Mitochondrial dysfunction and lipotoxicity

P Schrauwen, V Schrauwen-Hinderling, J Hoeks… - … et Biophysica Acta (BBA …, 2010 - Elsevier
P Schrauwen, V Schrauwen-Hinderling, J Hoeks, MKC Hesselink
Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 2010Elsevier
Mitochondrial dysfunction in skeletal muscle has been suggested to underlie the
development of insulin resistance and type 2 diabetes mellitus. Reduced mitochondrial
capacity will contribute to the accumulation of lipid intermediates, desensitizing insulin
signaling and leading to insulin resistance. Why mitochondrial function is reduced in the (pre-
) diabetic state is, however, so far unknown. Although it is tempting to suggest that skeletal
muscle insulin resistance may result from an inherited or acquired reduction in mitochondrial …
Mitochondrial dysfunction in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus. Reduced mitochondrial capacity will contribute to the accumulation of lipid intermediates, desensitizing insulin signaling and leading to insulin resistance. Why mitochondrial function is reduced in the (pre-)diabetic state is, however, so far unknown. Although it is tempting to suggest that skeletal muscle insulin resistance may result from an inherited or acquired reduction in mitochondrial function in the pre-diabetic state, it cannot be excluded that mitochondrial dysfunction may in fact be the consequence of the insulin-resistant/diabetic state. Lipotoxicity, the deleterious effects of accumulating fatty acids in skeletal muscle cells, may lie at the basis of mitochondrial dysfunction: next to producing energy, mitochondria are also the major source of reactive oxygen species (ROS). Fatty acids accumulating in the vicinity of mitochondria are vulnerable to ROS-induced lipid peroxidation. Subsequently, these lipid peroxides could have lipotoxic effects on mtDNA, RNA and proteins of the mitochondrial machinery, leading to mitochondrial dysfunction. Indeed, increased lipid peroxidation has been reported in insulin resistant skeletal muscle and the mitochondrial uncoupling protein-3, which has been suggested to prevent lipid-induced mitochondrial damage, is reduced in subjects with an impaired glucose tolerance and in type 2 diabetic patients. These findings support the hypothesis that fat accumulation in skeletal muscle may precede the reduction in mitochondrial function that is observed in type 2 diabetes mellitus.
Elsevier