When gain is greater than loss: effects of physical activity on insulin sensitivity after short‐term inactivity in older subjects

Lack of physical activity is an instigator of numerous chronic diseases and a leading cause of mortality in the Western world (Booth et al. 2012). Among the chronic diseases most influenced by physical inactivity are metabolic and cardiovascular diseases, a notion strongly supported by epidemiological data as well as by studies using experimental models in animals and humans (Booth et al. 2012). Indeed, data are pouring out of studies demonstrating that reduced activity disrupts metabolic function. In humans, an attractive and highly translational experimental model to study the ramifications of free‐living physical inactivity, due to its simulation of real‐life scenarios, is reduced ambulatory activity via step reduction. In this model, individuals are subjected to an ∼50–80% reduction in daily steps for several days to weeks. Studies using this model have revealed that decreased ambulatory activity reduces insulin sensitivity in non‐obese healthy young men (Knudsen et al. 2012). Whether reduced ambulatory activity produces similar metabolic effects in older adults, and the mechanisms by which this occurs, has remained unknown. In addition, an important but previously unaddressed question is whether, in older individuals, insulin resistance caused by short‐term modest inactivity can be fully rescued by the return to previous activity levels. Studying the metabolic effects of short‐term inactivity in older individuals, and their capacity to re‐establish normal function, is particularly relevant because ageing is associated with both greater occurrence and severity of debilitating life events (illness, orthopaedic injuries, etc.) that substantially impinge physical activity levels.

In this issue of The Journal of Physiology, Reidy et al. (2018) eloquently fill this important information gap by studying a cohort of older adults (5 women and 7 men) before, after 2 weeks of reduced physical activity, and following 2 weeks of recovery (i.e. return to activity). The authors found that a short‐term ∼60% decline in daily steps reduced whole‐body insulin sensitivity by ∼15% (assessed via hyperinsulinaemic–euglycaemic clamp), an effect that was interestingly driven by data from men. Remarkably, after the 2 weeks of return to activity insulin sensitivity rebounded above baseline levels (i.e. above pre‐inactivity) by ∼14% (Fig. 1). Insulin resistance caused by inactivity was accompanied by some mild indices of skeletal muscle inflammation; however, in contrast to the hypothesis proposed by the authors, changes in inactivity‐induced insulin sensitivity were not related to changes in serum or intramuscular ceramides.

Figure 1.

Schematic summarizing the main findings of the study by Reidy et al

As noted, a main observation of this study is the capacity of older subjects to not only recover their levels of insulin sensitivity with return to activity but to actually surpass them. This regain of function after 2 weeks of inactivity followed by return to ambulatory activity is fundamentally intriguing especially when considering that, based on step counts, subjects did not fully achieve their normal activity levels. This finding supports the notion that physical activity is pivotal to preservation of metabolic function in older adults and, encouragingly, suggests that one can gain from physical activity more than one can lose from a lack thereof.

Although the study was not statistically powered to examine sex effects, it is inevitable to draw attention to the observation that women appeared to be protected against inactivity‐induced insulin resistance. Sex differences are commonly attributed to sex hormones; however, because in this study women were of postmenopausal age, a period during which in general women more closely resemble men hormonally and metabolically, it is tempting to deduce that this apparent sexual dimorphism is probably unrelated to the sex hormones typically thought to be protective in women (i.e. oestrogen). Certainly, more studies are needed to confirm if indeed older women are protected against insulin resistance associated with the knock‐down of physical activity and interrogate the mechanisms underlying this protection afforded by female sex.

While outside the scope of this perspective article, an important organ that should be considered as a viable target for maintaining metabolic function in the setting of inactivity is the skeletal muscle microvasculature. Indeed, insulin‐stimulated skeletal muscle blood flow and capillary recruitment play a key role in the delivery of glucose and insulin to skeletal muscle, the primary site for glucose disposal (Wasserman et al. 2018). That is, limited insulin‐stimulated vasodilatation and reduced skeletal muscle perfusion impair glucose uptake and contribute to glycaemic dysregulation. A number of studies from animals and humans demonstrate that physical activity promotes an increase in vascular insulin sensitivity in skeletal muscle (Padilla et al. 2015). As such, given the growing evidence from our group and others that excessive sitting and reduced ambulatory activity disrupts peripheral vascular function, a reasonable hypothesis is that skeletal muscle microvascular dysfunction, and particularly microvascular insulin resistance, contributes to inactivity‐induced impairments in glucose disposal to skeletal muscle. Likewise, it is plausible that restoration of metabolic function with return to activity is in part mediated by an enhancement of vascular insulin actions that facilitates transport of insulin and glucose to skeletal muscle. Undoubtedly, more research is warranted to mechanistically test this important hypothesis.

Additional information

Competing interests

The authors have no conflicts of interest to report.

Funding

JP is supported by National Institutes of Health grants K01 HL125503 and R01 HL137769.