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.
Highlights
When the blood glucose concentration rises above its set point, pancreatic beta cells secrete insulin [1], a peptide hormone that provokes an orchestrated anabolic response to the raised glucose availability by altering the behaviour of multiple organs [2]
In which respiration is increased—for example in kidney and skeletal muscle at the onset of diabetic kidney disease (DKD) and chronic kidney disease (CKD), respectively—oxygen consumption appears to have been uncoupled from ATP synthesis [39,133], which may be related to oxidative stress
It will be important to confirm, that the generally decreased ATP synthesis capacity is due to intrinsic mitochondrial defects, as it cannot be excluded that mitochondrial ATP supply declines in response to pathological changes in energy demand
Summary
When the blood glucose concentration rises above its set point, pancreatic beta cells secrete insulin [1], a peptide hormone that provokes an orchestrated anabolic response to the raised glucose availability by altering the behaviour of multiple organs [2]. Skeletal muscle is a major contributor to the systemic anabolic response, as insulin-sensitive glucose uptake by this comparably large tissue accounts for more than 70% of the whole-body glucose disposal [3]. Obesity (body mass index ≥30 kg/m2) is a broadly accepted risk factor of systemic insulin resistance [8], and loss of skeletal muscle insulin sensitivity is the first sign of such resistance in human subjects [2]. T2D may cause various complications [10], including diabetic kidney disease (DKD—[11]). It has been estimated [12] that 609 million adults were obese in 2015, which amounts to roughly 10% of the global population.
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