One in Five With Type 2 Diabetes Nonresponsive to Exercise

Miriam E Tucker

November 20, 2014

About one in five people with type 2 diabetes do not respond favorably to exercise, a new literature review finds.

Taken together, the data suggest that between 15% and 20% of patients with type 2 diabetes will not experience improvements in HbA1c, insulin sensitivity, percent body fat, or muscle mitochondrial content even with supervised exercise.

Clinically, the findings mean that a patient may be truly attempting to comply with an exercise prescription and simply not responding to it, just as some people don't respond to weight-loss drugs, the researchers say.

The paper was published online November 20 in the Journal of Clinical Endocrinology and Metabolism by Dr Natalie A Stephens (Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando and Sanford Burnham Medical Research Institute, Orlando) and Dr Lauren M Sparks (Sanford Burnham Medical Research Institute).

"While it may be the case that some people aren't [complying], what we're showing is that there's an actual subgroup that are putting in the effort and doing the exercise and still not reducing their blood glucose or improving their blood sugar control," Dr Sparks told Medscape Medical News.

The name given to this recently discovered epigenetic phenomenon, "exercise resistance," should be viewed as akin to insulin resistance, rather than that the patient is resistant to the idea of exercise, she noted.

She also stressed that this doesn't mean doctors should not recommend exercise to all patients with type 2 diabetes, because it has other beneficial effects.

An Epigenetic Phenomenon

Drs Stephens and Sparks believe that "exercise resistance" in human skeletal muscle is the result of deficiencies within the genes that regulate fatty-acid oxidation, glucose uptake, and overall utilization of glucose and fat.

"We're hypothesizing that these people have a 'brake' on their DNA. So when they exercise, the brake isn't getting released. Perhaps a drug company could develop a compound to 'unlock' the brake so people could benefit from the exercise," Dr Sparks said.

The paper provides an overview of animal, in vitro, and clinical studies related to this phenomenon; the researchers also reference unpublished data of their own and from other collaborators.

While exercise resistance is probably not limited to people with type 2 diabetes, they may be more prone to it. The data suggest that they are more likely to have impaired exercise capacity and perceive a greater effort during aerobic exercise than do nondiabetic patients, even after adjustment for relative work intensity, the doctors write.

In an unpublished study they conducted, significantly varying responses in muscle mitochondrial content and fatty-acid oxidation rates were seen among 42 men and women with type 2 diabetes following 9 months of aerobic, resistance, or combination exercise training. Glucose homeostasis and/or muscle-substrate metabolism did not improve in 20%, despite the intensive, supervised exercise regimen.

Meanwhile, another published study found overlap in resting ATP-synthesis rates after training among lean and obese individuals and those with type 2 diabetes. Resting in vivo mitochondrial function did not improve after a 3-week aerobic exercise training intervention in some individuals, whereas others achieved resting in vivo mitochondrial function comparable to that of lean, healthy individuals (J Clin Endocrinol Metab. 2011;96: 1160-1168).

And several other trials have demonstrated that the response to exercise training is in large part inherited, including older twin studies and more recent findings in family members, the authors say.

For example, in more than 400 individuals who underwent a 20-week aerobic-exercise intervention, researchers found specific quantitative trait loci linked to changes in plasma insulin, triglycerides, and glucose homeostasis in response to the exercise, suggesting that there are sequence variations dictating this exercise response, Dr Stephens and Sparks write.

And in "exciting" new research, muscle-specific microRNAs (myomiRs) also have appeared to play a role in the skeletal-muscle response to exercise, with one study showing that myomiRs were differentially expressed in healthy individuals defined as high responders or low responders after 12 weeks of resistance training (J Appl Physiol (1985). 2011;110:309-317).

What's Next?

Dr Sparks is hopeful that this paper will attract researchers who have data sets that can be examined further for this phenomenon through cellular and DNA analysis.

Meanwhile, she emphasized that clinicians shouldn't stop recommending exercise.

"Right now we don't have a solid answer. This is just a call to action….Exercise has other beneficial effects on quality of life that we haven't measured here. Hopefully the science can catch up and start to answer these questions.

"But realize just because [clinicians] don't see improvement in their patients they should not immediately dismiss them or assume they're not exercising," she told Medscape Medical News.

Dr Stephens and Dr Sparks have reported they have no relevant financial relationships.

J Clin Endocrinol and Metab. November 20, 2014. Available at: http://press.endocrine.org/toc/jcem/0/0.

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