Studying the Link Between Exercise and Insulin Sensitivity

New research may help explain why traditional exercise regimens fail to boost insulin sensitivity in some patients with prediabetes: activation of TGFβ and TGFβ target genes.

Investigators recruited 20 middle-aged and sedentary patients who were at high risk of developing type 2 diabetes mellitus (T2DM) and subjected them to an 8-week program of walking and cycling designed to get patients to use about 80% of their maximum oxygen consumption (VO2 max).

Most of the patients saw significant increases in their insulin sensitivity (and thus significant reductions in their risk of developing T2DM), but insulin sensitivity remained unchanged in a handful of patients.

The study team then analyzed muscle samples taken from all patients immediately before and immediately after the exercise regimen and looked for systematic differences between patients whose insulin sensitivity had increased and those whose insulin sensitivity had remained the same.

They found that in “non-responding” patients whose insulin sensitivity remained unchanged, exercise activated a messenger substance called TGFβ and its target genes, which are associated with increases in inflammatory and macrophage markers. No such activation occurred in responding patients.

“TGFβ1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells,” the study authors wrote in Diabetes. “Activated TGFβ1 signaling down-regulates the abundance of PGC1α, AMPKα2, mitochondrial transcription factor TFAM, and of mitochondrial enzymes. Thus, the data suggest that increased TGFβ activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.”

The failure of some cohort patients to translate increased exercise into increased insulin sensitivity was not unusual. Regular exercise greatly increases insulin sensitivity in most pre-diabetic patients, but trials typically find that no change in about 20% of all patients.

The investigators who conducted the new study did find some changes when they compared pre-exercise and post-exercise muscle samples from patients whose insulin sensitivity did increase. Such patients saw increased activation in genes associated with burning glucose and fat.

Although the analysis provided extra information about how different people respond to regular exercise, the investigators warned that their work did not explain why responses vary or whether different people might respond to different types of exercise.

“At the moment we are still trying to understand what causes TGFβ to be activated in the muscle of some participants. There is some evidence that a different training program where the intensity or length of training is adapted to an individual’s ability to respond to physical exercise would be successful, and would help to prevent diabetes,” said co-author Cora Weigert, PhD, heads a research unit at the University of Tübingen’s Institute for Diabetes research. “I myself am convinced that everyone — given a suitable training program – can lower their personal diabetes risk.”

A number of previous studies have investigated how exercise increases insulin sensitivity in most people with prediabetes. For example, a 2004 study that appeared in Diabetes Care found that exercise increases adiponectin, a circulating adipocytokine with anti-inflammatory properties that is inversely related to insulin resistance.