulin resistance. Such effects were not observed after transplanting the microbiota of non-responders.
Regular exercise has beneficial effects on blood glucose control and insulin sensitivity, and is therefore an interesting strategy to prevent and mitigate type 2 diabetes. Unfortunately, in some people, exercise does not cause a favourable metabolic response, a phenomenon called “exercise resistance”. The causes of this phenomenon have not been clearly established, although some researchers have suggested that genetic predispositions and epigenetic changes may contribute to this.

A growing body of data indicates that an imbalance in the gut microbiota (dysbiosis) plays an important role in the development of insulin resistance and type 2 diabetes. Several different mechanisms are involved, including an increase in intestinal permeability and increased endotoxemia, changes in the production of certain short chain fatty acids and branched-chain amino acids, and disturbances in bile acid metabolism. Changes in the composition and function of the gut microbiota have been observed in people with type 2 diabetes and prediabetics. One study also showed that transplanting a healthy person’s microbiota into the intestines of people with metabolic syndrome results in increased microbial diversity and improved blood sugar control as well as sensitivity to insulin.

The intestinal microbiota (formerly intestinal flora) is a complex ecosystem of bacteria, archaea (small microorganisms without nuclei), eukaryotic microorganisms (fungi, protists) and viruses, which has evolved with human beings for several thousands of years. A human gut microbiota, which can weigh up to 2 kg, is absolutely necessary for digestion, metabolic function, and resistance to infection. The human gut microbiota has an enormous metabolic capacity, with more than 1,000 different species of bacteria and 3 million unique genes (the microbiome).

Recent data indicate that exercise modulates the gut microbiota in humans as well as in other species of animals. For example, it has been found that the gut microbiota of professional athletes is more diverse and has a healthier metabolic capacity than the microbiota of sedentary people. However, it is still unclear how these exercise-induced changes in the microbiota are involved in the metabolic benefits (see figure below).

Figure. Changes in the gut microbiota and intestinal epithelium through exercise and health benefits. BDNF: Brain-derived neurotrophic factor (growth factor). From: Mailing et al., 2019.

A study published in Cell Metabolism tried to answer this question by performing an intervention in overweight, prediabetic and sedentary men. Study participants were randomly assigned to a control group (sedentary) or to a 12-week supervised training program. Blood and fecal samples were collected before and after the procedure. After the 12 weeks, modest but significant weight loss and fat loss were observed in people who exercised, with improvements in several metabolic parameters, such as insulin sensitivity, favourable lipid profiles, improved cardiorespiratory capacity and levels of adipokines (signalling molecules secreted by adipose tissues) which are functionally associated with insulin sensitivity. The researchers observed that there was a high interpersonal variability in the results. After classifying the participants as “non-responders” and “responders”, according to their insulin sensitivity score, the researchers analyzed the composition of each participant’s microbiota.

Among responders, exercise altered the concentration of more than 6 species of bacteria belonging to the genera Firmicutes, Bacteroidetes, and Probacteria. Among these bacteria, those belonging to the genus Bacteroidetes are involved in the metabolism of short chain fatty acids (SCFAs). Among the most striking differences between the microbiota of responders and non-responders, the researchers noted a 3.5-fold increase in the number of Lanchospiraceae bacterium, a butyrate producer (a SCFA), which is an indicator of intestinal health. The bacterium Alistipes shahii, which has already been associated with inflammation and is present in higher amounts in obese people, decreased by 43% in responders, while it increased 3.88 times in non-responders. The Prevotella copri bacteria proliferated at a reduced rate in the responders; it is one of the main bacteria responsible for the production of branched-chain amino acids (BCAAs) in the gut and contributes to insulin resistance.

The researchers then transplanted the fecal microbiota of responders and non-responders into obese mice. The fecal microbiota transplantation (FMT) of the responders had the effect in mice of reducing blood sugar and insulin as well as improving insulin sensitivity, while such favourable effects were not observed in mice that received a FMT from non-responders.

Mice saw their blood levels of SCFAs increase significantly, while the levels of BCAAs (leucine, isoleucine, valine) and aromatic amino acids (phenylalanine, tryptophan) decreased after receiving the microbiota from responders. In contrast, mice that received the microbiota from non-responders saw opposite changes in the levels of these same metabolites. BCAA supplementation attenuated the beneficial effects of FMT from responders on blood sugar regulation and insulin sensitivity, while SCFA supplementation in mice that received the microbiota of non-responders partially corrected the defect in blood glucose regulation and insulin sensitivity.

Taken together, these results suggest that the gut microbiota and its metabolites are involved in the beneficial metabolic effects caused by exercise. In addition, this study indicates that poor adaptation of the gut microbiota is partly responsible for the lack of a favourable metabolic response in people who do not respond to exercise.

Health risks of a sedentary lifestyle

Health risks of a sedentary lifestyle

Physical inactivity and unhealthy eating have become major public health issues since, combined, these two poor lifestyle habits are the second leading cause of death after smoking in the United States. Physical inactivity is also associated with an increased risk of developing or worsening chronic diseases such as heart failure, cardiovascular disease, stroke, type 2 diabetes, hypertension, some cancers, and osteoporosis. In Canada, 76% of adult men and 79% of adult women do not perform the minimum physical activity recommended by the World Health Organization, i.e., 150 minutes/week, and Canadian adults spend an average of 9 hours 48 minutes of their waking hours doing sedentary activities. Recent research on physical activity suggests that it is no longer sufficient to follow the minimal recommendations of public health agencies to minimize the risk of cardiovascular disease. Physical inactivity and sedentary behaviour each have their own health effects that need to be addressed separately to better understand their distinct mechanisms.

According to a systematic review and meta-analysis of 16 prospective studies and 2 cross-sectional studies of 794,577 participants, highly sedentary people are 112% more likely to have diabetes than those who are not sedentary, and they have a 147% higher risk of cardiovascular events, a 90% higher risk of mortality from cardiovascular disease, and a 49% higher risk of all-cause mortality. Another study on sedentary behaviours (driving and watching television) was conducted in the United States from 1989 to 2003 among 7,744 men aged 20 to 89 who had no history of cardiovascular disease. Participants who reported driving more than 10 hours/week or engaging in two sedentary behaviours (driving and watching television) more than 23 hours/week had an 82% and 64% higher risk of dying from cardiovascular disease than those who reported driving less than 4 h/week or driving and watching TV less than 11 h/week, respectively. Participants who were physically active at work and in their leisure time, but were otherwise sedentary, were less at risk of dying from cardiovascular disease than those who were both sedentary and physically inactive. Moreover, having a normal blood pressure, a healthy weight, and being older were associated with a lower risk of cardiovascular death.

“Physical activity” has been defined as any body movement produced by skeletal muscles that requires energy expenditure, and “exercise” as a subcategory of physical activity. Exercise involves structured and repeated behaviour in order to maintain or improve physical fitness. One method to more accurately estimate the intensity of physical activity is to use the Metabolic Equivalent of Task (MET) method. A MET unit is the energy spent at rest. Physical activity can be considered low intensity (<3 METs), moderate intensity (3-6 METs), and high intensity (>6 METs). Defining what is “sedentary behaviour” or “physical inactivity” is more difficult, and not everyone agrees on a definition. The objective measurement of physical activity, using an accelerometer-type physical activity monitor, for example, makes it possible to better assess sedentary behaviours than with the data obtained by questionnaires. Accelerometry allows researchers to record daily the time participants devote to activities at all levels of intensity: sedentary, light, moderate and high. To illustrate the usefulness of this technique, Pate et al. present the cases of two people who have very different activity profiles. Subject A could be considered a sedentary person in several studies since they do not engage in moderate or intense physical activity for at least 30 minutes a day. However, if the analysis of the accelerometer data shows that the subject was sedentary for 25% of the day, they were doing low intensity activities for about 75% of that day. Subject B could be considered as an active person in most studies, as they engage in medium-high intensity physical activity during the day for 1 hour. The accelerometer data, however, show that subject B spends most of the day (70%) in sedentary life (sitting on a chair, for example) or engaging in low-intensity physical activity (23%). In total, subject A, considered “inactive” according to conventional criteria, expended more energy (26.3 METs) than subject B, considered “active” (23.6 METs).

A study of the sedentary behaviours of Americans aged 45 and over showed that a large proportion of total sedentary time is accumulated over long, uninterrupted periods. Participants in this study spent an average of more than 11 hours of their day being sedentary and almost half of this sedentary time was accumulated over periods of 30 minutes or more. Sedentary periods of more than 20, 30, 60 and 90 minutes accounted for 60%, 48%, 26% and 14% of total sedentary time, respectively. Several factors, including older age, male gender, obesity, winter, and low levels of physical activity, were associated with prolonged sedentary behaviours. Laboratory studies have shown that long periods of uninterrupted sedentary behaviours have cardiometabolic effects, suggesting that it is not only the total sedentary time that is important for the risk of cardiovascular disease but also how this time is accumulated.

Data from an epidemiological study seem to confirm this hypothesis since adults whose sedentary behaviour extended over long uninterrupted periods had a less favourable cardiometabolic profile (larger waist circumference, lower HDL cholesterol level, and other markers) compared to that of people who interrupt their periods of inactivity, regardless of the total duration of sedentary time. A recent study of 7,985 people aged 45 or older indicates that the risk of mortality increases not only with the number of hours of sedentary life but also with the duration of each of the uninterrupted sedentary periods. People who were both very sedentary (≥12.5 hours per day) and for long uninterrupted periods (≥10 min/period) had the highest risk of death.

Spending long periods of time sitting is very common in modern societies, and this will only increase with future technological and social innovations. In addition to promoting regular physical exercise, public health organizations will likely also need to include a reduction in sedentary time in their guidelines and emphasize the importance of taking “active” breaks. It is important to note that taking breaks does not necessarily mean exercising, but may include walking for a minute, getting a glass of water, or doing light housework for those working at home. It’s as simple as that!