THE ROLE OF PHYSICAL ACTIVITY IN THE PREVENTION OF TYPE 2 DIABETES

Multiple lines of epidemiological evidence attest to the fact that physical activity can reduce the risk of development for T2DM. An early study in the mid-1970s surveyed diabetes and it complications, using a 50g oral glucose load, in 500 Japanese migrants living on the U.S. island of Hawaii and compared it with 430 Japanese living in Hiroshima Prefecture.¹⁴ The age and sex adjusted prevalence of T2DM in Japanese living in Hawaii was 12.3% and almost twice that of those living in Hiroshima at 6.9%. From the physical activity perspective, 86.1% of the men and 81.3% of the women living in Hiroshima were or had been engaged in moderate to heavy levels of occupational physical activity compared with only SCIENTIFIC CONTRIBUTIONS

SCIENTIFIC CONTRIBUTIONS

45.7% of Japanese men and 15.7% of women living in Hawaii.¹⁴ In a similar observation, Pima Indians living a traditional lifestyle in north-western Mexico who were reporting high amounts of heavy and moderate occupational work had a prevalence of T2DM of 10.5% in women and 6.3% in men. This compared with 37% and 54 % in Pima Indians living on reservations in Southern Arizona.¹⁵ These early observations suggested a role for heavy occupational physical activity in the prevention of T2DM.

Economic development often parallels increases in T2DM with a greater prevalence in urban than rural communities² - although in recent years there has been a rapid and notable increase in rural settings as well² – and reduced occupational physical activity associated with urbanisation may be one reason for the increase in disease occurrence. Singapore itself is a case in point where the prevalence of T2DM increased from 2.0% to 9.0% between 1975 and 1998 at a time when the country was undergoing rapid economic changes and development. ^4,16 Indeed, the prevalence of regular leisure time physical activity in 1998 was 16.8%.⁴ Although this increased to 19.0% by 2010, physical inactivity is still widespread with more than half (54.0%) of Singaporeans not partaking in any leisure-time physical activity each week. ⁴ Thus, whilst occupational activity may play an important role in the prevention of diabetes in developing countries or rural communities, in developed countries such as Singapore, where fewer numbers of individuals partake in heavy occupational work, the promotion and role of leisure-time activity in reducing the risk of developing T2DM is of greater interest.

Data from prospective cohort studies indicate that regular leisure-time physical activity reduces the risk for T2DM development. The Nurses’ Health Study in the U.S. surveyed the physical activity habits and volume of 70,102 female nurses, aged 40 to 65 years for 8 years beginning in1986 with updated surveys in 1988 and 1992.¹⁷ The relative risk for developing T2DM decreased across quintiles of physical activity, with a 46% risk reduction in the most active versus the least active group. This reduction was attenuated, but was still significant, to 26% after adjusting for body mass index. In women who did not perform vigorous physical activity but who walked, there was a risk reduction of 42% compared with those women in the lowest quintile for walking volume, which was attenuated to 26% after adjustment for

While data from the Nurses’ Health Study and those from several other prospective cohort studies in Western countries show similar associations between physical activity and subsequent risk of T2DM, it should be noted that not all studies in Asian populations are as convincing. The Shanghai Women’s Health Study followed 70,658 women free of diabetes at baseline over 4.6 years.¹⁸ No significant reduction in risk of T2DM development was found across quartiles of leisure-time physical activity or for activities of daily living. The risk reduction for the most active individuals completing

>3.5 hours of leisure-time physical activity each week was calculated as 17% and for those who completed

>2 hours of walking each day as 11% compared with individuals reporting no leisure-time physical activity or <60 minutes of walking per day, respectively. These reductions were attenuated further with adjustment for body mass index and waist-to-hip ratio. ¹⁸ Further evidence for an attenuated effect of physical activity on the reduction in risk for T2DM in Asians comes from a prospective study conducted in the U.S.

which directly compared postmenopausal women of different ethnicities.¹⁹ No significant association between physical activity and T2DM risk was seen in Asian women although an association was present for Caucasian women. Some caution is needed in interpreting this observation as the cohort size of the Caucasian women in the study was >10-fold greater than that of the Asian women.¹⁹ However, in at least one other U.S. study, no protective effect was seen from vigorous work or moderate physical activity in Japanese men although a significant trend was seen in other ethnic groups.²⁰ The strongest evidence for a role of physical activity in reducing the risk of developing T2DM comes from randomised controlled trials. For T2DM, it is possible to easily identify individuals with prediabetes who are at high risk of developing the disease with the progression rate to diabetes estimated as ~3-18%

in these individuals and in some studies, the 10-year incidence for individuals with impaired glucose tolerance is as high as 60%.^5,21 This high event rate and fast disease progression has allowed researchers and clinicians to undertake randomised clinical trials with sufficient power to evaluate the effects of lifestyle interventions on T2DM. Thus, over the last 30 years a substantial number of randomised trials across different populations globally, including within Asia, have shown that lifestyle interventions - incorporating physical activity, dietary change and

The Da Qing Impaired Glucose Tolerance and Diabetes Study was the earliest study to demonstrate significant reduction in the incidence of progression to T2DM in individuals with impaired glucose tolerance.²² Conducted over a 6-year period from 1986 to 1992 it involved 577 individuals (283 males and 322 with a body mass index ≥25 kg/m²) from 33 health care clinics within the city of Da Qing in Heilongjiang, China. Individuals were randomised to either a control group or one of three treatment groups: (i) diet only, (ii) exercise only, or (iii) diet plus exercise. Follow-up examinations were conducted every 2 years to identify those individuals who progressed to T2DM. Individuals in the diet group were prescribed a diet with goals relating to energy, macronutrient and alcohol intake and also daily quantities of cereals, vegetables, meat, milk and oils.

Individuals in the exercise only group were taught and encouraged to increase the amount of leisure-time physical activity by 1-2 units per day. One unit of exercise was equivalent to 30 minutes of slow walking, 20 minutes of brisk walking, 10 minutes of jogging, or 5 minutes of activities such as skipping, basketball or swimming. The diet plus exercise group received similar information to the individual diet and exercise groups. Individuals in the control group received general information about diabetes and impaired glucose tolerance including brochures with instructions for diet or increased leisure-time physical activities but no formal group counselling sessions for behaviour change. Cumulative incidence of T2DM at 6 years was 67.7% in the control group compared with 43.8%, 41.1% and 46.0% in the diet, exercise and diet plus exercise groups, respectively.

A proportional hazards analysis found a 31%, 46%

and 43% reduction in risk of developing T2DM in the diet, exercise and diet plus exercise groups.²² Whilst the data from the Da Qing Study were notable, one criticism is that participants were randomised by clinic. Moreover, the unsupervised nature of the intervention prevented assessment of the extent to which instructions were followed within each group and could be one explanation for why the diet plus exercise group did not show greater gains than individuals in the single treatment groups. Some of these criticisms were addressed in subsequent randomised controlled trials. The Finnish Diabetes Prevention Study randomly assigned 522 middle-aged (mean age 55 years), overweight individuals (172 men) with impaired glucose tolerance to a control or lifestyle intervention group with a mean duration of follow-up of 3.2 years.²³ The control group was provided general oral and written information about diet and exercise at baseline. Those individuals in the

intervention group were encouraged to achieve five major lifestyle goals: (i) reduce body mass by 5% or greater, (ii) reduce fat intake to <30% of total energy, (iii) reduce saturated fat intake to <10 of total energy, (iv) increase dietary fibre to ≥15g per 100 kcal, and (v) complete 30 minutes of moderate intensity exercise per day. For the exercise goal, endurance exercise was recommended to increase cardiorespiratory fitness and supervised, progressive circuit-type resistance training was offered to strengthen large muscle groups and improve body composition.

Participation in the circuit-training ranged from 50-85% at different centres within the first year. At four years, the cumulative incidence of T2DM was 11.0% in the intervention group and 23.0% in the control group. The risk of developing T2DM during the trial was reduced by 58.0% in the intervention group.²³ Two points are of great interest. Firstly, for individuals in the intervention group who did not meet the weight loss goal but did achieve the exercise goal during the first year, the odds ratio for developing T2DM was 0.2 compared with individuals in the intervention group who maintained a sedentary lifestyle. This ratio increased to 0.3 but maintained statistical significance after adjusting for baseline body mass index. Secondly, there were no cases of diabetes development in 64 participants (49 intervention group, 15 control group) who achieved four or five of the initial stated goals.²³

Randomised controlled trials have also demonstrated that lifestyle intervention is as powerful as early pharmacological treatment in preventing progression to T2DM in high risk groups. The Indian Diabetes Prevention Programme randomised 531 middle-aged, overweight Indians (mean age 46 years; mean body mass index 26 kg/m²) into four groups: (i) control, (ii) lifestyle modification, (iii) metformin (250-500 mg twice per day), and (iv) lifestyle modification plus metformin.²⁴ Individuals in the lifestyle modification group were encouraged to complete ≥30 minutes of leisure-time or occupational (if applicable) physical activity per day and an individualised diet designed to maintain appropriate body weight, reduce intake of total and saturated fat and simple sugars and refined carbohydrate and increase fibre intake. The median follow-up period was 2.5 years and the 3-year cumulative incidence of T2DM was 55.0%, 39.3%, 40.5%, and 39.5% in the four groups, respectively.

The relative risk reduction was 28.5%, 26.4% and 28.3% in the lifestyle, metformin and lifestyle plus metformin groups, respectively. Of note, although body mass significantly increased in the control group over 36 months, there was no significant SCIENTIFIC CONTRIBUTIONS

SCIENTIFIC CONTRIBUTIONS

weight loss in any intervention group and waist circumference did not change in any group during the study. However, physical activity participation showed an improvement from 41.7% to 58.8%

and 45.9% to 62.9% in the lifestyle and lifestyle plus metformin groups over 30-36 months.²⁴ The findings from this trial were similar to the Diabetes Prevention Program in the U.S. which randomised 3,234 middle-aged, overweight individuals (32%

men; mean age 51 years; mean body mass index 34 kg/m²) with impaired fasting glucose or impaired glucose tolerance to a placebo, metformin (850 mg twice daily) or lifestyle modification program which had the goals of 7% weight loss and ≥150 minutes per week of physical activity.²⁵ The incidence of T2DM was reduced by 58% with lifestyle modification and 31% with metformin compared with placebo; the lifestyle intervention was significantly more effective than placebo. An important aspect of this U.S. study was that it was a multi-ethnic cohort, including Asians, and sub-analyses revealed that the reduction in risk of T2DM with lifestyle intervention was similar across ethnic groups.²⁵

Collectively, the epidemiological evidence demonstrates that physical activity is associated with a decreased risk for developing T2DM in healthy individuals and those at high risk of developing the disease. Published long-term follow-up from the Da Qing Study²⁶, the Finnish Diabetes Prevention Study²⁷ and the Diabetes Prevention Program in the U.S.²⁸ have shown that the protective effects of lifestyle intervention persist for 10-20 years. Moreover, these interventions provides some protection against the microvascular complications associated with T2DM as well as the onset of the disease.²⁹ Current physical activity guidelines issued by the World Health Organisation³⁰ and the National Physical Activity Guidelines issued by the Health Promotion Board in Singapore³¹ stipulate that all adults should complete 150 minutes of moderate-intensity or 75 minutes of vigorous intensity aerobic activity, in bout of at least 10 minutes at a time, each week. Several of the studies highlighted provide empiric evidence that an activity volume in line with these guidelines can reduce the risks associated with the developing the disease. Importantly the protection afforded by physical activity was consistent across ethnic groups including Asians.

Physical activity and cardiovascular disease in individuals with type 2 diabetes

College of Sports Medicine and American Diabetes Association in 2010 recognised that physical activity was central to the management and prevention of T2DM because it can help treat and control the associated glucose, lipid and blood pressure abnormalities associated with the disease as well as aid in weight loss and maintenance.³² Moreover, regular physical activity can improve cardiovascular fitness.³² These factors, along with the strong evidence demonstrating it can reduce the risk of developing T2DM in individuals with prediabetes as part of a lifestyle intervention programme, lead to the initiation of the Look AHEAD (Action for Health in Diabetes) Study in the U.S.³³ The Look AHEAD study is the only randomised controlled trial assessing the effect of intentional weight loss brought about by intensive lifestyle intervention on cardiovascular morbidity and mortality in overweight and obese individuals with T2DM. The trial involved 5,145 overweight and obese T2DM patients from 16 centres across the U.S. randomised to an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity or to a diabetes support and education group (control group). The primary outcome in the study was a composite of death from any cardiovascular cause, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for angina.³³ Early results were promising with participants in the intervention group demonstrating greater percentage weight loss, greater improvements in fitness, glycated haemoglobin, systolic and diastolic blood pressure, high density lipoprotein cholesterol and triglycerides after 4 years of follow-up.³⁴ However, the trial was stopped on the basis of a futility analysis when the median follow-up was 9.6 years.³³ Despite continued greater weight loss and greater reduction in glycated haemoglobin, improvements in fitness and all measured cardiovascular risk factors, except low-density-lipoprotein cholesterol, with lifestyle intervention there was no reduction in the rate of death from cardiovascular events.³³

Though data from the Look AHEAD study were intensely disappointing and demonstrate the limits of intensive lifestyle interventions and physical activity as a panacea for all ills, several findings from the study were encouraging. Patients randomised to the intervention group were more likely to have a partial remission of T2DM in the first 4 years of the trial than individuals in the control group.³⁵ Moreover, during the early years of the trial there

of physical activity in individuals with T2DM by clinicians along with appropriate pharmacological intervention.

Exercise and insulin sensitivity

Many of the benefits realised with physical activity result from acute and chronic improvements in insulin action accomplished from physical activity which is aerobic in nature or with resistance type exercise and training.³² That exercise increases the sensitivity of the glucose transport process to insulin skeletal muscle was discovered in 1982.^36,37 Glucose transport into skeletal muscle is via the glucose transporter 4 (GLUT4) protein which is modulated by both insulin and muscle contractions.³⁷ Much of the benefit of physical activity appears to be from the most recent bout taken because detraining or an absence of physical activity rapidly leads to increases in glucose and reductions in the sensitizing effect of insulin.^38-40 Experimental studies have shown that activity as brief as 30 minutes can improve glucose disposal, glucose tolerance or insulin sensitivity on the same day.⁴¹ These studies probably reflect immediate effects of muscle contraction as it is widely accepted that prior activity increases glucose transport for a short-period post-exercise which is independent of insulin.³⁷ Longer duration exercise bouts or consecutive days of activity effect these parameters when the assessment is ≥12 hours post-exercise reflecting improved insulin-stimulated pathways.⁴²

Physical activity recommendations

The most comprehensive guidelines for exercise in individuals with or at high risk of T2DM have been produced from the American College of Sports Medicine and American Diabetes Association.³² These guidelines summarised and categorised the evidence available from exercise studies using empiric evidence from many of the randomised controlled epidemiological and laboratory studies described previously. Current recommendations are that at least 150 minutes per week of moderate intensity physical activity should be undertaken as part of lifestyle changes to reduce the risk of T2DM development in high risk individuals. Individuals with T2DM should undertake at least 150 minutes per week of moderate to vigorous aerobic exercise spread across at least 3 days per week, with no more than 2 consecutive days between bouts of aerobic activity. In addition, they should undertake moderate to vigorous resistance training at least 2-3 days per week. Benefits from aerobic and resistance training will include improved insulin action, blood glucose

control and fat oxidation and storage in skeletal muscle. Resistance exercise will also enhance skeletal muscle mass. Thus, a combination of the two types of exercise each week is recommended.

Milder forms of exercise such as tai chi and yoga have shown mixed results in their ability to improve blood glucose in longer term training studies. Finally, individuals with T2DM will benefit from a physical examination from a physician before undertaking an exercise programme more intense than brisk walking.³²

CONCLUSION

There is strong, consistent evidence that physical activity reduces the risk of developing T2DM in high risk individuals. Although physical activity and lifestyle modification bringing about intentional weight loss does not reduce mortality and non-fatal cardiovascular disease incidence in individuals with T2DM, other benefits from physical activity and other lifestyle changes are worthwhile. Moreover, there is good evidence to support the benefits of physical activity and exercise training on insulin action, blood glucose control and fat oxidation and storage in skeletal muscle, as well as cardiovascular fitness. A minimum of 150 minutes of moderate-to-vigorous physical activity and 2 days of resistance exercise each week, in line with guidelines in Singapore, the U.S. and from the World Health Organisation, is recommended for individuals at risk of the T2DM or presently diagnosed with the disease.

REFERENCES

1. American Diabetes Association. Standards of Med-ical Care in Diabetes – 2014. Diabetes Care 2014;

37(S1):S14-S79.

2. International Diabetes Federation. IDF Diabetes Atlas.

6^th Edition. International Diabetes Federation, 2013.

ISBN: 2-930229-85-3.

3. World Health Organisation. Global Report on Diabetes – Executive Summary. World Health Organisation, 2016.

Available: www.who.int/diabetes/global-report 4. Ministry of Health. National Health Survey 2010

Singa-pore. Epidemiology and Disease Control Division, Minis-try of Health, Singapore 2010. ISBN:978-981-08-8540-3.

5. Yudkin JS & Montori VM. The epidemic of pre-diabetes:

the medicine and the politics. BMJ 2014; 349g:4485.

6. Barnett AH, Eff C, Leslie RDG, Pyke DA. Diabetes in identical twins: A study of 200 pairs. Diabetologia 1981;

20:87–93.

7. Newman B, Selby JV, Slemenda C, et al. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 1987; 30:763–8.

8. Bergman RN, Ader M. Free fatty acids and pathogenesis

8. Bergman RN, Ader M. Free fatty acids and pathogenesis