Exercise can counter diabetes damage

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One way exercise can counter the damage of diabetes is by enabling activation of a natural system we have to grow new blood vessels when existing ones are ravaged by this disease, scientists report.

Angiogenesis is the ability to form new blood vessels, and diabetes not only damages existing blood vessels, it hinders this innate ability to grow new ones in the face of disease and injury, say experts at the Vascular Biology Center at the Medical College of Georgia.

Endothelial cells line our blood vessels and are essential to that new blood vessel growth.

Now the MCG scientists have the first evidence that in the face of diabetes, even one 45-minute session of moderate intensity exercise enables more exosomes, submicroscopic packages filled with biologically active cargo, to deliver directly to those cells more of the protein, ATP7A, which can set angiogenesis in motion, they report in The FASEB Journal.

Not unlike the most sophisticated and efficient delivery services we have all come to rely upon, particularly during the pandemic, what exosomes carry depends on where they come from and where they are headed, says Dr. Tohru Fukai, MCG vascular biologist and cardiologist.

While he and co-corresponding author MCG vascular biologist Dr. Masuko Ushio-Fukai are not yet certain of the origin of these helpful exosomes, it’s clear that one place they deliver is to endothelial cells, Fukai says.

In both an animal model of type 2 diabetes and a handful of healthy 50-something-year-olds, two weeks of volunteer running on a wheel for the mice and that one cardio session for the humans increased levels of ATP7A in the exosomes that attached to endothelial cells.

At that point, the activity did not significantly impact the weight of the mice, the scientists note, but it did also increase a marker of endothelial function and factors like, vascular endothelial growth factor, needed for angiogenesis.

Exercise also increased the amount of the powerful, natural antioxidant extracellular superoxide dismutase, or SOD3, but it’s the heavier payload of ATP7A, which is also known to deliver the essential mineral copper to cells, that is key to making good use of the SOD3 present, Ushio-Fukai says.

SOD3, is an important natural antioxidant produced by vascular smooth muscle cells in the walls of blood vessels as well as skeletal muscle cells, which helps us maintain healthy levels of reactive oxygen species, or ROS. ROS is a natural byproduct of our use of oxygen that is an important cell signal, enabling a variety of functions. But in diabetes, high blood sugar levels result in high ROS levels that instead hinder important normal functions.

The Fukais have shown that ATP7A levels are reduced in diabetes. They also now have some of the first evidence that exosomes circulating in the plasma of sedentary animal models of type 2 diabetes actually impair angiogenesis when placed in a dish with human endothelial cells, as well as in an animal model of wound healing.

The scientists suggest that synthetic exosomes, already under study as drug-delivery mechanisms, could one day work as an “exercise mimetic” to improve patients’ ability to grow new blood vessels when diabetes has damaged their innate ability.

In fact, they have already generated exosomes in which SOD3 is overexpressed and found improved angiogenesis and healing in a mouse model of diabetes.

The way it’s supposed to work is SOD3 is naturally silenced in endothelial cells, so they must get it from other cells, notes Ushio-Fukai, hence the importance of exosome delivery. SOD3 must then bind to endothelial cells at its natural spot called the heparin-binding domain, and the copper transporter ATP7A must be present to enable SOD3 to be active there, Fukai says. Both ATP7A and the binding site are key, Fukai notes. For example, when they removed the binding site from the endothelial cells, which can happen in nature, the benefits were lost.

Once on the scene and active, SOD3 converts the ROS superoxide into hydrogen peroxide, or H2O2, another signaling ROS that helps support normal endothelial cell function. The Fukais have reported that in human endothelial cells, overexpressing SOD3 promotes angiogenesis by increasing H2O2.

A copper connection also runs throughout this process as endothelial cells regularly use a lot of copper, and ATP7A, known to transport the essential mineral that we consume in foods like nuts and whole grains, is dependent on copper itself.

Physical exercise, like running or walking on treadmill, prompts muscles to contract which in turn prompts release of exosomes into the blood.

When Fukai was a postdoc in the Emory University Section of Cardiology he was part of the research group that was the first to show that exercise increases SOD3 activity. SOD3 levels decrease with age and with some disease states like diabetes and hypertension.

Exosomes are being studied as biomarkers for a wide range of diseases like cancer and diabetes as well as precise treatment delivery tools. For example, exosomes produced by a cancer cell will hone right back to a cancer cell.

About 1 in 10 Americans have diabetes, according to the Centers for Disease Control and Prevention.


Physical activity, types and known benefits

Physical activity can take several forms. Aerobic exercises are activities that use larger muscles that rely primarily on energy provided by aerobic metabolism. These exercises are suggested to enhance the quality of life in individuals with type 2 diabetes (Figure 1). Aerobic training, which may include activities such as running, jogging, cycling and swimming, can vary from moderate to vigorous in intensity that typically last 20 min.26,27

High-intensity interval training consists of repeated periods of intense exercise separated by intervals of rest. 28 Resistance training consists of exercises aimed at increasing muscle strength and stamina using bodyweight, devices or resistance bands. 26 Flexibility and balance are essential for preserving joint range of motion and might to be useful for people with diabetes. Yoga, upper and lower body stretches are examples of stretching exercises that will help an individual become more flexible. 26

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Figure 1.
Physical activity types and known benefits.27,29

The benefits of physical activity for acute and chronic health conditions are well studied, including its positive influence on blood glucose levels in people with type 2 diabetes. It was suggested in two different studies that most of the improvements in insulin action were attributed to the acute effects of a recent bout of exercise, with most people reporting a drop in their blood glucose levels during low- to moderate-intensity exercise and for 2–72 h afterwards.30,31 Acute enhancements in insulin sensitivity have also been observed in women with type 2 diabetes who participate in either low-intensity or high-intensity walking for comparable energy expenditure. 32

Furthermore, a review study reported that exercise interventions alone have been effective in avoiding increases in blood glucose, body weight, lipids, blood pressure, cardiovascular disease and mortality and raise the overall quality of life in type 2 diabetes patients. 33 A randomised control trial recently examined the impact of 8 weeks of high-intensity training focussed on functional and multijoint motions on glucose control and body composition in overweight or obese adults.

The adult sedentary type 2 diabetes group showed a substantial increase in β-cell activity after 10–20 min of training 3 times a week, a decrease in fat storage, maintenance of body weight, increased cardiovascular health, lipid metabolism and low-density lipoprotein cholesterol as well as enhanced insulin sensitivity. 34 Another study followed 13 overweight and obese adults with type 2 diabetes for 6 weeks who participated in functional high-intensity training that included aerobic and resistance training varying from 8 to 20 min per session 3 days a week.

The results showed a substantially reduced fat mass and adiponectin, diastolic blood pressure, blood lipids and metabolic syndrome and increased basal fat oxidation and high molecular weight adiponectin. The conclusion drawn from the study was that functional high-intensity training enhanced insulin sensitivity. 35

A 16-week multicentre randomised controlled trial assessed exercise in the prevention of metabolic syndrome and found that low-volume, high-intensity interval training (51 min/week) was as effective as high-volume, high-intensity interval training (114 min/week) and moderate-intensity continuous training (150 min/week) in minimising metabolic syndrome severity. 36

Research also suggests that replacing sedentary behaviour with light-intensity physical activity could be effective for reducing diabetes risk markers. 37 Even one session of aerobic exercise per week, 50 min of treadmill walking at 70% of maximum oxygen consumption will boost whole-body insulin sensitivity in people with type 2 diabetes. 38 Therefore, it is possible that resistance exercise training also improves blood sugar regulation and insulin action in people with type 2 diabetes.39,40

In a randomised control trial, older men with newly diagnosed type 2 diabetes who did twice-weekly progressive resistance training for 16 weeks showed a 46.3% rise in insulin action, 7.1% drop in fasting blood glucose levels and a substantial loss of abdominal fat. 41 Another randomised control trial aimed to determine how low-volume, high-intensity interval training affected cardiometabolic risk and exercise ability in women with type 2 diabetes. 28

The key finding was that the low-volume, high-intensity interval training programme successfully lowered fasting glucose and HbA1c levels over 16 weeks, despite the daily dose of glucose-lowering therapies being reduced. 28 The low-volume, high-intensity interval training programme also improved lipid profile, blood pressure, endurance performance and body composition. 28

Several studies have highlighted that aerobic exercise enhances mitochondrial density, insulin sensitivity, oxidative enzymes, blood vessel compliance and reactivity, lung function, immune function and cardiac performance among people with type 2 diabetes. 42 In adults with type 2 diabetes, high-intensity interval training facilitates rapid improvements in skeletal muscle oxidative ability, insulin sensitivity and glycaemic control.28,43

Interestingly, short bouts of near-maximal intensity aerobic exercise (20 min) result in post-exercise insulin action improvements lasting up to 24 h. 27 Therefore, aerobic exercise may improve functional capacity, fitness and health-related quality of life in people with type 2 diabetes. 44

Both aerobic and resistance exercise have been shown to enhance skeletal muscle, adipose tissue and liver health and control insulin sensitivity, which are related to weight loss. Aerobic exercise, however, showed a slightly greater significant reduction in HbA1c (difference of 0.18%) compared with resistance exercise. 27

One systematic review assessed the impact of resistance exercise of varying intensities on HbA1c, insulin and blood glucose levels in people with type 2 diabetes. 29 After resistance exercise, there was a correlation between intensity and resistance training resulted in reduced HbA1c (p = 0.006) and insulin (p = 0.015) levels in a meta-regression study.

Subgroup analysis indicated that high-intensity exercise was associated with lower HbA1c than low- to moderate-intensity exercise. 29 In addition, the differences in HbA1c and insulin levels between the subgroups were statistically significant, indicating that participation in high-intensity resistance exercise has significant benefits. 29 Standing on one foot, tai chi and heel-to-toe walking are some exercises that can help people improve their balance to avoid falling. 26

Stretching improves range of motion and flexibility around joints; it, however, does not affect glycaemic control. 45 Likewise, balance training helps reduce the risk of falling by improving balance and gait, even when peripheral neuropathy is present. 46 Tai chi training in diabetes and neuropathic patients will enhance glycaemic regulation, balance, neuropathic symptoms and some qualitative aspects of life in adults with diabetes and neuropathy. 47

Similarly, increased unstructured physical activity (e.g. errands, housework, dog walking or gardening) improves everyday energy expenditure and weight control.48,49 Walking activity effectively reduces postprandial hyperglycaemia and improves glycaemic control in people with prediabetes and type 1 and type 2 diabetes, particularly after meals.50–52

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554560/


More information: Exercise improves angiogenic function of circulating exosomes in type 2 diabetes: Role of exosomal SOD3, The FASEB Journal (2022).

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