December 6 — 7, 2007 Advisory Committee Meeting Minutes

Metabolic Health Subcommittee Report

Judith Regensteiner, Ph.D. led the presentation of the Metabolic Health Subcommittee report. Dr. Regensteiner outlined the presentation with the five questions the subcommittee developed:

1. Can physical activity prevent diabetes?

2. What is the relationship between physical activity and prevention of Type 2 Diabetes?

3. Is there a relationship between physical activity and Type 2 Diabetes?

4. If there is a relationship between physical activity and Type 2 Diabetes what is the dose-response relationship?

5. What is the relationship between physical activity and Type 2 Diabetes in adults, youth, men, women and ethnic groups and are the relationships different among these groups?

It is known that physical activity and exercise has metabolic and cardiovascular benefits for diabetes. While there are studies that indicate physical activity can prevent Type 2 Diabetes it is important to note that there are not a lot of studies. Due to this fact it will also be important for this committee to highlight what is not know and what needs further work.

Both observational and randomized control studies have addressed the interaction between diabetes, physical activity and exercise. Most randomized controlled trials have used a combination of life-style treatments including diet and exercise which makes it harder to ascertain the benefits of exercise alone. Observational epidemiological studies using self-report mechanisms such as questionnaires have consistently shown the benefit of higher levels of physical activity towards the prevention of diabetes.

Three major randomized controlled trials have addressed the independent effect of effect of physical activity in as much as they were able. Two studies, the Finnish Diabetes Prevention study and the American Diabetes Prevention Program (DPP) both had a lifestyle arm including both exercise and diet. The Ching study in China included an exercise alone arm. Due to the extreme complexity of such trials and the cost associated it has been generally deemed not as effective to conduct studies using exercise only arms.

The DPP study found weight loss as the dominant predictor of reduced incidence of diabetes; however, physical activity and diet did predict weight loss. In many such studies when comparing individuals who did not lose weight compared to individuals that achieved their physical activity goal there was a 44% lower incidence of diabetes even though they did not lose weight. This would seem to conclude that physical activity itself does have a protective role against diabetes.

When trying to determine the appropriate dose of exercise one can conclude a specific amount of activity will have benefit in preventing diabetes; however, it is difficult to determine whether a lower or higher dose would have better results. While determining the appropriate dose is problematic one can conclude that there is strong evidence that physical activity has a major role in preventing Type 2 Diabetes as well as cardiovascular events and mortality. It seems consistent in men and women as well as along ethnic groups from the existing studies available but more data could lead to more powerful conclusions. The results in youth are now pending from the Today Study.

The second question addressed by the subcommittee, "what is the relationship between physical activity and gestational diabetes (GDM)," is a very important area due to the rising levels of obesity in the population. No randomized controlled trials have prospectively assessed whether physical activity can prevent GDM. Observational studies do seem to support the benefits of physical activity in reducing GDM. One such study conducted by Jennifer Dempsey, an obstetrician, seemed to conclude that 30 minutes of exercise five times a week yields benefits. Overall, more studies and data is needed in this area in order to produce a strong evidence based conclusion.

Dr. Regensteiner then introduced Dr. Timothy Church to address the metabolic syndrome and whether physical activity can prevent the metabolic syndrome. Metabolic syndrome is important to address because it can put individuals at high risk for diabetes, cardiovascular disease and premature all-cause mortality.

Dr. Church referenced several studies in which the majority of which supported the fact that physical activity prevents metabolic syndrome. One study, the Kuopio Study focusing on eschemic heart disease looked at both physical activity and fitness is important to note because it shows a true dose-response relationship. A weakness of the study is the fact that it only looked at men. Also, there are no exercise studies that focused exclusively on the treatment of metabolic syndrome. The Heritage Study, which was an uncontrolled study, analyzed fitness and genes in association with a host of risk factors. Most of the outcomes in this study showed the improved benefits of 20 weeks of aerobic exercise. In summary, there is an inverse association between physical activity level and the development of the metabolic syndrome. The association appears to be dose-response and not threshold in nature.

Dr. Regensteiner next introduced Dr. Amy Huebschmann to address the prevention of complications of diabetes and Type 1 Diabetes. Outlining her remarks, Dr. Huebschmann noted she will be specifically discussing the role of physical activity in the prevention of microvascular complications and when possible note a dose-response relationship and any differences between genders.

The following specific complications were reviewed: nphropathy, neuropathy and the attendant problems associated with neuropathy progression including ulcers, fall risk and retinopathy. There are very few randomized studies that have looked at the complications in relation to physical activity. With regards to neuropathy, one randomized trial in both Type 1 and Type 2 Diabetes was positive. Additionally, in Kriska's work (males only), there was a reduction in the instance of neuropathy and a case control study was negative. With regards to nephropathy, one out of the four observational studies was positive in both men and women. An additional study at Kriska was positive for reduction of nephropathy in men only. Two cross-sectional studies were negative. For retinopathy, only one of the seven studies showed benefit, which may indicate a lower benefit in this condition. In conclusion the evidence for primary prevention is poor to fair; however, it does suggest a possible relationship between the primary prevention of neuropathy and nephropathy and certainly no increased risk of retinopathy. In the area of secondary prevention we are also limited by the amount of data available to study but similarly to primary prevention there seems to be a possible beneficial relationship.

Dr. Huebschman next reviewed the sub-committees review of the relationship between physical activity and prevention of cardiovascular complications. One meta-analysis summarizing over 1,000 subjects with Type 2 Diabetes compared the effects of three different types of training regimen, either an aerobic training regimen, a resistance strength training regimen or combined aerobic and strength training. The results indicate that all three methods of training improved insulin sensitivity with greater effects from combined training, followed by aerobic and then resistance training. Additional cardiovascular risk factors were improved in both the combined training regimen and aerobic training regimen but not the resistance training regimen. Also, a study linking the NHANES database physical activity data to the National Death Index showed that more than two hour per week of walking was associated with a 41% reduction in cardiovascular mortality. More than two hours per week was associated with a 30% reduction. Studies such as the Nurses Health Study shows a significant dose-response, although it is undetermined whether the dose-response flattens out at greater levels of exercise.

In conclusion, the role of exercise in reducing cardiovascular risk seems particularly beneficial in individuals with Type 2 Diabetes and impaired glucose tolerance as compared with individuals who are normal glycemic. Dose-response would suggest that greater than 120 minutes per week of exercise is optimal and that aerobic or combined aerobic and resistance exercise would be best. Further data would be beneficial to determine if there are differences between genders.

Finally, Dr. Huebschman discussed the relationship between physical activity and the prevention of Type 1 Diabetes. As there is no known relationship with regards to primary prevention the sub-committee focused on the benefits to secondary prevention. In terms of glycemic control there are many small interventional studies which are roughly split 50/50 as to whether physical activity has a benefit. A few larger cross-sectional studies show similar modest reductions. Safety and exercise should also be discussed along with Type 1 Diabetes. The benefits of physical activity in this area come at the expense of increased risk of hypoglycemia. Normal protection from hypoglycemia in normal subjects comes from counter-regulatory hormones. Individuals with Type 1 Diabetes adjust less so there is risk of bottoming out on sugars.