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Are There Really Exercise Non-Responders?

by Dr. Sheri Colberg, Ph.D., FACSM

“Are Some Individuals Programmed to Fail?” asked a recent review by Stephens and Sparks published in the Journal of Clinical Endocrinology and Metabolism in November 20141. The authors claimed that up to 20 percent of people with type 2 diabetes (T2D) are non-responders, that is, resistant to the beneficial effects of exercise training of all types.

The main findings of that review follow: “Supervised exercise training results in substantial response variations in glucose homeostasis, insulin sensitivity, and muscle mitochondrial density, wherein approximately 15–20% of individuals fail to improve their metabolic health with exercise. Classic genetic studies have shown that the extent of the exercise training response is largely heritable, whereas new evidence demonstrates that DNA hypomethylation is linked to the exercise response in skeletal muscle. DNA sequence variation and/or epigenetic modifications may, therefore, dictate the exercise training response.” The authors cited lack of overall improvements in HbA1c, muscle mitochondrial content, body fat, and body mass index in non-responders with T2D for all types of exercise training programs.

Not surprisingly, I have some issues with their conclusions. For starters, a large part of the data that they used to “prove” their point came from animal research. Successive generations of rats were bred until they had either a very high aerobic capacity or a low one, and the review suggested that these findings apply directly to human genetics. However, human are much more genetically heterogeneous than lab rats, and human muscles can change their aerobic capacity with training, suggesting a strong environmental impact on exercise outcomes2.

The review also noted that “several [clinical] studies have established that insulin resistance, slowed muscle perfusion kinetics, and slowed oxidative phosphorylation correlate with exercise defects in persons with T2D” and suggested this potentially explains the non-responders. In contrast, a recent systematic review of 18 training studies concluded that normal training adaptations to aerobic exercise are possible in adults with T2D and impaired glucose tolerance3, again suggesting that environmental factors are a more likely explanation.

What are some of these environmental factors? For starters, a big issue with human aerobic training studies — one not addressed by this review — is that not all individuals in exercise studies end up training similarly, despite the good intentions of the researchers. I know from experience after conducting hundreds of graded exercise tests on older individuals with diabetes that their maximal capacity can be artificially lowered for myriad reasons beyond my control, such as their lack of motivation (most are sedentary individuals being asked to do unfamiliar maximal work), localized muscle fatigue (during cycle ergometer testing in particular), excess body fat (aerobic capacity is expressed per kg body mass, not relative to total muscle mass) and other exercise limitations (e.g., joint issues and diabetes-related complications like heart or peripheral vascular disease). In short, most subjects with T2D are max tested and erroneously concluded to have a lower-than-actual aerobic capacity, and then their training exercise levels are based on that low maximum. As a result, many non-responders may simply not be training as hard or well as everyone else, hence the lesser response in their measured training benefits.

The review offered further “proof” from studies that tested human myotubes in a laboratory and then made conclusions about how whole human muscles — with a variety of muscle fiber types in them — act in an intact human body during exercise training. The authors of the review stated, “It is tempting to speculate that those individuals with T2D that display exercise resistance in vivo also have an intrinsic exercise resistance of their muscle cells in terms of these metabolic outcomes.” However, numerous environmental factors impact insulin resistance in vivo, not just exercise training, and those other factors could also impact the myotube responses in vitro.

Another confounding environmental variable in almost all training studies is the potential impact of diet on measured outcomes like insulin action and HbA1c. When diet is not controlled by the researchers (and it seldom is during exercise training studies), the impact of food intake can override the benefits of the exercise itself, both how long insulin action is elevated and glycemic control4. In other words, it’s entirely possible to virtually negate the effects of the last bout of exercise and diminish its acute (and chronic) metabolic benefits in a T2D population.

In response to this question (Are There Really Exercise Non-Responders?), my conclusion can only be that the studies of exercise responses in people with T2D are likely inherently flawed, not necessarily the potential to respond itself. Even if there are actual non-responders for the variables focused on in the November review, the other health benefits of exercise are innumerable and should never be discounted. Even breaking up sitting time has measurable metabolic benefits5. So, get up and go be active!

References:

  1. Stephens NA, Sparks LM: Resistance to the beneficial effects of exercise in type 2 diabetes: Are some individuals programmed to fail? J Clin Endocrinol Metab 2014 Nov 20:jc20142545. [Epub ahead of print]
  2. Pruchnic R, Katsiaras A, He J, Kelley DE, Winters C, Goodpaster BH: Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am J Physiol Endocrinol Metab 2004;287:E857-862
  3. Wang Y, Simar D, Fiatarone Singh MA: Adaptations to exercise training within skeletal muscle in adults with type 2 diabetes or impaired glucose tolerance: a systematic review. Diabetes Metab Res Rev 2009;25:13-40
  4. Hagobian TA, Braun B: Interactions between energy surplus and short-term exercise on glucose and insulin responses in healthy people with induced, mild insulin insensitivity. Metabolism 2006;55:402-408
  5. Dunstan DW, Kingwell BA, Larsen R, Healy GN, Cerin E, Hamilton MT, Shaw JE, Bertovic DA, Zimmet PZ, Salmon J, Owen N: Breaking Up Prolonged Sitting Reduces Postprandial Glucose and Insulin Responses. Diabetes Care 2012;35:976-983

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