Metabolic flexibility and insulin resistance
Jose E. Galgani,1,2Cedric Moro,1and Eric Ravussin1
1Pennington Biomedical Research Center, Baton Rouge, Louisiana; and2Institute of Nutrition and Food Technology,
University of Chile, Santiago, Chile
Submitted 2 July 2008; accepted in final form 22 August 2008
Galgani JE, Moro C, Ravussin E. Metabolic flexibility and insulin resistance.
Am J Physiol Endocrinol Metab 295: E1009–E1017, 2008. First published Sep-
tember 2, 2008; doi:10.1152/ajpendo.90558.2008.—Metabolic flexibility is the
capacity for the organism to adapt fuel oxidation to fuel availability. The inability
to modify fuel oxidation in response to changes in nutrient availability has been
implicated in the accumulation of intramyocellular lipid and insulin resistance. The
metabolic flexibility assessed by the ability to switch from fat to carbohydrate
oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant
subjects; however, this “metabolic inflexibility” is mostly the consequence of
impaired cellular glucose uptake. Indeed, after controlling for insulin-stimulated
glucose disposal rate (amount of glucose available for oxidation), metabolic
flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To
understand how intramyocellular lipids accumulate and cause insulin resistance, the
assessment of metabolic flexibility to high-fat diets is more relevant than metabolic
flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate
muscle lipid oxidation in the face of high lipid supply may lead to increased muscle
fat accumulation and insulin resistance. Surprisingly, very few studies have inves-
tigated the response to high-fat diets. In this review, we discuss the role of glucose
disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic
flexibility. Additionally, we emphasize the bias of using the change in respiratory
quotient to calculate metabolic flexibility and propose novel approaches to assess
metabolic flexibility. On the basis of current evidence, one cannot conclude that
impaired metabolic flexibility is responsible for the accumulation of intramyocel-
lular lipid and insulin resistance. We propose to study metabolic flexibility in
response to high-fat diets in individuals having contrasting degree of insulin
sensitivity and/or mitochondrial characteristics.
fuel selection; insulin sensitivity; mitochondria; lipid oxidation; skeletal muscle
LIPID ACCUMULATION IN SKELETAL MUSCLE of sedentary people is
associated with impaired insulin-stimulated glucose metabo-
lism (31). A reduced capacity of oxidative tissues and organs to
adjust lipid oxidation to lipid availability can lead to tissue
accumulation of lipids as triglycerides. Excess lipid accretion
and/or lower triglyceride turnover can induce lipotoxicity, as
reflected by the cellular accumulation of ceramides and dig-
lycerides (39). These lipid species ultimately impair insulin
signaling through different mechanisms, either increased serine
phosphorylation of the insulin receptor and insulin receptor
substrate 1 and/or reduced serine phosphorylation of PKB/Akt
(38, 60) (Fig. 1). Therefore, the ability to increase lipid oxida-
tion as a function of their availability eventually reduces the
formation of ceramides and diglycerides leading to improved
In general, the ability of a system (i.e., whole organism,
organ, tissue, or cell) to adjust fuel oxidation to fuel availability
is known as metabolic flexibility. This term was coined by
Kelley and Mandarino as “the capacity to switch from predom-
inantly lipid oxidation and high rates of fatty acid uptake
during fasting conditions to the suppression of lipid oxidation
and increased glucose uptake, oxidation, and storage under
insulin-stimulated conditions” (26). In line with the above
definition, the switch from carbohydrate to lipid oxidation
[drop in respiratory quotient (RQ)] during an overnight fast or
in response to high-fat diets should also be part of the assess-
ment of metabolic flexibility (Fig. 2).
There is now a growing interest to assess the influence of
metabolic flexibility, particularly to dietary fat as a mechanism
to explain how lipids can accumulate in skeletal muscle. The
switch in fuel oxidation will depend on the type and amount of
nutrient available for oxidation at the cellular level. In tissues
and organs, fuel availability (glucose, fatty acids, and amino
acids) is integrated at the cellular level by fuel sensors that
activate or inhibit specific metabolic pathways (47, 50). In
response to fuel oversupply, anabolic pathways are activated,
whereas the activity of hydrolytic and lipolytic pathways is
increased when fuel availability is restricted. In addition, the
ability to change substrate oxidation in response to nutritional
status will depend on the genetically determined balance be-
tween cellular oxidation and storage capacities.
For example, in skeletal muscle, white (glycolytic) or red
(oxidative) muscle homogenates respond differently to a sup-
ply of fatty acids or glucose. Glycolytic fibers have low rates of
Address for reprint requests and other correspondence: E. Ravussin, Pen-
nington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA
70808 (e-mail: Eric.Ravussin@pbrc.edu).
Am J Physiol Endocrinol Metab 295: E1009–E1017, 2008.
First published September 2, 2008; doi:10.1152/ajpendo.90558.2008.
0193-1849/08 $8.00 Copyright © 2008 the American Physiological Society http://www.ajpendo.orgE1009
fat oxidation compared with oxidative fibers (30), which have
high mitochondrial density and oxidative enzyme activities. As
a consequence, the oxidative capacity of skeletal muscle may
be of utmost importance to boost lipid oxidation to the level of
lipid supply and therefore modulate insulin sensitivity. If
skeletal muscle cannot match fat oxidation to lipid uptake, fat
accumulation will ensue, which in turn will cause insulin
This review discusses the studies in which metabolic flexi-
bility has been measured at the whole body level or specifically
in skeletal muscle tissue or in muscle cells with particular
emphasis on the comparison between insulin-resistant and
insulin-sensitive individuals. In addition, we discuss the main
determinants of metabolic flexibility, how metabolic flexibility
should be measured, and which questions need to be answered
to better understand the pathophysiology of insulin resistance.
Metabolic Flexibility and Macronutrient Oxidative
During long-term energy balance, macronutrient oxidation
eventually has to match macronutrient intake such that no
macronutrients are stored or lost (10). In other words, not only
does 24-h energy expenditure have to be equal to 24-h energy
intake, but 24-h RQ has to be equal to 24-h food quotient (FQ).
The 24-h RQ corresponds to the mean proportion of macronu-
trient oxidized over a day, whereas 24-h FQ represents the
proportion of daily dietary macronutrients available for oxida-
tion (5). Many studies have shown that when people are in
energy balance then 24-h RQ eventually matches 24-h FQ (6,
Fig. 1. Model for fat-induced insulin resistance describing how a failure to
appropriately store lipids into subcutaneous adipose tissue (quantitatively predom-
inant) will lead to ectopic lipid deposition into visceral fat and insulin-sensitive
tissues such as liver and skeletal muscle. These tissues will progressively develop
a state of lipotoxicity, altering insulin signaling and action and contributing to
whole body insulin resistance and deterioration of glucose tolerance.
Fig. 2. Different features of metabolic flexibil-
ity during overnight fasting (A), during a hy-
perinsulinemic clamp (B), in response to a
high-carbohydrate diet (C), and in response to
a high-fat diet (D). Metabolically flexible (F)
and inflexible (E) subjects.
METABOLIC FLEXIBILITY AND INSULIN RESISTANCE
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