Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

Abstract

Aims/hypothesis Chronic stimulation of β 2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of β 2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β 2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg −1 day −1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and Anastasia Kalinovich and Nodi Dehvari contributed equally to this study.

ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes

“…1, D-F). This is supported by a previous report studying glucose uptake in muscle cells in response to adrenergic stimulation (27,28). Furthermore, we observed, in response to increased cAMP levels, a degradation of TXNIP and the activation of GLUT1, but not GLUT4-mediated glucose uptake.…”

Macrophage beta2-adrenergic receptor is dispensable for the adipose tissue inflammation and function

“…While our data show that endogenous macrophage B2AR signaling does not regulate local or systemic inflammation in lean and obese states, it might still be stimulated pharmacologically above its physiological threshold level to reduce inflammation and alleviate the severity of metabolic disease. Given that B2AR agonists have also been shown to improve systemic insulin sensitivity in obese animals through their action on skeletal muscle cells [ 58 ], in future it would be of interest to compare the efficacy of B2AR agonists in Adrb2 ΔLyz2 and control mice, in order to see what beneficial anti-inflammatory effects can be attributed to B2AR signaling specifically in macrophages, as compared to other cell types expressing B2ARs.…”

Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes

“…Glucose uptake, measured as DOG uptake, was increased both after acute and chronic treatment with terbutaline. This has previously been well-studied in vivo , but in vitro studies have mainly been limited to mouse ( Ito et al., 2019 ) and rat ( Kalinovich et al., 2020 ; Koziczak-Holbro et al., 2019 ; Nevzorova et al., 2006 ; Sato et al., 2014 ) skeletal muscle cells with only few reports from human myotubes ( Koziczak-Holbro et al., 2019 ; Sato et al., 2014 ). It is important to note that there are issues of translation between studies performed in rodent cells and human cells due to rodents having a higher energy expenditure and metabolic flux than human cells ( Wang et al., 2012 ).…”