Reply from Lykke Sylow, Lisbeth L. V. Møller, Maximilian Kleinert, Erik A. Richter and Thomas E. Jensen.

Abstract

We would hereby like to bring forward the following comments to the letter from Dr Miller to the Editor of The Journal of Physiology. In our recent study, we identified a novel role for the Rho GTPase Rac1 and the actin cytoskeleton in stretch-stimulated glucose transport in skeletal muscle. In his letter, Dr Miller discusses the potential relevance of Rac1 in statin-mediated hyperglycaemia based on previous findings by Dr Klip and Dr Satoh, as well as ours, showing that Rac1 is involved in insulin-, contraction- and stretch-stimulated glucose transport (JeBailey et al. 2007; Ueda et al. 2010; Sylow et al. 2013a,b2013, 2015) in skeletal muscle. We thank Dr Miller for raising this interesting point and we believe Dr Miller touches upon a fundamental challenge for medications targeted at Rac1 in relation to several diseases, such as hypertension, cardiac disease and cancer. Skeletal muscle is a major site of post-prandial glucose disposal and plays a key role in whole-body glucose homeostasis. Statins (HMG-CoA reductase inhibitors) may cause hyperglycaemia by inhibiting the insulin-stimulated intracellular activation of Rac1. Several mechanisms act together to control cellular activity of Rac1. One such mechanism is prenylation which attaches Rac1 to the plasma membrane. Statins inhibit the synthesis of isoprenoid intermediates (Goldstein & Brown, 1990; Liao & Laufs, 2005) and thereby prevent the ‘anchoring’ of Rac1 at the plasma membrane, which is necessary for the activation of Rac1. Whether statin treatment inhibits muscle Rac1 and thereby causes whole-body hyperglycaemia is currently unknown but it will be important to investigate this in the future. Rac1 inhibition may be desirable in some diseases. For instance, there is evidence that Rac1 is a regulator of cardiac hypertrophy. Thus, increased Rac1 activation has been identified in human hypertrophic hearts (Lu et al. 2006), in failing myocardium (Maack et al. 2003), and in patients with atrial fibrillation (Adam et al. 2007). In mice, overexpressing the constitutively active form of Rac1 induced a dramatic cardiomyopathy phenotype (Sussman et al. 2000). On the other hand, cardiac-specific Rac1 knockout mice were protected from developing cardiac hypertrophy in response to angiotensin II-induced hypertension (Satoh et al. 2006) and streptozotocin-induced type I diabetes (Li et al. 2010). Another example is cancer progression, where the oncogene Rac1 is often constitutively activated in, for example, breast, pancreatic, lung, prostate and gastric cancer (for reviews on GTPases in tumorigenesis see Karlsson et al. 2009; Alan & Lundquist, 2013). Therefore, cancer research has focused on finding novel ways to inhibit Rac1 (Mack et al. 2011). Regardless of whether the inhibition of Rac1 is unintentional (statins) or intentional (hypertrophy, cancer), the recently highlighted importance of Rac1 in skeletal muscle glucose uptake suggests that pharmacological drugs that affect Rac1 activity might inadvertently decrease insulin sensitivity in muscle and thereby reduce glucose tolerance and induce hyperglycaemia. In a recent study, we investigated the potential adverse effects of the cancer drug AZD-8055, an inhibitor of the oncogenic mTOR kinase, and found that it reduced insulin sensitivity and muscle glucose uptake through its effects on mTOR complex 2 in muscle (Kleinert et al. 2014). This provides direct proof of concept for the unintentional side-effects of certain drugs on glucose metabolism. However, in our studies, muscle-specific Rac1 knockout mice do not display hyperglycaemia and are only slightly glucose intolerant, suggesting that inhibition of muscle Rac1 may not have severe whole-body effects on glycaemic control in lean mice (Sylow et al. 2013a). Whether combined muscle Rac1 inhibition and obesity could elicit a hyperglycaemic phenotype is unknown and is under current investigation in our laboratory. Clearly, the complexity of the involvement of Rac1 in various tissues suggests that caution is required when considering Rac1 as a direct therapeutic target. A huge challenge for future drug development will be to develop drugs that specifically target the relevant organs and tissues.