http://www2.warwick.ac.uk/fac/med/newsfront/?newsItem=094d402513631e4601137249474419c5
New Warwick diabetes research published in New Scientist
Research led by Warwick Medical School's Dr Antonio Ceriello into the
effects of diabetes has been published in the June 30 edition of New
Scientist magazine. His team has have uncovered a process that locks the
body’s metabolism in a diabetic state after only relatively limited exposure
to high glucose levels.
Researchers were already aware that there seems to be a point of no return
in the onset of diabetes. This was apparent in the Diabetes Complications
and Control Trial (DCCT) in the 1990s when Type 1 diabetic patients were
either placed on standard or intensive treatment regimens to normalize their
glucose levels. Because complications were so profoundly reduced in patients
with tight glucose control, all the remaining DCCT patients were switched
early onto intensive therapy. However a follow-up study found that several
years after switching to intensive therapy the patients who started the
trial on only the standard treatment regimen continued to have more
complications than those who received intensive therapy throughout the
trial.
Research since has speculated that exposure to high glucose levels quickly
creates a metabolic memory in which diabetes persists long after glucose
levels have been corrected. Research to date suggested that oxidation played
a role but the exact mechanism was unknown.
The Warwick research team, led by Dr Antonio Ceriello, have now proven that
the damage seems to be done in a process called glycation when early on in a
period of high glucose levels glucose sugar molecules are able to bind to
proteins in the mitochondria of cells (the parts of cells governing the
production and regulation of energy). This persists even if glucose levels
later fall to normal. This inhibits and distorts the mitochondria’s normal
function and results in an overabundance of the production of free radicals
(or Reactive Oxygen Species – ROS) which cause oxidation and thus continued
diabetic complications.
The researchers proved their hypothesis by taking tissue and exposing it to
2 weeks of high levels of glucose, followed by one week of normal glucose –
however for half the tissue they also applied several antioxidants at the
end of the two weeks of high glucose. The tissue without antioxidants levels
of glucose stress remained high but where antioxidants had been applied
there was a dramatic fall in the incidence of free radicals and there was
also a significant drop in 5 of the 6 key markers for high glucose stress.
The research confirms the need for very early tight control of glucose
levels to avoid diabetic complication and that that control must be
supplemented with the use of antioxidant agents to mitigate the progression
of complications.
However long term use of antioxidants can in itself produce health problems
so in a further research published this month the team have tested the use
of the AT-1 receptor blocker Telmisartan and found it can be used in exactly
the same way to suppress the build up of free radicals without the side
affects that long term use of antioxidants would cause.
Dr Ceriello is now beginning to look at how to move beyond simply
suppressing the problematic production of free radicals and actually finding
ways of reversing the glycation process itself thus erasing the harmful
"metabolic memory".
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http://www.newscientist.com/article/mg19426104.200-how-to-stop-diabetes-wreaking-lasting-havoc.html
How to stop diabetes wreaking lasting havoc
29 June 2007
NewScientist.com news service
Andy Coghlan
One of the nasty tricks that diabetes has up its sleeve is the ability to
carry on harming people long after they have got the level of glucose in
their blood under control. Now researchers think they may be able to stop
this, using cheap available drugs.
The idea builds on the discovery that when cells are exposed to the high
levels of glucose typical of diabetes, proteins within the cells'
mitochondria suffer damaging changes. The proteins become permanently
attached to sugar-like molecules called glycans, and this not only prevents
them doing their job properly but also makes them produce harmful molecules
called reactive oxygen species.
The reactive oxygen species circulate throughout the body, attacking and
damaging tissues, particularly in the limbs and eyes. Because the changes to
the cellular proteins are not reversible, they continue to pump out these
molecules even when glucose levels have returned to normal. "This
contributes to the development of diabetic complications," says Antonio
Ceriello of the University of Warwick in Coventry, UK, whose team now think
there may be a way to stop this happening.
The clue came from lab experiments in which they took damaged cells that had
been previously exposed to high levels of glucose, and showed that the
reactive molecules could be neutralised by exposing the cells to
antioxidants such as alpha-lipoic acid (Diabetologia, DOI:
10.1007/s00125-007-0684-2).
In a trial on 36 patients undergoing insulin treatment for type 1 diabetes,
they were then able to show that injections of vitamin C could have the same
effect in people, as did a blood-pressure-lowering drug called telmisartan.
"These compounds can counteract the 'memory' because they work inside cells
to block free-radical production," says Ceriello, who will publish the
results of the trial in the journal Diabetes Care.
“In a trial of 36 patients, injections of vitamin C neutralised the reactive
molecules that were responsible for the damage”The researchers point out,
however, that people would have to take such antioxidants for life, to mop
up the continuous supply of reactive molecules being produced by the damaged
proteins. So they are now looking for other potential drugs that might
permanently reverse the chemical changes that stopped the protein's normal
function.
Ian Frame, research manager at the charity Diabetes UK, cautions that the
timescale of the experiments was relatively short, so the proposed
treatments might not work in people with chronic diabetes. However, he does
say the results are a "step forward" in establishing how reactive oxygen
species contribute to long-term complications of diabetes.
From issue 2610 of New Scientist magazine, 29 June 2007, page 11
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