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Diabetes Pathophysiology and Genetics
dysfunction in insulin-resistant individuals. Consistent with this In patients with type 2 diabetes, interventions aimed at decreasing
scenario, short-term (48–72 hours) physiological elevation of the insulin resistance with weight loss and increased physical activity
plasma FFA concentration in lean healthy individuals has also been or with thiazolidinedions have also yielded inconsistent results.
shown to decrease the expression of PGC-1 and numerous other While weight loss and increased physical activity were
mitochondrial genes involved in oxidative phosphorylations.
55
associated with increased oxidative capacity and reversal of the
mitochondrial morphological changes associated with insulin
Most recently, we have demonstrated that an increase in FACoA resistance,
61,62
the decrease in insulin resistance caused by caloric
concentration inhibits mitochondrial ATP synthesis in vitro in restriction
61
or with rosiglitazone
63
was not associated with any
mitochondria isolated from skeletal muscle of NGT healthy lean improvement in mitochondrial function. These conflicting results
subjects.
56
This observation is consistent with the decline in suggest that factors other than mitochondrial dysfunction
oxidative phosphorylation
39
and the decreased expression of genes contribute to the development of insulin resistance in subjects with
encoding for mitochondrial proteins
55
observed following an type 2 diabetes.
elevation in the plasma FFA concentration in lean healthy
individuals, and provides strong evidence that an elevation in Summary and Conclusions
plasma FFA concentration can cause an acquired mitochondrial Although there is appealing evidence from both in vivo and ex vivo
defect in oxidative phosphorylation. human studies to implicate a mitochondrial defect (reduced
mitochondrial number and/or function) in oxidative phosphorylation
In summary, an inherited defect in mitochondrial function, with or with the development of skeletal muscle increased insulin
without a decrease in mitochondrial density, would be expected to resistance, the cause–effect relationships between insulin resistance
result in impaired lipid oxidation, an increase in intramyocellular and mitochondrial dysfunction remain to be defined. Furthermore,
lipid content and the development/exacerbation of insulin the nature of the mitochondrial defect, i.e. quantitative versus
resistance. Conversely, an increase in fatty acid flux into the functional, remains to be definitively established. Such a
mitochondria, e.g. secondary to obesity and tissue fat overload or mitochondrial defect, in the face of excessive endogenous
adipocyte resistance to the antilipolytic effect of insulin, could lead (increased lipolysis) or exogenous (overfeeding and obesity) FFA
to an acquired defect in mitochondrial function. There is supply, would be expected to lead to the accumulation of fat in
experimental evidence to support both of these scenarios, which insulin-sensitive tissues, e.g. skeletal muscle and liver, resulting in
are not mutually exclusive. the development of insulin resistance. The cause–effect relationship
between insulin resistance and mitochondrial dysfunction can be
Discordance Between Insulin Resistance examined in longitudinal intervention studies.
and Mitochondrial Function
Due to the cross-sectional design of the above studies, it is A major challenge is to determine whether, in light of the enormous
impossible to establish causality between mitochondrial dysfunction potential to increase skeletal muscle mitochondrial oxidative
and insulin resistance in skeletal muscle. Studies in experimental capacity that can be observed during exercise, a ~30% decrease in
animals have altered mitochondrial function in skeletal muscle and mitochondrial function measured in vivo during the resting state
assessed the impact of this intervention on the subsequent can lead to an increase in intramyocellar fat content. It also remains
development of muscle insulin resistance. Unfortunately, these results to be determined whether strategies that specifically upregulate
have yielded conflicting results. Overexpression of the PGC-1 alpha mitochondrial function in skeletal muscle have a therapeutic
gene in skeletal muscle in mice in vivo enhanced mitochondrial potential to decrease insulin resistance and improve glucose
activity, augmented the expression of multiple proteins involved in fat tolerance in patients with type 2 diabetes. n
oxidation and glucose transport and increased by ~35% insulin-
stimulated glucose uptake in skeletal muscle.
57
Similarly, activation of
Muhammad A Abdul-Ghani is an Assistant Professor of
sirtuin 1 (SIRT1) with resveratrol in mice increased mitochondrial
Medicine in the Division of Diabetes at the University
function and protected the animal from diet-induced obesity and of Texas Health Science Center at San Antonio. His
insulin resistance.
58
Although these studies indicate that, in animal
clinical and basic research in diabetes focuses
primarily on molecular mechanisms of insulin
models, increasing mitochondrial oxidative capacity has a favourable
resistance, molecular mechanisms of β-cell failure in
effect on insulin sensitivity, a decrease in mitochondrial oxidative subjects with type 2 diabetes and the role of
capacity in skeletal muscle has also been shown to improve insulin
mitochondrial dysfunction in obesity and insulin
resistance. Dr Abdul-Ghani graduated from the Hebrew
sensitivity. Popisilik et al. reported that a reduction in mitochondrial
University and Hadassah Medical School, where he
oxidative capacity, brought about by knocking down apoptosis- received his MD and his PhD in physiology.
initiating factor (AIF), resulted in enhanced insulin sensitivity and
protection from fat-induced insulin resistance.
59
The results of these
Ralph A DeFronzo is a Professor of Medicine and
Chief of the Division of Diabetes at the University of
genetic manipulations should be interpreted with caution, as they
Texas Health Science Center at San Antonio. He is a
represent extreme situations where a complete lack of or marked
world-renowned authority on the pathogenesis of
overexpression of a protein is present. Therefore, they do not
type 2 diabetes, the insulin resistance syndrome
and the treatment of type 2 diabetes. Professor
reproduce the physiological situation and are likely to trigger other
DeFronzo’s major interests focus on the pathogenesis
compensatory mechanisms. For example, the impact of PGC-1 alpha
and treatment of type 2 diabetes, the central role of
overexpression on insulin sensitivity in skeletal muscle is time- and
insulin resistance in the metabolic–cardiovascular
cluster of disorders, known collectively as the insulin
magnitude-dependent.
57,60
Moreover, these genetic manipulations may
resistance syndrome, and the aetiology and treatment
have additional direct effects on insulin action that are independent
of diabetic nephropathy.
of changes in mitochondrial function.
22 EUROPEAN ENDOCRINOLOGY
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