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Type 2 diabetes as a redox disease

James D Watson

Physical exercise has long been widely regarded as The precise mechanism linking an oxidative Lancet 2014; 383: 84143
essential to human health.1 Yet, we do not know how environment with enhanced sensitivity to insulin in key Cold Spring Harbor Laboratory,
exercise-stressed skeletal muscle cells that generate tissues targeted by diabetes is still obscure. However, Cold Spring Harbor, NY, USA
(J D Watson ForMemRS)
reactive oxygen species such as hydrogen peroxide (H2O2) multiple studies14 over the past decade report that the
Correspondence to:
delayif not preventthe occurrence and severity of membranous sacs of the endoplasmic reticulum of
James D Watson, Cold Spring
diseases such as type 2 diabetes (as well as dementias, insulin-resistant rodents contain much higher Harbor Laboratory, 1 Bungtown
cardiovascular disease, and some cancers). Also proportions of unfolded polypeptides and many fewer Road, Cold Spring Harbor,
unexplained is the recent nding that metforminthe SS bonds than does normal endoplasmic reticulum. NY 11724, USA
most commonly used drug to treat type 2 diabetes24 Unlike almost all other cellular locations that have
and physical exercise seem to be benecial for several of reducing redox potentials, normal endoplasmic
the same diseases, including cancer, Alzheimers disease, reticulum has the oxidative redox potential necessary to
and cardiovascular disease.5,6 New evidence7 shows that form disulphide bonds. Only a third of all proteins are
combinations of short-term metformin treatment with stabilised by disulphide bonds, with most using van der
single acute bouts of exercise do not, as generally Waals interactions and hydrogen bonds to generate their
expected, enhance insulin sensitivity. In fact, metformin 3D shapes. Why only membrane-bound or secretory
alone can attenuate much of the oxidative eect of proteins require stabilisation by SS bonds remains
exercise.7 The reason why exercise and metformin have unclear. However, no uncertainty exists about the
opposing physiological consequences (oxidative vs potential disease-causing consequences of loweringif
reducing) has been shown by studies8 that suggest that not stoppingSS bond formation. How enzymes of the
giving mice metformin increases synthesis of the endoplasmic reticulum form the SS bonds of secretory
transcription factor Nrf2, which controls the downstream and membrane proteins is beginning to be understood.1517
synthesis of RNA molecules coding for major cellular Two structurally dierent oxidoreductive thiol enzymes
antioxidant enzymes. have essential roles. Protein disulphide isomerases can
I postulate that diabetes, dementias, cardiovascular directly insert the disulphide bond into target
disease, and some cancers are acceleratedif not largely polypeptides. By so doing, they become reduced and
causedby failure of the endoplasmic reticulum to unable to catalyse further SS insertion until reoxidised
generate sucient oxidative redox potential for disulphide by Ero1a protein of a dierent disulphide oxidase
bonds to be formed. Physical exerciseby generating protein family that contains avin adenine dinucleotide.
large numbers of reactive oxygen speciescreates the By oxidising protein disulphide isomerase, Ero1 becomes
oxidative redox potential needed to oxidise the free sulph- reduced and only resumes activity when it is reoxidised
hydryl groups of cysteine into the disulphide bonds used by passing electrons to molecular oxygen (O2) which
to stabilise the 3D conformation of physiologically active generates H2O2.
proteins. Compelling evidence that reductive redox After these two thio-oxide reductases were identied,
potentials might be the molecular essence of type 2 researchers began to investigate whether the insertion of
diabetes rst came to my attention in early 2013 when I SS bonds into nascent proteins harms protein folding
learned from a 2009 German study that consumption of in patients with type 2 diabetes. The rst such attempt
physiological amounts of the antioxidants vitamin C and was made in 2005 by Hungarian biochemists led by
vitamin E abrogated the capacity of physical exercise to Gabor Nardaii.18 They found that the polypeptide chain of
make insulin more eective in lowering blood sugar protein disulphide isomerase in rat models of type 2
concentrations.7,9 This nding is supported by similar diabetes had relatively more reduced SH groups than did
studies of other antioxidants in man.1012 Further non-diabetic animals. By contrast, the polypeptides of
suggestive evidence for the importance of an oxidative Ero1 of diabetic rats had more oxidised SS bonds than
environment for promoting the action of insulin comes did non-diabetic rats. These results are compatible with
from patients with rare mutations impairing the diabetic cells having higher reductive redox potentials.
production of antioxidant selenoproteins. Despite Hopefully, these ndings will stimulate a more thorough
unequivocal evidence for a primary and severe deciency examination of SS bond creation in human patients
of antioxidants including oxidative damage in tissues with type 2 diabetes.
such as skin, these patients maintain supranormal Metformin actually seems to interfere with the
insulin sensitivity even if they are obese.13 Insulin benecial eects of exercise in patients with diabetes.7,9
resistance and type 2 diabetes might very well arise This apparent paradox requires an explanation.
through insucient supplies of key reactive oxygen Metformin has long been known to activate AMP-
species that normally oxidise key molecules controlling activated protein kinase (AMPK; the main cellular
blood sugar concentrations. mediator of metabolic stress), but it does so indirectly.19

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