Author Response

We thank Gentzel for his valuable comments and suggestions¹ on our recently published clinical recommendations regarding exercise assessment and prescription in type 2 diabetes mellitus (T2DM) for physical therapists in private and home care settings.² We agree with the comment that physical therapists should focus on the impact of exercise intervention on molecular cascades that are related to T2DM. In this way, exercise interventions are implemented to cure disease (affecting the molecular cascades that are related to insulin resistance [IR], which is the precursor for the development of T2DM), instead of symptomatic control only (lowering blood glucose content). It follows that physical therapy might be on the verge of a new era: physical therapists could be able to cure T2DM by exercise intervention, instead of simply suppressing symptoms of disease. However, to achieve such an ambiguous goal, it is important that: (1) research be conducted to further understand the development of insulin resistance (IR) and the impact of exercise intervention on these molecular cascades and (2) physical therapists follow the literature and adjust their exercise therapies accordingly.

We would like to provide a brief overview of the pathophysiology of IR and how we could tackle IR by exercise intervention. It should be kept in mind, however, that the pathophysiology of IR is extremely complex and not yet fully understood. Moreover, the mechanisms mentioned below are not complete, as an in-depth discussion would be beyond the scope of this response. However, we believe that obtaining some knowledge about the etiology of IR and the impact of exercise intervention on molecular cascades leading to IR would contribute to more effective exercise prescription in patients with T2DM.

Type 2 diabetes mellitus results from sustained IR. It thus follows that when we aim to cure T2DM, we should aim to restore insulin sensitivity. Insulin resistance is present in skeletal muscle cells and adipocytes (besides the liver), which are organs that could be targeted by exercise intervention. The exact cause of IR, however, remains a topic of intense debate, although great progress has been made in our understanding of the etiology of IR during the last decade. According to current literature, different mechanisms of IR are being proposed, although it is highly possible that the combination of these mechanisms contributes to IR.³

On the one hand, it is argued that IR results from the accumulation of intramuscular lipids and lipid metabolites, especially in the presence of a reduced lipid oxidation capacity.³ Such accumulation would ultimately lead to defects in skeletal muscle insulin signaling and thus to impaired muscle glucose transport.³ If this mechanism would be valid, exercise interventions in people with T2DM should focus on the improvement of fat oxidation capacity and the decrease in intramuscular lipids. However, simply executing low-intensity exercise bouts, with the aim to acutely stimulate fat oxidation, fails to improve glycemic control with greater magnitude in patients with T2DM in the long term, as opposed to isocaloric high-intensity exercise bouts.^4,5 It thus might be necessary to more aggressively force the skeletal muscles to oxidize intramuscular triacylglycerols by, for example, providing pharmacologic support during exercise (acute lowering in blood free fatty acid content would acutely increase intramuscular fat oxidation)⁶ or exercise training in a fasting condition.⁷ Both treatment strategies remain to be studied during long-term exercise intervention in patients with T2DM. We await the outcomes from these studies with great interest.

Other researchers, however, propose to prescribe low-volume, high-intensity interval exercise bouts in patients with T2DM.⁸ This training method would lead to a significantly greater increase in skeletal muscle mitochondrial density or content, leading the way to greater skeletal muscle fat oxidation capacity. Although it has been shown that high-intensity interval exercise training—as opposed to continuous moderate-intensity exercise training—is more effective in improving skeletal muscle oxidative capacity and endurance capacity, its additional impact on the improvement in insulin sensitivity in the long term in patients with T2DM remains uncertain.⁹ It thus remains speculative whether physical therapists do have the opportunity to remediate IR by applying different exercise training approaches with the aim to affect molecular cascades in the skeletal muscles (related to intramuscular fat content/oxidation).

It is often reported that IR results from a state of chronic whole-body inflammation that originates from dysfunction of enlarged adipocytes (obesity). Physical therapists should be aware of the fact that adipocytes are highly active protein (adipokines) and cytokine secreting organs. Adipocyte hypertrophy, as well as adipocyte atrophy, is accompanied by an altered secretion of these adipokines and cytokines. It is currently assumed that severe adipocyte hypertrophy would lead to cellular stress that, in turn, would result in oxidative stress and inflammatory responses.¹⁰ Moreover, it has been observed that adipocytes in people who are obese are infiltrated by mononuclear cells, further contributing to an inflammatory response.¹¹ This mechanism would give way to elevated secretion of proinflammatory cytokines and adipokines. From this mechanism, it would seem logical that adipose tissue mass loss through exercise intervention would lead to an improvement in insulin sensitivity. Indeed, the latter has been noticed frequently. Moreover, it has been established that exercise volume is an important determinant of the improvement in glycemic control in patients with T2DM.⁵ This finding could be explained by the fact that exercise interventions with greater exercise volumes often lead to elevated adipose tissue mass loss (and thus greater adipocyte atrophy).¹² Based on this logic, it follows that exercise interventions with large exercise volumes should be prescribed in patients with T2DM to remediate IR.

On the other hand, it is now known that skeletal muscles affect the whole-body inflammatory status by secreting a whole array of muscle-derived cytokines (myokines),¹¹ thereby explaining a reduction in whole-body inflammation in the presence of a minimal body weight loss during exercise intervention. Interleukin-6 especially seems an interesting candidate to lower IR by acute exercise. A profound increase in skeletal muscle interleukin-6 secretion during acute exercise is present and seems to suppress IR significantly.¹³ However, how exercise should be prescribed to lower whole-body inflammation (contributing to improved insulin sensitivity) through secretion of myokines remains speculative, especially in patients with T2DM. Also here, we are awaiting results from exercise studies with great expectations.

From the above, we hope that physical therapists will become convinced to redefine the treatment targets of exercise intervention in patients with T2DM in the near future. The etiology of IR will be further explored in greater detail, leading us to a greater understanding of this disease, while other researchers simultaneously explore the impact of different training modalities on these newly discovered molecular cascades of IR. It is very likely that physical therapists will enter a new era in which they have the opportunity to implement exercise interventions with the aim to cure, instead of to provide care for, T2DM. We certainly hope that this will be the case for other chronic diseases as well.

• © 2013 American Physical Therapy Association