Is skeletal muscle mitochondrial dysfunction a cause or an indirect consequence of insulin resistance in humans?

The precise cause of insulin resistance and type 2 diabetes is unknown. However, there is a strong association between insulin resistance and lipid accumulation - and, in particular, lipotoxic fatty acid metabolites - in insulin-target tissues. Such accumulation is known to cause insulin resistance, particularly in skeletal muscle, by reducing insulin-stimulated glucose uptake. Reduced fat-oxidation capacity appears to cause such lipid accumulation and, over the past few years, many studies have concluded that decreased mitochondrial oxidative phosphorylation could be the initiating cause of lipid deposition and the development of insulin resistance. The aim of this review is to summarize the latest findings regarding the link between skeletal muscle mitochondrial dysfunction and insulin resistance in humans. At present, there are too few studies to definitively conclude that, in this context, mitochondria are functionally impaired (dysfunction in the respiratory chain). Indeed, insulin resistance could also be related to a decrease in the number of mitochondria or to a combination of this and mitochondrial dysfunction. Finally, we also consider whether or not these aberrations could be the cause of the development of the disease or whether mitochondrial dysfunction may simply be the consequence of an insulin-resistant state.

Effects of changes in water compartments on physiology and metabolism.

There is paramount evidence to suggest the importance of cell volume changes for the regulation of cell function, including protein metabolism. Among many other effects, cell swelling inhibits proteolysis and stimulates protein synthesis. However, most of the data pertinent to this theory relate to in vitro experiments. This paper reviews the evidence about the relevance of cell swelling and changes in water compartments to regulation of metabolism at the whole body level in animals and humans. Protein metabolism is most likely regulated by cellular hydration in health and disease. Cellular hydration appears to bear no effect on energy metabolism. The relationship between cellular hydration and lipolysis deserves to be verified. There appears to be a possible weak effect on glucose metabolism. Further studies are therefore necessary to challenge the cell swelling theory. If confirmed, strategies to modify cellular hydration could be used to improve metabolic orientations especially in the critically ill.

[Thyroid hormones and obesity]. / Hormones thyroïdiennes et obésité

Although the stimulating effect of thyroid hormones on energy metabolism has been recognized for more than a century, the relation between thyroid function and weight control and obesity remains unclear. We review here the effects of thyroid hormones, hyperthyroidism, and hypothyroidism on body composition and the parameters of energy metabolism.

Dexamethasone impairs muscle energetics, studied by (31)P NMR, in rats.

AIMS/HYPOTHESIS: Glucocorticoid treatments are associated with increased whole-body oxygen consumption. We hypothesised that an impairment of muscle energy metabolism can participate in this increased energy expenditure. METHODS: To investigate this possibility, we have studied muscle energetics of dexamethasone-treated rats (1.5 mg kg(-1) day(-1) for 6 days), in vivo by (31)P NMR spectroscopy. Results were compared with control and pair-fed (PF) rats before and after overnight fasting. RESULTS: Dexamethasone treatment resulted in decreased phosphocreatine (PCr) concentration and PCr:ATP ratio, increased ADP concentration and higher PCr to gamma-ATP flux but no change in beta-ATP to beta-ADP flux in gastrocnemius muscle. Neither 4 days of food restriction (PF rats) nor 24 h fasting affected high-energy phosphate metabolism. In dexamethasone-treated rats, there was an increase in plasma insulin and non-esterified fatty acid concentration. CONCLUSIONS/INTERPRETATION: We conclude that dexamethasone treatment altered resting in vivo skeletal muscle energy metabolism, by decreasing oxidative phosphorylation, producing ATP at the expense of PCr.