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Physical Activity - worth the effort in insulin resistance?

Dr. B. Brouwers, biomedisch wetenschapper

To date, 2.1 billion people are either overweight (BMI >25 kg/m2) or obese (BMI > 30 kg/m2) [1]. Although being overweight or having obesity is not necessarily harmful itself, it dramatically increases the chance to develop obesity-related comorbidities [2]. One of these comorbidities is type 2 diabetes (DM II). More than 90% of the people that have DM II, have a BMI higher than 25 kg/m2 [3]. DM II is related to the development of cardiovascular disease, kidney disease, nerve disease, blindness, and amputations [4], and therefore a significant cause of premature mortality.

DM II is characterized by a gradual decline in the body’s sensitivity to insulin. Insulin is the most important hormone that regulates blood glucose concentrations and stimulates tissue growth. In healthy individuals, insulin increases glucose uptake in skeletal muscle, and limits the release of glucose from the liver. When insulin resistance develops, insulin cannot execute its function effectively. Insulin-stimulated glucose uptake in skeletal muscle becomes lower, and the capacity of insulin to block the release of glucose from the liver diminishes. This will lead to elevated blood glucose concentrations.

The most important goal in the treatment of insulin resistance is to achieve and maintain optimal blood glucose levels (< 6.1 mmol/l). While there are several insulin sensitizing drugs on the market, physical activity is still one of the most efficient ways to improve a person’s insulin sensitivity. This was shown by comparing the effect of metformin (a first line drug treatment for insulin resistance) to supervised exercise training in insulin resistant men and women [5]. Twelve weeks of metformin therapy improved insulin sensitivity by 15%. However, 3 times a week 60 minutes supervised exercise training for 12 weeks improved insulin sensitivity by 50%.

Direct and indirect effects on insulin sensitivity
The high efficiency of physical activity can be explained by the fact that it improves insulin sensitivity both directly and indirectly. In the 1990’s, it was a common believe that the insulin sensitizing effect of physical activity originated from a decrease in body weight: Higher physical activity increases energy expenditure, which eventually leads to weight loss, and in turn, weight loss is very well known to increase insulin sensitivity [6]. Nevertheless, since the early 2000’s, a myriad of intervention studies have also shown that increased physical activity improves insulin sensitivity directly, even when body weight was constant [7, 8]. Thus, physical activity improves insulin sensitivity not only indirect via weight loss, but also directly via other ways.

Higher glucose uptake is the main mechanism of action
The most important direct insulin sensitizing effect of physical activity takes place in skeletal muscle, the organ that is responsible for 85% of the total glucose uptake in the body. Several studies have measured skeletal muscle insulin sensitivity directly, before and after a supervised exercise training protocol [5, 9, 10]. All these studies concluded that glucose uptake by skeletal muscle improves dramatically after exercise training. This is easy to understand, since skeletal muscle is the organ that is actively trained.

After glucose is taken up by the skeletal muscle, it has 2 “faiths”. It can either be used as an immediate energy source for oxidation, or it can be stored as glycogen (the polysaccharide of glucose) to be used as an energy source in times when more energy is needed (for example during fasting). Physical activity can increase both the oxidation and the storage of glucose in skeletal muscle [5, 10, 11].

Higher glucose uptake is regulated by acute and chronic effects
Higher glucose oxidation and higher glucose storage in skeletal muscle can be influenced by both acute and chronic effects of physical activity [4, 11].

Acute effects take place during, and immediately after a single bout of physical activity. Contraction-stimulated glucose uptake increases glucose oxidation during the physical activity bout [4, 11]. When the exercise bout is completed, glucose oxidation will return to resting values. Then the insulin-stimulated storage of glucose (as glycogen) will become more important [11]. This second acute effect takes place in the first 2 - 72 hours after a bout of physical activity, after which it also disappears.

Chronic effects of physical activity are effects that occur due to long term training. When a person engages in an physical activity program for several weeks, structural and physiological changes in the skeletal muscle can occur. For example, muscle mass might increase, and the phenotype of the skeletal muscle will be a change from a more sedentary one to a more trained phenotype. The chronic effects do not really have a significant role in increasing glucose oxidation, since this is only increased during a physical activity bout. However, the chronic effects of physical activity will further enhance storage of glucose (as glycogen) in skeletal muscle [11].

Thus both single bouts of physical activity themselves, as long-term training effects can contribute to higher glucose uptake in skeletal muscle, which will lead to a better regulation of blood glucose concentrations.

What intensity and type of physical activity is recommended?
The current guidelines of the American Diabetes Association target 150 minutes of vigorous or moderate-intensity physical activity per week to prevent and treat insulin resistance [4].

Vigorous physical activity is defined as physical activity that requires a large amount of effort, causes rapid breathing and a substantial increase in heart rate (70-85 % of the maximum heart rate) [12]. Vigorous physical activity can either be intense resistance exercise, intense aerobic exercise, or a combination of both. All of those increase insulin sensitivity [9, 10, 13], but a combination of aerobic and resistance exercise is believed to be the most efficient to improve insulin sensitivity [4]. The rationale behind this is that resistance exercise and aerobic exercise both improve insulin sensitivity in a different way. Resistance exercise increases total skeletal muscle mass, and more skeletal muscle mass will result in higher total glucose uptake. Aerobic exercise training does not increase skeletal muscle mass, but improves the efficiency of the skeletal muscle to take up glucose - the same amount of skeletal muscle will take up more glucose. A combination of resistance and aerobic exercise triggers both effects, and is therefore believed to be the most efficient.

Moderate-intensity physical activity is defined as activity that requires a moderate amount of effort and noticeably accelerates the heart rate (50-70 % of the maximum heart rate) [12]. Examples are brisk walking, gardening, and walking your domestic animals. That moderate-intensity physical activity is efficient has been in shown in a study where walking for 30 minutes a day, for 6-7 days a week improved insulin sensitivity after 6 months [7]. However, the improvement in insulin sensitivity that is achieved with moderate-intensity physical activity is often more modest compared to what is achieved with vigorous physical activity. Moderate-intensity physical activity mainly activates the oxidative effects, but has less effect on increasing the storage of glucose as glycogen in skeletal muscle. Also, moderate-intensity physical activity does not increase skeletal muscle mass, nor will it results in a decrease in body weight [14].

Expert opinion
A recent analysis in 20.000 people concluded that a decrease in physical activity, more than an increase in caloric intake, is related to the high amount of people that are overweight and obese today [15]. Increasing physical activity is therefore the most straightforward therapy to turn this problem around.
Using physical activity as a first line treatment has several advantages. First, it can already be implemented in healthy overweight and obese people to prevent the development of insulin resistance. When somebody has developed insulin resistance, it is the most efficient way to lower blood glucose concentrations back to normal values in a relatively short time. Second, increased physical activity will lower body weight via increased energy expenditure (when caloric intake is kept constant). Third, physical activity also improves cardiovascular health which is, like insulin sensitivity, often impaired in people that are overweight or obese.
Physical activity should be performed for at least 150 minutes per week, with maximal 72 hours in between each exercise bout to be the most effective. Therefore, physical activity should be performed at least 3 times a week, with no more than 2 consecutive days without physical activity between exercise sessions. If possible, a vigorous physical activity program should be implemented, ideally a combination of resistance and aerobic exercise.
However, in older, unfit people with a higher change for cardiovascular complications, moderate-intensity physical activity might be easier to implement at first. After an initial period of moderate-intensity physical activity, and when fitness has improved, intensity can be increased. 

Reference list
[1] OECD (2014) Obesity update
[2] National Diabetes Data Group of the National Institute of Diabetes and Digestive and Kidney Diseases NIoH (1995) Diabetes in America 2: 734
[3] Organization WH (2013) Obesity and Overweight
[4] Colberg SR, Sigal RJ, Fernhall B, et al. (2010) Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care 33: e147-167
[5] Malin SK, Gerber R, Chipkin SR, Braun B (2012) Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care 35: 131-136
[6] Williams KV, Kelley DE (2000) Metabolic consequences of weight loss on glucose metabolism and insulin action in type 2 diabetes. Diabetes Obes Metab 2: 121-129
[7] Duncan GE, Perri MG, Theriaque DW, Hutson AD, Eckel RH, Stacpoole PW (2003) Exercise training, without weight loss, increases insulin sensitivity and postheparin plasma lipase activity in previously sedentary adults. Diabetes Care 26: 557-562
[8] Ross R (2003) Does exercise without weight loss improve insulin sensitivity? Diabetes Care 26: 944-945
[9] Malin SK, Haus JM, Solomon TP, Blaszczak A, Kashyap SR, Kirwan JP (2013) Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes. Am J Physiol Endocrinol Metab 305: E1292-1298
[10] Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E, et al. (2010) Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes 59: 572-579
[11] Perseghin G, Price TB, Petersen KF, et al. (1996) Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 335: 1357-1362
[12] Organization WH (2004) Global Strategy on Diet, Physical Activity and Health
[13] Bucci M, Huovinen V, Guzzardi MA, et al. (2016) Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers. Diabetologia 59: 77-86
[14] Batacan RB, Jr., Duncan MJ, Dalbo VJ, Tucker PS, Fenning AS (2015) Effects of Light Intensity Activity on CVD Risk Factors: A Systematic Review of Intervention Studies. Biomed Res Int 2015: 596367
[15] Ladabaum U, Mannalithara A, Myer PA, Singh G (2014) Obesity, abdominal obesity, physical activity, and caloric intake in US adults: 1988 to 2010. Am J Med 127: 717-727 e712