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AONM Cell Symbiosis Therapy (CST) Series
Diabetes: A mitochondrial perspective
Gilian Crowther MA (Oxon), ND/NT, mBANT, mNNA, CNHC reg, AONM©
The mitochondria – the powerhouses of our cells –
play a vital role in the pathogenesis of diabetes. In
the words of a very recent review, there is now
“evidence to indicate that diabetes and its
complications result at least partially from pathogenic
processes at the mitochondrial level.”[1] If we can
understand what these pathogenic processes are,
we have all the more chance of working out what can
be done to correct them. Professor Denis McGarry
asked at the beginning of his famous Banting Lecture
in 2001, after a lifetime of studying diabetes: “I
sometimes think that the question of what causes
type 2 diabetes might be one of the most frequently
asked and least satisfactorily answered in the history
of diabetes research.”[2] Perhaps a mitochondrial
perspective can help approach an answer in areas
where a glucocentric or lipocentric perspective has
not done so far.
Excess glycaemic calorie intake is certainly a starting
point: this is so common in our current lifestyle. High
calorie/high glycaemic intake causes an intensive
rate of substrate input along the electron transport
chain that generates our high-efficiency adenosine
triphosphate (ATP) for energy within the
mitochondria. This is known as a “high proton-motive
force”. However, this is often combined with low
energy expenditure: how often are we fleeing from
lions (or the equivalent) in terms of energy output?
Our sedentary lifestyles mean our ATP generation is
often more than we are actually able to use. If this
continues unabated, the reactive oxygen species
(ROS) generated along the electron transport chain
can build up more than we have antioxidants to
quench. If this happens, they damage proteins, DNA
and lipids in membrane components, eventually
resulting in mitochondrial dysfunction.[3] Plus we
lose the ability to produce ATP efficiently.
One strategy of the mitochondria when this happens
is to release a quantity of the potential energy that
builds along the electron transport chain just before
conversion into ATP using uncoupling proteins.[4]
This leads to membrane depolarization and can
eventually
shut
down
mitochondrial
ATP
generation.[5] This protects the mitochondria from
excess oxygen radicals that would otherwise destroy
them, but the disadvantage is that downregulated
mitochondria mean energy has to be generated in
the cytosol instead, along an “emergency generator”
pathway that is not intended to be used long term.
Cytosolic energy production is very inefficient (only 2
ATP per mole of glucose instead of around 36).[6]
Easy then to understand the fatigue of diabetics, and
in many cases the sense of needing to eat
(hyperphagia). The body is starving, energy is not
going into the cells efficiently, but does not do so
however much is eaten.
The situation now becomes a vicious cycle, as when
the mitochondria are down, the key substrate the
body uses for energy is glucose. So now we have
larger volumes of glucose being ferried into the cells.
The cells however are aware that they do not wish to
be exposed to high levels of glucose long term. Just
think of HbA1c, a marker of diabetes: this glycated
haemoglobin rises higher the more plasma glucose
we are exposed to – basically sugar attaching to our
red blood cells, partially blocking their functionality.
Our cells are programmed to protect the organism at
all costs, and will do their best to resist the damaging
effects of high blood glucose levels. The solution,
from the cells’ point of view, is insulin resistance –
stop the glucose from getting into the cells.
Another pathway that stops working when the
mitochondria are downregulated is the body’s natural
way of burning fats: the beta oxidation pathway. This
is in the mitochondria, so if the mitochondria are
down, this will no longer be functional. If you cannot
oxidize lipids in the mitochondria, you develop higher
levels of free fatty acids accumulating both in the
blood plasma (elevated triglycerides) and elevated
intramyocellular lipids (lipids in the muscle, where
they should not be).[7] This free fatty acid excess is
a key factor in impairing insulin secretion – this may
even be part of the body’s intelligent feedback
system, as these elevated lipids are a signal that the
mitochondria are down, and blood glucose is going
to rise. “It is now apparent that elevation of plasma
free fatty acids plays a pivotal role in the
development of type 2 diabetes by causing insulin
resistance.”[8] Not to forget that sugars form a large
part of the substrate for our triglycerides anyway, not
just fats. So both the sugars and the fats that can no
longer be burnt in the mitochondria because they
have shut down now build up around the body in
adipose tissue, and as intramyocellular lipids. Free
fatty acids when circulating result in “very significant
suppression of insulin-mediated glucose uptake,”[9]
correlated most tightly with intramyocellular lipids.
Protection is always the key: “Most cells are able to
reduce the transport of glucose inside the cell when
they are exposed to hyperglycemia”.[10] Certain
cells in the body however are unable to do this when
exposed to hyperglycaemia: capillary endothelial
cells in the retina, mesangial cells in the renal
glomerulus, neurons and Schwann cells in peripheral
nerves. These are the cells and organs often
damaged first in frank diabetes. Again, the
mitochondria are (unwittingly) the key player. As
Michael Brownlee describes in “The pathology of
diabetic complications: a unifying mechanism,”[11]
the backlog along the electron transport chain
discussed at the outset cannot be released by the
emergency “blowout” mechanism, leading to more
ROS than the mitochondria are able to quench with
antioxidants.[12] These ROS damage proteins, DNA
and lipids in membrane components of the
mitochondria.[13]
Brownlee
suggests
that
mitochondrial dysfunction occurs as a “unifying
mechanism” for microvascular and macrovascular
complications through the production of ROS.[14]
Arguments are rife within academia as to whether the
“glucocentric” or “lipocentric” view is most important
in explaining the pathogenesis of diabetes. Perhaps
we should simply think about it as “mitocentric.”
Caring for your mitochondria targets the essence of
the problem, and can help to restore cell
functionality. How to do that will be the subject of a
future article.
Endnotes
1. Chen X, et al. Mitochondria in the pathogenesis of
diabetes:
a
proteomic
view.
Protein
Cell.
2012 Sep;3(9):648-60
2. McGarry, JD. Dysregulation of fatty acid metabolism in
the
etiology
of
type
2
diabetes.
Diabetes. 2002 Jan;51(1):7-18
3. Op cit.
4. Rousset S, et al. The biology of mitochondrial
uncoupling
proteins.
Diabetes
February
2004
vol. 53 no. suppl 1 p.130-135
5. Lamson DW, et al. Mitochondrial Factors in the
Pathogenesis
of
Diabetes:
A
Hypothesis
for
Treatment. Altern Med Rev. 2002;7:94-111.
6. Rolfe, D. F., Brown, G. C. (1997). Cellular energy
utilization
and
molecular
origin
of
standard
metabolic rate in mammals. Physiol Rev. 77(3):731-58
7. McGarry, JD. Op cit.
8. Boden G, Markku L. Lipids and glucose in type 2
diabetes. Diabetes Care, volume 27, no. 9,
2004
9. McGarry, JD. Op cit.
10. Brownlee M. The pathobiology of diabetic
complications: a unifying mechanism. Diabetes
2005;54:1615–1625
11. Ibid.
12. Lamson DW, et al. Mitochondrial Factors in the
Pathogenesis
of
Diabetes:
A
Hypothesis
for
Treatment. Altern Med Rev. 2002;7:94-111.
13. Op cit.
14. Brownlee M. Op cit.
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