while there is little debate that low mitochondria content or poor mitochondrial capacity or performance is associated with ir in muscle , the current debate is centered on whether or not some aspect(s ) of mitochondrial biogenesis , content , or energetics actually cause ir . i will make the case that the majority of evidence supports the claim that mitochondrial derangements can cause ir in humans . in order to set the stage for this argument first , we must first accept that ir can be defined as a decreased insulin - stimulated glucose uptake by muscle cells or tissues , as this provides a quantitative integrated measurement of insulin action . at first this seems obvious ; let s not , however , allow that defects in insulin - signaling , glut4 translocation or content , or other parameters upstream of glucose uptake be held up as direct evidence . that is because  and the second consideration  impairment in insulin - stimulated glucose uptake can occur without alterations in classical insulin signaling pathways . for example , ir induced by palmitate or oxidative stress can occur without diminished akt phosphorylation ( 4 ) . mitochondria are now widely recognized to have numerous complex functions , many of which have been implicated in skeletal muscle insulin resistance . we must agree that mitochondria deficiency should not be defined as merely inadequate atp generation or reduced fatty acid oxidation , as has been argued in previous commentaries ( 5,6 ) . to the contrary , mitochondria are very dynamic organelles with many roles , including mediating oxidative stress , cellular redox state , and generating signaling molecules ( fig . 1 ) . we must also put a heavy emphasis on human ir . while appreciating that mechanistic , causal studies are difficult  if not impossible  to perform in human subjects , we must also , however , eventually be able to translate mechanistic studies to human health and disease . i will also argue that we are just now beginning to understand some of the other potential roles that mitochondria may have in governing metabolism , including ir . now , although a dearth of information or poor understanding is itself not a good basis for an argument that the phenomenon is true , arguing against a causal role for mitochondria in ir without acknowledging the possibility that mitochondria can cause ir is a dangerous position to hold . i will present emerging evidence that expands the outdated simplistic view of mitochondria as merely being involved in energy generation to include a broader role for mitochondria in cell signaling , redox , oxidative stress , and likely ir . ( 7 ) supported a model in which increased mitochondrial fatty acid oxidation in muscle leads to an accumulation of acetyl - coa and citrate , thereby inhibiting pyruvate dehydrogenase and phosphofructokinase , respectively . this inhibition then increases glucose-6-phosphate concentrations , inhibiting hexokinase and resulting in reduced glucose uptake and oxidation . fatty acid cycle was operative in all tissues under all circumstances ( 8) , these early studies spawned a series of subsequent investigations examining the biochemical mechanisms of reciprocal glucose and fatty acid oxidation . several groups of investigators in the 1990s led resurgence in the field to investigate the link between fatty acid oxidation and skeletal muscle ir . kelley and mandarino ( 9 ) reported that , in contrast to the predictions of the original glucose  fatty acid cycle , during conditions of hyperglycemia and high glucose oxidation , fat oxidation was concomitantly lower in muscle of individuals with type 2 diabetes , and this effect was exacerbated by obesity ( 10,11 ) . other studies also reported that glucose inhibits fat oxidation ( 12 ) , calling it the reverse randle cycle . these findings were also consistent with observations that skeletal muscle in obesity - induced ir has increased levels of malonyl - coa ( 13 ) , thereby inhibiting carnitine palmitoyl transferase ( cpt ) and thus fatty acid oxidation ( 14 ) . more recently , a prevalent hypothesis has been put forth to link mitochondria with ir , whereby lower mitochondrial content or impairments in mitochondrial fatty acid oxidation lead to excess accumulation of intramyocellular lipids , most notably diacylglycerol and ceramides ( 15 ) . although attractive , there is considerable debate about whether or not this  lipotoxicity  or excess nonadipose tissue ( ectopic ) lipid is mechanistically linked with ir , and further , whether this can be tied to altered mitochondrial capacity for fatty acid oxidation . human studies reported that skeletal muscle in obese subjects either without or with type 2 diabetes was inherently poor at oxidizing fatty acids ( 11 ) , or had reduced mitochondrial capacity for oxidative metabolism ( 1 ) . it has been argued that mitochondrial capacity for fatty acid oxidation is not the root cause of ir because , even in ir of obesity and type 2 diabetes , mitochondria have an excess capacity to maintain adequate fatty acid oxidation and provide energy during resting conditions in which energy demand is low , for example during resting ( 5,6 ) . hence the muscle mitochondria in ir and diabetes have more than adequate capacity for energy production during resting conditions . substrate selection , on the other hand , can be independent of energy demand . for example , chronic exercise training results in higher proportion of energy generated from fatty acid oxidation at the same absolute energy demand ( 16 ) . reduced mitochondria content and capacity results in a proportionate shift away from fatty acid oxidation during noninsulin stimulated conditions , leading over time to lipid accumulation and ir . this metabolic inflexibility that occurs in ir muscle is characterized by both lower fatty acid oxidation in the basal , fasting state and a lower glucose uptake in the insulin - stimulated state ( 17 ) . one of the arguments made that mitochondrial deficiency is disconnected from ir derives from either pathological conditions or genetic animal models of severe mitochondrial deficiency ( 18 ) . in these extreme examples , energy derived from oxidation of fatty acids is essentially abolished , so that glucose is practically the only substrate available  in both basal and insulin - stimulated conditions . therefore , these models in which glucose is necessarily the default substrate do not provide convincing evidence against the mitochondrial link with ir . another argument that altered mitochondrial fatty acid oxidation may play a role in ir is suggested by genetic models in which shifting substrate selection toward fat oxidation protects against diet - induced ir . acetyl - coa carboxylase deficient mice exhibit the expected increase in fatty acid oxidation ( presumably because of lower malonyl coa levels to inhibit cpt-1 ) and protection against obesity - induced ir ( 19 ) . other studies using muscle - specific acetyl - coa carboxylase deficient animals have not observed a similar metabolic phenotype ( 20 ) , perhaps because of a compensatory decrease in overall glucose oxidation and increase in de novo lipogenesis . however , in model systems in which cpt-1 is overexpressed in skeletal muscle , fat oxidation is increased together with improved insulin sensitivity ( 21 ) . taken together , genetic manipulation in animal models or in cell systems has often led to contradictory and confusing results . again , although these model systems have been useful to demonstrate potential causes of ir , we must look at the human data to support or refute these model systems . another line of evidence used to refute a causal role for mitochondria in ir is from studies in rodents in which high - fat feeding causes ir while increasing mitochondria in muscle ( 22 ) . moreover , overexpression of lipoprotein lipase in muscle provides greater free fatty acid exposure to stimulate peroxisome proliferator  activated receptor- and stimulate mitochondrial biogenesis ( 23 ) . ( 24 ) who found that a short - term high - fat diet downregulates mitochondrial genes . first , chronic high - fat feeding or obesity is not associated with an increase in mitochondria or oxidative capacity in humans ( 25 ) . on the contrary we need to consider many confounders when comparing the data from rodents fed high - fat diets with cross sectional studies of obese humans ( e.g. , physical activity , chronic vs. acute effects of fat overload ) . ( 26 ) recently reported that reductions in lipoprotein lipase play a key role in reduced mitochondrial content in human ir through decreased peroxisome proliferator thus we need to be careful in how we interpret the animal model data used to refute a role for mitochondria in ir . human evidence to support a link between mitochondria and ir may also appear to be inconsistent . it should follow from the mitochondrial - lipotoxicity hypothesis , that lower mitochondrial capacity in ir states still maintains an adequate reserve capacity to oxidize fatty acids and can not lead to excess accumulation of intramuscular lipids . this contention can be countered by acknowledging that higher mitochondria content and capacity are associated with a higher proportion of fatty acid oxidation during resting conditions ( 17 ) . thus , although mitochondrial capacity in ir conditions should be adequate to oxidize fatty acids and maintain lower intramuscular lipids , it is likely that a lower total mitochondrial capacity can lead to a shift in substrate selection in the fasting or exercise condition away from fatty acid oxidation , which would lead to lipid accumulation and ir . of course , although poor mitochondrial performance can lead to ir , ir can develop in the setting of lipid oversupply without low mitochondrial content or function ( 27 ) . in other words , ir can develop because of lower mitochondrial capacity , but does not require it because there are many other possible causes of ir . we have used energy restriction weight loss and exercise programs to examine how intervention - induced changes in mitochondria , muscular lipids , and ir track with one another . these interventions are reasonably good models to distinguish between increases in energy demand and reductions in energy supply . to summarize these studies : exercise increases mitochondria content and capacity for fatty acid oxidation and improves ir ( 28 ) . diet - induced weight loss , however , improves ir without increasing mitochondrial capacity ( 29 ) . one interpretation is that this is solid proof that mitochondria are not in a causal pathway to ir . it is quite likely , however , that just as there are many paths to develop ir , there are several means to improve ir . exercise improves mitochondria content and capacity , decreases ceramides ( 30 ) , and improves ir . although it is possible that these are simply phenomena all occurring as an adaption to exercise , this leaves the door ajar to the possibility that exercise improves ir by increasing the proportion of energy derived from mitochondrial fatty acid oxidation during resting conditions , thereby partitioning fatty acids away from lipotoxic moieties . an alternative compatible explanation linking mitochondria to ir is that reductions in oxidative stress with either exercise or energy restriction can improve ir . in this next section , i will argue that this and other facets of mitochondrial energetics are likely causally linked with ir . during the past few years , interesting insights have come to light from genetic models of ir in which high rates of incomplete fat oxidation and by - products of fatty acid catabolism are associated with ir ( 31 ) . in these models , this might suggest that in the setting of low energy demand , e.g. , a sedentary lifestyle , a metabolic overload stress on the mitochondria contributes to ir . it remains to be determined whether an increase in mitochondria content or capacity  even in low energy demand states  may act as a buffer to reduce this metabolic stress and maintain insulin sensitivity . glucose transport is a key defect in systemic glucose disposal , and some have argued that this is the primary derangement governing ir in muscle ( 32 ) . recent studies in animal models have challenged the concept by demonstrating a more distributed control of glucose flux involving hexokinase during conditions in which glucose transport is maximized ( 33 ) . this should be viewed in the context of studies demonstrating hexokinase binding to mitochondria ( 34 ) and its link to thioredoxin - interacting protein ( txnip ) as well as txnip effects to inhibit glucose uptake in humans ( 35 ) . thus it is quite possible that reduced mitochondrial content or remodeling in ir states results in decreased overall hexokinase binding and subsequently a reduced phosphorylation of glucose and diminished glucose uptake . another attractive paradigm gaining acceptance is that mitochondria - derived reactive oxygen species ( ros ) act as signaling molecules ( 36 ) . anderson et al . ( 37 ) demonstrated that in obese rodents and humans that elevated mitochondrial - mediated oxidative stress was related to ir , and that antioxidant scavenging improved ir . in support of a role of mitochondrial oxidative stress in ir , lee et al . ( 38 ) reported that overexpression of a mitochondria - targeted catalase resulted in a reduction in diacylglycerol and protection against aging - induced ir . moreover , it is well accepted that ros activate several aspects of cell signaling related to insulin action ( 39 ) . an interesting study by shi and colleagues ( 40 ) reported that remodeling of cardiolipin , a phospholipid specific to mitochondria , plays a key role in mediating mitochondrial o2 consumption , oxidative stress and ir . the links among inflammation , mitochondria and ir have only recently begun to be appreciated . txnip has also been implicated in type 2 diabetes , and is associated with ros - dependent nod - like receptor 3 inflammasome activation after its detachment from thioredoxin ( 41 ) . zhou et al . ( 41 ) found that inhibition of mitochondrial respiratory chain activity , which causes ros generation , activates the nod - like receptor 3 inflammasome , and further , that the mitochondria voltage - dependent anion channels are crucial for inflammasome activation . this inflammatory response has also been shown to contribute to changes in the extracellular matrix , an altered mechanosignal transduction , and reduced mitochondrial content and function associated with ir . taken together , these studies indicate that oxidative stress and inflammation are important aspects of mitochondrial energetics and play a role in ir . in summary , human type 2 diabetes and obesity are associated with a reduced mitochondrial capacity and ir . the etiology and underlying mechanisms of skeletal muscle ir are not clear , in part because there are many cellular causes of ir . lipid overload , derangements in fatty acid oxidation , oxidative stress , and inflammation have all been shown to cause ir . further , the majority of the available evidence indicates that mitochondria play a role in these forms of human skeletal muscle ir . mitochondrial deficiency , as articulated previously from the perspective of reduced oxidative capacity or low fatty acid oxidation , should be more broadly defined to include mitochondria s various complex roles in health and disease . by accepting that mitochondria are complex organelles with many functions and that there are multiple pathways leading to ir , we will more fully appreciate that mitochondria may cause ir . then we will be able to advance a clearer understanding of this complex pathology .
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 .