The Journal of Physiology | 2021
Move it or lose it: limb immobilisation results in impaired postprandial skeletal muscle glucose uptake
Abstract
Physical activity and exercise are both beneficial to general health and reduce all-cause mortality risk (Zhao et al. 2020). Additionally, high physical inactivity is a strong predictor of developing several cardiometabolic risk factors such as glucose intolerance, dyslipidaemia, metabolic syndrome and obesity (Rezende et al. 2014). One of the mechanisms through which physical inactivity causes metabolic disturbances is reduced glucose disposal, primarily by reduced insulin stimulation in skeletal muscle glucose uptake (Bienso et al. 2012). Moreover, physical inactivity promotes impaired lipid trafficking and increased intramuscular lipid content (Bienso et al. 2012). However, Bienso et al. did not investigate the temporal relation, magnitude and localisation of physical inactivity in causing metabolic disturbances, and thus these responses have remained incompletely understood. Therefore, in a recent investigation published in The Journal of Physiology, Burns et al. sought to examine the effects of forearm immobilisation on single limb glucose and lipid metabolism (Burns et al. 2021). Previous mechanistic observations related to physical inactivity and metabolism by Bienso et al. found that 7 days of bed rest decreased skeletal muscle glucose transporter type 4 (GLUT4) and hexokinase II protein expression (Bienso et al. 2012). In addition, short-term bed rest reduced insulin-mediated activation of glycogen synthase and phosphorylation of Akt following a hyerinsulinaemic euglycaemic clamp (Bienso et al. 2012). From a functional standpoint, the bed rest also reduced leg glucose uptake. These results indicate that 7 days of bed rest elicits a reduction in the content and activity of key glucoregulatory proteins involved in uptake and storage. However, it was unclear whether reduced glucose uptake caused the reduction in the glucoregulatory protein content/activity or vice versa. If a reduction in glucose uptake precedes downregulation of glucoregulatory protein content/activity through a negative feedback loop, it would necessitate a relatively rapid reduction in peripheral glucose uptake. Therefore, Burns et al. aimed to unveil the temporal relationship between extended periods of forearm immobilisation and local skeletal muscle glucose uptake. In addition to physical inactivity impairing glucose regulation, even short-term physical inactivity is associated with exaggerated postprandial lipaemia (Burns et al. 2021). Furthermore, compared to physically inactive adults, athletes exhibit attenuated postprandial lipaemia. Specifically, one study found that the area under the curve for serum triglyceride concentrations following a high fat meal was lower in athletes compared to sedentary adults (Das et al. 2018). Taken together, these findings indicate that dietary fat intolerance could be significantly exacerbated by short-term sedentary bouts and high levels of long-term sedentary behaviour. However, the site(s) of physical inactivity-induced lipid intolerance is unclear because lipid disposal involves integrated responses by the liver, muscle (skeletal and cardiac) and adipose tissues. Thus, a second aim of the investigation by Burns et al. was to determine whether forearm immobilisation reduces local skeletal muscle lipid uptake, and to elucidate the time course of such responses. Burns et al. hypothesised that single arm immobilisation would blunt postprandial glucose uptake and lipid uptake in the immobilised limb. For the experimental design, the investigators immobilised participants’ lower arm with a fitted cast for 3 days, while the contralateral arm was left mobile. Arterialised venous blood sampling was used as a much safer alternative to direct arterial blood sampling in order to assess glucose and fat uptake. The arterialised venous blood from a dorsal foot vein was compared to the localised venous blood in each arm to determine localised glucose and lipid disposal. Thus, for each visit, three cannulae were placed to enable serial blood sampling. The investigation used two similar protocols. In study A, participants underwent a daily 3 h fasted oral glucose tolerance test (OGTT). Time points for the OGTT included before the cast was fitted, and 24, 48 and 72 h after cast placement. Blood flow was continuously measured via Doppler ultrasound for the duration of each OGTT in the immobilised arm at pre-cast fitting and 72 h post in the non-immobilised arm. Blood was drawn periodically from all three sites of cannulation to assess local glucose and insulin concentrations. Study B employed a similar approach to study A, but the investigators performed four separate 7 h high fat mixed meal (HFMM) challenges to assess lipid disposal before the cast was fitted, and 24, 48 and 72 h post cast placement. Blood flow was assessed continuously for the first 3 h and once every hour thereafter until the end of the HFMM. Blood was sampled periodically before and following HFMM for glucose, insulin, free fatty acid, and triacylglycerol concentrations. The research team observed that forearm glucose disposal did in fact decrease after immobilisation. After immobilisation glucose disposal also decreased during the OGTT by 38% at 24 h, 57% at 48 h, and 46% at 72 h, and during the HFMM by 46% at 24 h and 51% at 48 h. In contrast, lipid disposal remained unchanged after 48 h of immobilisation, outside of free glycerol uptake, which increased dramatically. Interestingly, in study A, following the OGTT, brachial artery blood flow was increased after 24 h of immobilisation. However, it returned to baseline levels by 48 and 72 h after immobilisation. The study produced several interesting and novel findings. For example, the short time frame (i.e. 24 h) of inactivity needed to impair local glucose uptake is important given the rising prevalence of physical inactivity in most societies. In study A, participants were administered an OGTT, which is clinically relevant since it can be used to diagnose type 2 diabetes. And in