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Mitochondrial Deficiency Is

Associated With Insulin


Resistance
1. Bret H. Goodpaster
+Author Affiliations
1. From the Division of Endocrinology and Metabolism, Department
of Medicine, School of Medicine, University of ittsburgh,
ittsburgh, ennsylvania
1. !orresponding author" #ret $. %oodpaster, bgood&pitt.edu.

'e(t Section
Abstract
)he specific cellular underpinnings or mechanisms of insulin resistance *+,- are
not clear. $ere + present evidence to support a causal association bet.een
mitochondrial energetics and +,. A large body of literature indicates that
mitochondrial capacity for o(idative metabolism is lo.er in human obesity and
type / diabetes. 0hether or not mitochondria play a causal role in +, is hotly
debated. First, +, can be caused by many factors, many of .hich may or may
not involve mitochondria. )hese include lipid overload, o(idative stress, and
inflammation. )hus the first tenet of an argument supporting a role for
mitochondria in +, is that mitochondria derangements can cause +,, but +,
does not have to involve mitochondria. )he second tenet of this argument is
that animal models in .hich o(idative metabolism are completely abolished are
not al.ays physiologically or pathologically relevant to human +,, in .hich
small metabolic perturbations can have profound effects over a prolonged
period. 1astly, mitochondria are comple( organelles, .ith diverse functions,
including lin2s .ith cell signaling, o(idative stress, and inflammation, .hich in
turn can be connected .ith +,. +n summary, mitochondrial 3deficiency4 is not
merely a reduced energy generation or lo. fatty acid o(idation5 this concept
should be e(panded to numerous additional important functions, many of
.hich can cause +, if perturbed.
)he most common forms of human s2eletal muscle insulin resistance *+,- are
associated .ith 1- obesity, particularly abdominal obesity and e(cess
accumulation of lipids in nonadipose tissues such as liver and s2eletal muscle5
and 2- physical inactivity. +dentifying a common cellular basis for these
conditions, ho.ever, remains elusive. +mpairments in mitochondrial energetics
have been lin2ed to each of these conditions. 6besity has been reported to be
associated .ith reduced mitochondria content and altered mitochondrial
performance *1-. hysical inactivity is associated .ith lo.er mitochondrial
biogenesis and content */-. !onversely, e(ercise is a potent inducer of
mitochondria biogenesis *7-. )hus it is not surprising that considerable
attention has been given to the possibility that mitochondria play a role in +,.
#ut of course associations do not infer that derangements in mitochondria
cause +,. Although many of these arguments can be made for other insulin8
sensitive tissues such as liver, this line of reasoning to support a role for
mitochondria in +, .ill focus on s2eletal muscle.
revious Section'e(t Section
DEE!"#I$G %HE ARG&ME$%
0hile there is little debate that lo. mitochondria content or poor mitochondrial
capacity or performance is associated .ith +, in muscle, the current debate is
centered on .hether or not some aspect*s- of mitochondrial biogenesis,
content, or energetics actually cause +,. + .ill ma2e the case that the ma9ority
of evidence supports the claim that mitochondrial derangements can cause +,
in humans. +n order to set the stage for this argument, it is important to
outline some fundamental truisms that support this vie..
First, .e must first accept that +, can be defined as a decreased insulin8
stimulated glucose upta2e by muscle cells or tissues, as this provides a
:uantitative integrated measurement of insulin action. At first this seems
obvious5 let;s not, ho.ever, allo. that defects in insulin8signaling, %1U)<
translocation or content, or other parameters upstream of glucose upta2e be
held up as direct evidence. )hat is because=and the second consideration=
impairment in insulin8stimulated glucose upta2e can occur .ithout alterations
in classical insulin signaling path.ays. For e(ample, +, induced by palmitate or
o(idative stress can occur .ithout diminished A2t phosphorylation *<-. +n other
.ords, there are multiple .ays of inducing +, *Fig. 1-.

'IG. 1.
'IG. 1.
Mitochondria are no. .idely recogni>ed to have numerous comple( functions,
many of .hich have been implicated in s2eletal muscle insulin resistance.
0e must agree that mitochondria deficiency should not be defined as merely
inade:uate A) generation or reduced fatty acid o(idation, as has been argued
in previous commentaries *?,@-. )o the contrary, mitochondria are very
dynamic organelles .ith many roles, including mediating o(idative stress,
cellular redo( state, and generating signaling molecules *Fig. 1-. 0e must also
put a heavy emphasis on human +,. 0hile appreciating that mechanistic,
causal studies are difficult=if not impossible=to perform in human sub9ects,
.e must also, ho.ever, eventually be able to translate mechanistic studies to
human health and disease.
+ .ill also argue that .e are 9ust no. beginning to understand some of the
other potential roles that mitochondria may have in governing metabolism,
including +,. 'o., 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 +, .ithout ac2no.ledging the
possibility that mitochondria can cause +, is a dangerous position to hold. + .ill
present emerging evidence that e(pands the outdated simplistic vie. of
mitochondria as merely being involved in energy generation to include a
broader role for mitochondria in cell signaling, redo(, o(idative stress, and
li2ely +,.
revious Section'e(t Section
EAR!( EIDE$)E !EADI$G %" %HE *MI%")H"$DRIA
H(#"%HE+I+,
)he landmar2 studies by ,andle et al. *A- supported a model in .hich
increased mitochondrial fatty acid o(idation in muscle leads to an accumulation
of acetyl8!oA and citrate, thereby inhibiting pyruvate dehydrogenase and
phosphofructo2inase, respectively. )his inhibition then increases glucose8@8
phosphate concentrations, inhibiting he(o2inase and resulting in reduced
glucose upta2e and o(idation. Although some cast doubt on .hether this
glucoseBfatty acid cycle .as operative in all tissues under all circumstances
*C-, these early studies spa.ned a series of subse:uent investigations
e(amining the biochemical mechanisms of reciprocal glucose and fatty acid
o(idation.
Several groups of investigators in the 1DDEs led resurgence in the field to
investigate the lin2 bet.een fatty acid o(idation and s2eletal muscle +,. Felley
and Mandarino *D- reported that, in contrast to the predictions of the original
glucoseBfatty acid cycle, during conditions of hyperglycemia and high glucose
o(idation, fat o(idation .as concomitantly lo.er in muscle of individuals .ith
type / diabetes, and this effect .as e(acerbated by obesity *1E,11-. 6ther
studies also reported that glucose inhibits fat o(idation *1/-, calling it the
reverse ,andle cycle. )hese findings .ere also consistent .ith observations
that s2eletal muscle in obesity8induced +, has increased levels of malonyl8!oA
*17-, thereby inhibiting carnitine palmitoyl transferase *!)- and thus fatty
acid o(idation *1<-.
revious Section'e(t Section
MI%")H"$DRIA- 'A%%( A)ID ".IDA%I"$- A$D
I$%RAM(")E!!&!AR !I#ID+
More recently, a prevalent hypothesis has been put forth to lin2 mitochondria
.ith +,, .hereby lo.er mitochondrial content or impairments in mitochondrial
fatty acid o(idation lead to e(cess accumulation of intramyocellular lipids, most
notably diacylglycerol and ceramides *1?-. Although attractive, there is
considerable debate about .hether or not this 3lipoto(icity4 or e(cess
nonadipose tissue *ectopic- lipid is mechanistically lin2ed .ith +,, and further,
.hether this can be tied to altered mitochondrial capacity for fatty acid
o(idation. $uman studies reported that s2eletal muscle in obese sub9ects
either .ithout or .ith type / diabetes .as inherently poor at o(idi>ing fatty
acids *11-, or had reduced mitochondrial capacity for o(idative metabolism *1-.
+t has been argued that mitochondrial capacity for fatty acid o(idation is not
the root cause of +, because, even in +, of obesity and type / diabetes,
mitochondria have an e(cess capacity to maintain ade:uate fatty acid
o(idation and provide energy during resting conditions in .hich energy
demand is lo., for e(ample during resting *?,@-. )here is no :uestion that
total energy flu( is driven by energy demand. $ence the muscle mitochondria
in +, and diabetes have more than ade:uate capacity for energy production
during resting conditions. Substrate selection, on the other hand, can be
independent of energy demand. For e(ample, chronic e(ercise training results
in higher proportion of energy generated from fatty acid o(idation at the same
absolute energy demand *1@-. + .ould also argue that=at the same energy
demand=reduced mitochondria content and capacity results in a proportionate
shift a.ay from fatty acid o(idation during noninsulin stimulated conditions,
leading over time to lipid accumulation and +,. )his metabolic infle(ibility that
occurs in +, muscle is characteri>ed by both lo.er fatty acid o(idation in the
basal, fasting state and a lo.er glucose upta2e in the insulin8stimulated state
*1A-.
6ne of the arguments made that mitochondrial deficiency is disconnected from
+, derives from either pathological conditions or genetic animal models of
severe mitochondrial deficiency *1C-. +n these e(treme e(amples, energy
derived from o(idation of fatty acids is essentially abolished, so that glucose is
practically the only substrate available=in both basal and insulin8stimulated
conditions. )herefore, these models in .hich glucose is necessarily the default
substrate do not provide convincing evidence against the mitochondrial lin2
.ith +,.
Another argument that altered mitochondrial fatty acid o(idation may play a
role in +, is suggested by genetic models in .hich shifting substrate selection
to.ard fat o(idation protects against diet8induced +,. Acetyl8!oA carbo(ylase
deficient mice e(hibit the e(pected increase in fatty acid o(idation *presumably
because of lo.er malonyl !oA levels to inhibit !)81- and protection against
obesity8induced +, *1D-. 6ther studies using muscle8specific acetyl8!oA
carbo(ylase deficient animals have not observed a similar metabolic phenotype
*/E-, perhaps because of a compensatory decrease in overall glucose o(idation
and increase in de novo lipogenesis. $o.ever, in model systems in .hich !)8
1 is overe(pressed in s2eletal muscle, fat o(idation is increased together .ith
improved insulin sensitivity */1-. )a2en 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 +,, .e must loo2 at the human data to support or refute
these model systems.
Another line of evidence used to refute a causal role for mitochondria in +, is
from studies in rodents in .hich high8fat feeding causes +, .hile increasing
mitochondria in muscle *//-. Moreover, overe(pression of lipoprotein lipase in
muscle provides greater free fatty acid e(posure to stimulate pero(isome
proliferatorBactivated receptor8G and stimulate mitochondrial biogenesis */7-.
A counter to this is a study by Spar2s et al. */<- .ho found that a short8term
high8fat diet do.nregulates mitochondrial genes. )his evidence can also be
countered by evidence in humans. First, chronic high8fat feeding or obesity is
not associated .ith an increase in mitochondria or o(idative capacity in
humans */?-. 6n the contrary, mitochondria capacity is decreased .ith obesity
in humans */?-. 0e need to consider many confounders .hen comparing the
data from rodents fed high8fat diets .ith cross sectional studies of obese
humans *e.g., physical activity, chronic vs. acute effects of fat overload-.
Second, Morino et al. */@- recently reported that reductions in lipoprotein
lipase play a 2ey role in reduced mitochondrial content in human +, through
decreased pero(isome proliferatorBactivated receptor8G activation by
polyunsaturated fatty acids, eicosapentaenoic acid specifically. )hus .e need
to be careful in ho. .e interpret the animal model data used to refute a role
for mitochondria in +,.
$uman evidence to support a lin2 bet.een mitochondria and +, may also
appear to be inconsistent. +t should follo. from the mitochondrial8lipoto(icity
hypothesis, that lo.er mitochondrial capacity in +, states still maintains an
ade:uate reserve capacity to o(idi>e fatty acids and cannot lead to e(cess
accumulation of intramuscular lipids. )his contention can be countered by
ac2no.ledging that higher mitochondria content and capacity are associated
.ith a higher proportion of fatty acid o(idation during resting conditions *1A-.
)hus, although mitochondrial capacity in +, conditions should be ade:uate to
o(idi>e fatty acids and maintain lo.er intramuscular lipids, it is li2ely that a
lo.er total mitochondrial capacity can lead to a shift in substrate selection in
the fasting or e(ercise condition a.ay from fatty acid o(idation, .hich .ould
lead to lipid accumulation and +,. 6f course, although poor mitochondrial
performance can lead to +,, +, can develop in the setting of lipid oversupply
.ithout lo. mitochondrial content or function */A-. +n other .ords, +, can
develop because of lo.er mitochondrial capacity, but does not re:uire it
because there are many other possible causes of +,.
0e have used energy restriction .eight loss and e(ercise programs to e(amine
ho. intervention8induced changes in mitochondria, muscular lipids, and +,
trac2 .ith one another. )hese interventions are reasonably good models to
distinguish bet.een increases in energy demand and reductions in energy
supply. )o summari>e these studies" e(ercise increases mitochondria content
and capacity for fatty acid o(idation and improves +, */C-. Diet8induced .eight
loss, ho.ever, improves +, .ithout increasing mitochondrial capacity */D-.
6ne interpretation is that this is solid proof that mitochondria are not in a
causal path.ay to +,. +t is :uite li2ely, ho.ever, that 9ust as there are many
paths to develop +,, there are several means to improve +,. E(ercise improves
mitochondria content and capacity, decreases ceramides *7E-, and improves
+,. Although it is possible that these are simply phenomena all occurring as an
adaption to e(ercise, this leaves the door a9ar to the possibility that e(ercise
improves +, by increasing the proportion of energy derived from mitochondrial
fatty acid o(idation during resting conditions, thereby partitioning fatty acids
a.ay from lipoto(ic moieties. An alternative compatible e(planation lin2ing
mitochondria to +, is that reductions in o(idative stress .ith either e(ercise or
energy restriction can improve +,. +n this ne(t section, + .ill argue that this
and other facets of mitochondrial energetics are li2ely causally lin2ed .ith +,.
revious Section'e(t Section
MI%")H"$DRIA- ME%AB"!I) "ER!"AD- ".IDA%IE
+%RE++- A$D I$'!AMMA%I"$
During the past fe. years, interesting insights have come to light from genetic
models of +, in .hich high rates of incomplete fat o(idation and by8products of
fatty acid catabolism are associated .ith +, *71-. +n these models, +, .as
associated .ith elevated H8o(idation .ith no change in overall mitochondrial
respiration. )his might suggest that in the setting of lo. energy demand, e.g.,
a sedentary lifestyle, a metabolic overload stress on the mitochondria
contributes to +,. +t remains to be determined .hether an increase in
mitochondria content or capacity=even in lo. energy demand states=may act
as a buffer to reduce this metabolic stress and maintain insulin sensitivity.
%lucose transport is a 2ey defect in systemic glucose disposal, and some have
argued that this is the primary derangement governing +, in muscle *7/-.
,ecent studies in animal models have challenged the concept by
demonstrating a more distributed control of glucose flu( involving he(o2inase
during conditions in .hich glucose transport is ma(imi>ed *77-. )his should be
vie.ed in the conte(t of studies demonstrating he(o2inase binding to
mitochondria *7<- and its lin2 to thioredo(in8interacting protein *)I'+- as
.ell as )I'+ effects to inhibit glucose upta2e in humans *7?-. )hus it is :uite
possible that reduced mitochondrial content or remodeling in +, states results
in decreased overall he(o2inase binding and subse:uently a reduced
phosphorylation of glucose and diminished glucose upta2e.
Another attractive paradigm gaining acceptance is that mitochondria8derived
reactive o(ygen species *,6S- act as signaling molecules *7@-. Anderson et al.
*7A- demonstrated that in obese rodents and humans that elevated
mitochondrial8mediated o(idative stress .as related to +,, and that antio(idant
scavenging improved +,. +n support of a role of mitochondrial o(idative stress
in +,, 1ee et al. *7C- reported that overe(pression of a mitochondria8targeted
catalase resulted in a reduction in diacylglycerol and protection against aging8
induced +,. Moreover, it is .ell accepted that ,6S activate several aspects of
cell signaling related to insulin action *7D-. An interesting study by Shi and
colleagues *<E- reported that remodeling of cardiolipin, a phospholipid specific
to mitochondria, plays a 2ey role in mediating mitochondrial 6/ consumption,
o(idative stress and +,.
+nflammation has steadily gained acceptance as a li2ely cause of +,. )he lin2s
among inflammation, mitochondria and +, have only recently begun to be
appreciated. Mitochondrial )I'+ may also be an important lin2 bet.een
mitochondria and inflammation. )I'+ has also been implicated in type /
diabetes, and is associated .ith ,6S8dependent 'od8li2e receptor 7
inflammasome activation after its detachment from thioredo(in *<1-. Jhou et
al. *<1- found that inhibition of mitochondrial respiratory chain activity, .hich
causes ,6S generation, activates the 'od8li2e receptor 7 inflammasome, and
further, that the mitochondria voltage8dependent anion channels are crucial for
inflammasome activation. )hese data place mitochondrial signaling s:uarely in
the path of inflammation. )his inflammatory response has also been sho.n to
contribute to changes in the e(tracellular matri(, an altered mechanosignal
transduction, and reduced mitochondrial content and function associated .ith
+,. )a2en together, these studies indicate that o(idative stress and
inflammation are important aspects of mitochondrial energetics and play a role
in +,.
+n summary, human type / diabetes and obesity are associated .ith a reduced
mitochondrial capacity and +,. )he etiology and underlying mechanisms of
s2eletal muscle +, are not clear, in part because there are many cellular
causes of +,. 1ipid overload, derangements in fatty acid o(idation, o(idative
stress, and inflammation have all been sho.n to cause +,. Further, the
ma9ority of the available evidence indicates that mitochondria play a role in
these forms of human s2eletal muscle +,. Mitochondrial deficiency, as
articulated previously from the perspective of reduced o(idative capacity or lo.
fatty acid o(idation, should be more broadly defined to include mitochondria;s
various comple( roles in health and disease. #y accepting that mitochondria
are comple( organelles .ith many functions and that there are multiple
path.ays leading to +,, .e .ill more fully appreciate that mitochondria may
cause +,. )hen .e .ill be able to advance a clearer understanding of this
comple( pathology.
revious Section'e(t Section
A)/$"W!EDGME$%+
'o potential conflicts of interest relevant to this article .ere reported.
revious Section'e(t Section
'ootnotes
See accompanying articles, pp. 1E7@ and 1E<1.
K /E17 by the American Diabetes Association.
,eaders may use this article as long as the .or2 is properly cited, the use is
educational and not for profit, and the .or2 is not altered.
Seehttp"LLcreativecommons.orgLlicensesLby8nc8ndL7.EL for details.
revious Section

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