Low testosterone is associated with decreased expression of glut-4 and hexokinase 2 in muscle of the testicular feminised mouse
D McLaren1, D Kelly1, S Akhtar1, K Channer2 & T Jones1,3
Testosterone deficiency is a common in men with type two diabetes (T2D). We have shown testosterone replacement therapy (TRT) improves insulin resistance and glycaemic control. The mechanisms by which testosterone mediates this action are unknown but may be due to a combination of effects on muscle, liver and adipose tissues. This study investigates the expression of Glut4 and HK2, (two key proteins involved in insulin sensitivity) in muscle tissue of the testicular feminised (Tfm) mouse which exhibit non-functional androgen receptors and low circulating testosterone.
Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received either physiological testosterone replacement (mixed testosterone esters, Sustanon100) or placebo (saline) and were compared to wild-type littermates (WT). Striated muscles tissue was collected from the thigh. Expression of Glut 4 and HK2 mRNA and protein expression was analysed by qPCR and Western blotting.
There was a significant decrease in the relative mRNA expression of Glut−4 (0.59±0.14, P=0.02) and HK2 (0.5±0.16, P=0.01) in Tfm mice compared to WT. TRT did not significantly alter mRNA expression of Glut4 or HK2. Western blotting confirmed reduced protein expression of HK2 (0.33±0.09 vs 0.04±0.01, P=0.005) and Glut4 (1.05±0.22 vs 0.57±0.07, P=0.037) in Tfm mice compared to WT. TRT showed no change in HK2 protein expression compared to Tfm placebo (0.05±0.02 vs 0.04±0.01, P=0.627), but an increase in Glut4 was observed (1.09±0.16 vs 0.57±0.07, P=0.005).
Testosterone deficiency is associated with decreased expression of Glut4 and HK2. TRT did not have any effect on HK2 in the Tfm mouse suggesting that testosterone acts via the androgen receptor to stimulate HK2 expression. Although testosterone failed to increase Glut4 mRNA in the Tfm an increase in protein was observed indicating that post-translational mechanisms are involved. This study shows that testosterone has important actions on modulating glucose metabolism in muscle. This may explain part of the mechanism by which testosterone improves insulin sensitivity in T2D.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.