Mitochondrial Activity and Skeletal Muscle Insulin Resistance in Kidney Disease

Abstract

Insulin resistance is a key feature of the metabolic syndrome, a cluster of medical disorders that together increase the chance of developing type 2 diabetes and cardiovascular disease. In turn, type 2 diabetes may cause complications such as diabetic kidney disease (DKD). Obesity is a major risk factor for developing systemic insulin resistance, and skeletal muscle is the first tissue in susceptible individuals to lose its insulin responsiveness. Interestingly, lean individuals are not immune to insulin resistance either. Non-obese, non-diabetic subjects with chronic kidney disease (CKD), for example, exhibit insulin resistance at the very onset of CKD, even before clinical symptoms of renal failure are clear. This uraemic insulin resistance contributes to the muscle weakness and muscle wasting that many CKD patients face, especially during the later stages of the disease. Bioenergetic failure has been associated with the loss of skeletal muscle insulin sensitivity in obesity and uraemia, as well as in the development of kidney disease and its sarcopenic complications. In this mini review, we evaluate how mitochondrial activity of different renal cell types changes during DKD progression, and discuss the controversial role of oxidative stress and mitochondrial reactive oxygen species in DKD. We also compare the involvement of skeletal muscle mitochondria in uraemic and obesity-related muscle insulin resistance.

Keywords: ATP turnover; bioenergetics; diabetic nephropathy; energy metabolism; insulin signalling; muscle wasting; obesity; oxidative stress; renal sarcopenia; uraemic myopathy.

Figure 1

Skeletal muscle insulin signalling. Insulin activates its receptor (IR) and receptor substrate (IRS1), which comprise a ‘critical node’ in a branched signalling network that allows interaction with other pathways, for example those induced by cytokines [15]. Activation of this node triggers two major protein kinase cascades, i.e., the phosphatidylinositol-3-kinase (PI3K)—protein kinase B (AKT2 in skeletal muscle) pathway and the Ras-mitogen-activated protein kinase (MAPK) pathway, which both instruct muscle cells to engage with anabolic processes. Activated AKT2 has multiple effects: (i) It stimulates recruitment of the glucose transporter protein (GLUT4) to the plasma membrane, and is thus responsible for insulin-sensitive glucose uptake by muscle; (ii) it activates glycogen synthesis by inhibiting glycogen synthase kinase-3 (GSK3); (iii) it promotes mitochondrial biogenesis, protein synthesis, and cell growth and differentiation, effects that are all mediated through the stimulation of the mammalian target of rapamycin (mTOR); (iv) it suppresses protein breakdown by phosphorylating and thus deactivating Forkhead box O (FOXO) transcription factors that stimulate proteasome- and lysosome-mediated proteolysis. The MAPK pathway acts in concert with AKT2 to transmit insulin’s message to increase cell growth and differentiation.

Figure 2

Skeletal muscle insulin resistance. Obesity and CKD cause common stresses that impair insulin signalling by inhibiting IRS1 and AKT2, and thus attenuate the effect of insulin on the cellular activities listed in Figure 1. Metabolic acidosis affects insulin signalling in a similar way, but is restricted to CKD.