Nige's Diet & Nutrition Blog: Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?
Serendipity strikes again!
The picture that I used for the last post came from Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?
Fascinating stuff!
Serendipity strikes again!
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| The tipping point and the metabolic syndrome. |
Fascinating stuff!
BioMed Central
Page 1 of 26
(page number not for citation purposes)
Nutrition & Metabolism
Commentary
Lifestyle-induced metabolic inflexibility and accelerated ageing
syndrome: insulin resistance, friend or foe?
Alistair VW Nunn*
1
, Jimmy D Bell
1
and Geoffrey W Guy
2
Address:
1
Metabolic and Molecular Imaging Group, MRC Clinical Sciences Ce
ntre, Hammersmith Hospital, Impe
rial College London, Du Cane
Road, London, W12 OHS, UK and
2
GW pharmaceuticals, Porton Down, Dorset, UK
Email: Alistair VW Nunn* - alistair.nunn@btco
nnect.com; Jimmy D Bell - jimmy.bell@csc.mr
c.ac.uk; Geoffrey W Guy - gwg@gwpharm.com
* Corresponding author
Abstract
The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'
.
This is based on the notion th
at mitochondria may be able to
both amplify membrane-derived
redox growth signals as well as negatively regula
te them, resulting in an
increased AT
P/ROS ratio.
We suggest that '
redox-thriftiness'
leads to insulin resistance, which
has the effect of both protecting
the individual cell from
excessive growth/inflammatory stress,
while ensuring energy is channelled
to the brain, the immune system, and for storage.
We also suggest that fine tuning of redox-
thriftiness is achieved by hormetic (mild stress)
signals that stimulate mito
chondrial biogenesis and
resistance to oxidative stress, which improves me
tabolic flexibility. However, in a non-hormetic
environment with excessive calories, the protective
nature of this system may lead to escalating
insulin resistance and rising oxidative stress
due to metabolic inflexibility and mitochondrial
overload. Thus, the mitochondrially-associated re
sistance to oxidative stress (and metabolic
flexibility) may determine in
sulin resistance.
Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest that as oxidative stress determines functional longevity, a rather more descriptive term for the metabolic syndrome is the 'lifestyle-induced metabolic inflexibility and accelerated ageing syndrome'.
Ultimately, thriftiness is good for us as long as we have hormetic stimuli; unfortunately, mankind is attempting to remove all hormetic (stressful) stimuli from his environment.
