Mitochondrial Deficiency Is Associated With Insulin Resistance

The specific cellular underpinnings or mechanisms of insulin resistance (IR) are not clear. Here I present evidence to support a causal association between mitochondrial energetics and IR. A large body of literature indicates that mitochondrial capacity for oxidative metabolism is lower in human obesity and type 2 diabetes. Whether or not mitochondria play a causal role in IR is hotly debated. First, IR can be caused by many factors, many of which may or may not involve mitochondria. These include lipid overload, oxidative stress, and inflammation. Thus the first tenet of an argument supporting a role for mitochondria in IR is that mitochondria derangements can cause IR, but IR does not have to involve mitochondria. The second tenet of this argument is that animal models in which oxidative metabolism are completely abolished are not always physiologically or pathologically relevant to human IR, in which small metabolic perturbations can have profound effects over a prolonged period. Lastly, mitochondria are complex organelles, with diverse functions, including links with cell signaling, oxidative stress, and inflammation, which in turn can be connected with IR. In summary, mitochondrial “deficiency” is not merely a reduced energy generation or low fatty acid oxidation; this concept should be expanded to numerous additional important functions, many of which can cause IR if perturbed.The most common forms of human skeletal muscle insulin resistance (IR) are associated with 1) obesity, particularly abdominal obesity and excess accumulation of lipids in nonadipose tissues such as liver and skeletal muscle; and 2) physical inactivity. Identifying a common cellular basis for these conditions, however, remains elusive. Impairments in mitochondrial energetics have been linked to each of these conditions. Obesity has been reported to be associated with reduced mitochondria content and altered mitochondrial performance (1). Physical inactivity is associated with lower mitochondrial biogenesis and content (2). Conversely, exercise is a potent inducer of mitochondria biogenesis (3). Thus it is not surprising that considerable attention has been given to the possibility that mitochondria play a role in IR. But of course associations do not infer that derangements in mitochondria cause IR. Although many of these arguments can be made for other insulin-sensitive tissues such as liver, this line of reasoning to support a role for mitochondria in IR will focus on skeletal muscle.