When muscle doesn't ‘Rac’ it up, adipose tissue ‘AKTs’

Obesity is a major risk factor for developing insulin resistance in skeletal muscle (impaired glucose uptake), which, in turn, is a major risk factor for developing type 2 diabetes (T2D). The precise cellular mechanism(s) responsible for obesity‐associated skeletal muscle insulin resistance is unclear. Binding of insulin to its receptor on the muscle cell membrane causes autophosphorylation of tyrosine residues in the cytosolic portion of the receptor, which in turn results in downstream activation, via phosphorylation, of the insulin receptor substrate (IRS)–phosphoinositide‐3‐kinase (PI3K)–AKT signalling cascade. Once active, AKT initiates a series of signalling events that promote GLUT4 translocation from the cytosol to the cell membrane to enable glucose transport into the cell for energy production and storage (as glycogen – via phosphorylation and inhibition of glycogen synthase kinase). PI3K also phosphorylates and thereby activates Rac1, which promotes GLUT4 translocation by initiating actin remodelling to produce a scaffolding for GLUT4 trafficking. AKT and Rac1 act independently and synergistically to promote glucose uptake into skeletal muscle cells upon stimulation by insulin (Jaldin‐Fincati et al. 2017). Accordingly, defects in either insulin‐stimulated AKT or Rac1 activation can impair insulin‐mediated glucose uptake into skeletal muscle. Reduced insulin signalling to AKT is considered a primary cause for impaired insulin‐mediated glucose disposal in skeletal muscle of people with obesity and T2D. However, signalling to and downstream of AKT is often found intact in people with obesity, despite markedly impaired insulin‐mediated glucose disposal (Kim et al. 1999; Kim et al. 2003; Tonks et al. 2013). Insulin‐mediated Rac1 signalling was recently found to be impaired in people with obesity both in the presence and in the absence of T2D (Sylow et al. 2013). Impaired muscle Rac1, not AKT, signalling could therefore be an important initial defect on the path to obesity‐associated T2D.

In this issue of The Journal of Physiology, Raun et al. (2018) provide a detailed evaluation of the involvement of muscle Rac1 signalling in obesity‐associated insulin resistance by using genetically engineered mice. Muscle‐specific Rac1 deletion (Rac1 mKO) was induced at 12–16 weeks of age. The animals were then fed either standard mouse chow or a high‐fat diet (HFD) for 18 weeks. Wild‐type littermates fed standard chow or the HFD served as controls. Whole‐body insulin sensitivity and insulin‐mediated tissue (muscle and adipose) glucose uptake were assessed at the end of the dietary intervention by simultaneously administering a bolus of insulin and radiolabelled 2‐deoxyglucose (2DG). The dose of insulin administered was carefully chosen to achieve (i) plasma insulin concentrations within the normal physiological range and (ii) the same plasma insulin concentrations in the HFD fed and lean control mice. In wild‐type mice, HFD compared to standard chow feeding impaired whole‐body insulin tolerance due to both impaired insulin‐mediated muscle glucose uptake and impaired adipose tissue glucose uptake. The adverse effect of HFD feeding on glucose metabolism occurred despite normal insulin‐mediated AKT phosphorylation, most likely because of decreased Rac1 signalling (Sylow et al. 2013). Rac1 mKO blunted the insulin‐mediated suppression of plasma glucose concentration in both the standard chow and HFD fed mice. As expected, this was due to impaired insulin‐stimulated glucose uptake into skeletal muscle despite normal AKT signalling. These observations made in vivo were confirmed by incubating muscle isolated from the Rac1 mKO and control animals with insulin and 2DG to ascertain that the reduced insulin‐mediated glucose uptake in skeletal muscle in Rac1 mKO mice was indeed the result of an intrinsic muscle glucose transmembrane transport defect. Despite reduced muscle glucose uptake, muscle glycogen content was not affected by Rac1 mKO, which suggests that glycogen synthesis is regulated by AKT, but not Rac1. In the HFD, but not standard chow, fed mice, the adverse effect of Rac1 mKO on whole‐body insulin tolerance was in part compensated by increased insulin‐mediated AKT signalling and glucose uptake in adipose tissue. The authors also performed an intraperitoneal glucose tolerance test and found that HFD feeding impaired glucose tolerance whereas Rac1 mKO by and large had no effect on glucose tolerance, presumably because it increased adipose tissue glucose disposal; in addition, it tended to increase plasma insulin secretion – although, the difference in plasma insulin concentration was very small.

The data from this study provide several important new insights into the pathophysiology of obesity‐associated insulin resistance. First, they clearly demonstrate that Rac1 signalling is important for insulin‐mediated glucose disposal. They also suggest that AKT and Rac1 signalling potentially determine the fate of glucose once in the cell because Rac1 mKO did not reduce muscle glycogen storage, despite markedly reduced muscle glucose uptake. Third, they highlight the potential importance of adipose tissue glucose disposal as a regulator of plasma glucose concentration for two reasons: (i) in wild‐type mice, HFD‐induced insulin intolerance was caused by both impaired muscle glucose uptake and impaired adipose tissue glucose uptake, but the reduced adipose tissue glucose uptake rate was compensated by increased total body fat mass, which increased ∼4‐fold (from ∼2.5 to 10 g) while the adipose tissue glucose uptake rate decreased by ∼4‐fold (from ∼20 to 5 μmol g⁻¹ h⁻¹); and (ii) in Rac1 mKO mice, increased adipose tissue glucose uptake partially compensated for the reduced muscle glucose uptake. Lastly, they clearly demonstrate that the glucose tolerance test provides a poor assessment of metabolic function because redistribution of glucose uptake among insulin‐sensitive tissues and compensatory changes in insulin secretion and clearance can mask peripheral tissue metabolic dysfunction.

There are a few gaps that need to be filled in to complete our understanding of the observed phenomenon. First, actin remodelling and GLUT4 translocation were not assessed to ascertain this was indeed the mechanism by which altering Rac1 signalling altered glucose uptake. Second, Rac1 signalling in adipose tissue was not assessed, so it is not known whether concurrent with a compensatory increase in adipose tissue AKT signalling there was also a compensatory increase in adipose tissue Rac1 signalling in Rac1 mKO. Lastly, the messenger in the apparent muscle–adipose tissue cross talk in Rac1 mKO mice is unknown and it remains to be seen if the liver is part of this coordinated network to help prevent hyperglycaemia by augmenting insulin‐mediated suppression of glucose production.

In summary, the data by Raun et al. (2018) add valuable new information to the rapidly growing body of literature that highlights the importance of Rac1 signalling in maintaining glucose homeostasis. Based on the results from this study and current knowledge in the field, we propose the model of pathophysiological events leading to overnutrition and obesity‐associated T2D summarized in Fig. 1.

Figure 1. Effect of diet‐induced obesity on tissue glucose disposal and insulin and glucose tolerance.

Overnutrition initially causes insulin resistance in muscle and adipose tissue because of reduced Rac1 signalling. Increased insulin secretion and adipose tissue expansion at first compensate for this defect and help maintain euglycaemia despite reduced insulin‐mediated muscle glucose disposal. Eventually adipose tissue becomes dysfunctional because of inflammatory and endoplasmatic reticulum stress, which results in increased fatty acid release. Increased fatty acid delivery to the muscle impairs AKT signalling, which further reduces insulin‐mediated muscle glucose, which can no longer be fully compensated by insulin hypersecretion and adipose tissue expansion. Chronic insulin hypersecretion and lipotoxicity in the pancreas and muscle finally result in the insulin insufficiency, impaired muscle and adipose tissue glucose disposal and severe hyperglycaemia characteristic of T2D. FFA, free fatty acids; GT, glucose tolerance; T2D, type 2 diabetes. Black lines indicate the normal physiological response; dotted blue lines indicate a blunted response; thick blue lines indicate a compensatory increased response.

Additional information

Competing interests

None.

Author contributions

Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

The authors received salary support from NIH grants DK115400, DK56341 (Washington University School of Medicine Nutrition and Obesity Research Center), and UL1 TR000448 (Washington University School of Medicine Clinical Translational Science Award), a grant from the American Diabetes Association (ICTS 1‐18‐ICTS‐119) and the Atkins Obesity Award while working on this manuscript.