Diabetes / iron accumulation / beta cell destruction

[Doe]

It seems iron accumulation destroys beta cells leading to ..
diabetes .. Jeez .. have we heard of that somewhere ..
before ..?

J Clin Invest. 2003 Aug;112(4):527-34. Related Articles, Links

Frataxin deficiency in pancreatic islets causes diabetes due
to loss of beta cell mass.

Ristow M, Mulder H, Pomplun D, Schulz TJ, Muller-Schmehl
K, Krause A, Fex M, Puccio H, Muller J, Isken F, Spranger
J, Muller-Wieland D, Magnuson MA, Mohlig M, Koenig M,
Pfeiffer AF.

German Institute of Human Nutrition, Department Klinische
Ernahrung, 114 Arthur-Scheunert-Strasse, D-14558
Bergholz-Rehbrucke, Germany. mristow@mristow.org

Diabetes is caused by an absolute (type 1) or relative (type
2) deficiency of insulin-producing beta cells. We have
disrupted expression of the mitochondrial protein frataxin
selectively in pancreatic beta cells. Mice were born healthy
but subsequently developed impaired glucose tolerance
progressing to overt diabetes mellitus. These observations
were explained by impairment of insulin secretion due to a
loss of beta cell mass in knockout animals. This phenotype was
preceded by elevated levels of reactive oxygen species in
knockout islets, an increased frequency of apoptosis, and a
decreased number of proliferating beta cells. Hence,
disruption of the frataxin gene in pancreatic beta cells
causes diabetes following cellular growth arrest and
apoptosis, paralleled by an increase in reactive oxygen
species in islets. These observations might provide insight
into the deterioration of beta cell function observed in
different subtypes of diabetes in humans.

PMID: 12925693 [PubMed - indexed for MEDLINE]

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Expert Opin Investig Drugs 2003 Feb;12(2):235-245

Friedreich's ataxia: iron chelators that target the
mitochondrion as a therapeutic strategy?

Richardson D Iron Metabolism and Chelation Program, Children's
Cancer Institute Australia for Medical Research, High St (PO
Box 81), Randwick, Sydney, New South Wales, 2031, Australia.
d.richardson@ccia.org.au

[Record supplied by publisher]

Friedreich's ataxia (FA) is a severe inherited spinocerebellar
ataxia that primarily affects the nervous system and heart
leading to early confinement in a wheelchair and death. The
gene defective in FA, FRDA, encodes a mitochondrial protein
known as frataxin.( )A triplet repeat expansion within intron
1 of the FRDA gene results in a marked decrease in frataxin
expression. Over the last 5 years it has become clear that
this results in mitochondrial iron accumulation that generates
oxidative stress and results in damage to critical biological
molecules. Drugs that reduce oxidative stress have a limited
effect on the progression and pathology of the disease,
probably because these agents cannot remove the iron
accumulation. In this review, the potential of iron chelators,
namely the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone
(PCIH) analogues, as agents to remove mitochondrial iron
deposits is discussed. These ligands have been specifically
designed to enter and target mitochondrial iron pools, which
is a property lacking in desferrioxamine, the only chelator in
widespread clinical use. This latter drug may not have any
beneficial effect in FA patients, probably because of its
hydrophilicity that prevents mitochondrial access. Indeed,
standard chelation regimens will probably not work in FA, as
these patients do not exhibit gross iron-loading. Considering
that there is no effective treatment for FA, it is essential
that the therapeutic potential of iron chelators that target
mitochondrial iron pools is assessed experimentally.

PMID: 12556217

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Who loves ya. Tom

Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com Man
Is A Herbivore!
http://pages.ivillage.com/ironjustice/manisaherbivore DEAD
PEOPLE WALKING
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[markd]

Tom, no cigar, must say good try, but it's the old see what
you want to see problem. In both the rat and human examples, a
genetic disorder knocked out production of the Frataxin
protein, which has a role in iron regulation. This is not the
case with diabetics, in fact in the human case diabetics was
not a question at all but a nerve disorder. What you would
have to do is make a connection between the typical diabetic
and the absence of this protein, which isn't likely to happen.
I f diabetics, ie. humans, were not to have this protein then
all of them would also develope the nerve disorder, and they
don't. This is also another example of a serious flaw in your
logic and use of info, you parade two research projects side
by side which have in common some term and force conclusions
from it that can not be sustained.

>It seems iron accumulation destroys beta cells leading to ..
>diabetes .. Jeez .. have we heard of that somewhere ..
>before ..?
>
>
>J Clin Invest. 2003 Aug;112(4):527-34. Related
>Articles, Links
>
>
>Frataxin deficiency in pancreatic islets causes diabetes due
>to loss of beta cell mass.
>
>Ristow M, Mulder H, Pomplun D, Schulz TJ, Muller-Schmehl
>K, Krause A, Fex M, Puccio H, Muller J, Isken F, Spranger
>J, Muller-Wieland D, Magnuson MA, Mohlig M, Koenig M,
>Pfeiffer AF.
>
>German Institute of Human Nutrition, Department Klinische
>Ernahrung, 114 Arthur-Scheunert-Strasse, D-14558
>Bergholz-Rehbrucke, Germany. mristow@mristow.org
>
>Diabetes is caused by an absolute (type 1) or relative (type
>2) deficiency of insulin-producing beta cells. We have
>disrupted expression of the mitochondrial protein frataxin
>selectively in pancreatic beta cells. Mice were born healthy
>but subsequently developed impaired glucose tolerance
>progressing to overt diabetes mellitus. These observations
>were explained by impairment of insulin secretion due to a
>loss of beta cell mass in knockout animals. This phenotype
>was preceded by elevated levels of reactive oxygen species in
>knockout islets, an increased frequency of apoptosis, and a
>decreased number of proliferating beta cells. Hence,
>disruption of the frataxin gene in pancreatic beta cells
>causes diabetes following cellular growth arrest and
>apoptosis, paralleled by an increase in reactive oxygen
>species in islets. These observations might provide insight
>into the deterioration of beta cell function observed in
>different subtypes of diabetes in humans.
>
>PMID: 12925693 [PubMed - indexed for MEDLINE]
>
>-------------------------------------------------------------
>--------------
>------
>
>Expert Opin Investig Drugs 2003 Feb;12(2):235-245
>
>
>
>Friedreich's ataxia: iron chelators that target the
>mitochondrion as a therapeutic strategy?
>
>Richardson D Iron Metabolism and Chelation Program,
>Children's Cancer Institute Australia for Medical Research,
>High St (PO Box 81), Randwick, Sydney, New South Wales, 2031,
>Australia. d.richardson@ccia.org.au
>
>[Record supplied by publisher]
>
>
>Friedreich's ataxia (FA) is a severe inherited
>spinocerebellar ataxia that primarily affects the nervous
>system and heart leading to early confinement in a wheelchair
>and death. The gene defective in FA, FRDA, encodes a
>mitochondrial protein known as frataxin.( )A triplet repeat
>expansion within intron 1 of the FRDA gene results in a
>marked decrease in frataxin expression. Over the last 5 years
>it has become clear that this results in mitochondrial iron
>accumulation that generates oxidative stress and results in
>damage to critical biological molecules. Drugs that reduce
>oxidative stress have a limited effect on the progression and
>pathology of the disease, probably because these agents
>cannot remove the iron accumulation. In this review, the
>potential of iron chelators, namely the
>2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH)
>analogues, as agents to remove mitochondrial iron deposits is
>discussed. These ligands have been specifically designed to
>enter and target mitochondrial iron pools, which is a
>property lacking in desferrioxamine, the only chelator in
>widespread clinical use. This latter drug may not have any
>beneficial effect in FA patients, probably because of its
>hydrophilicity that prevents mitochondrial access. Indeed,
>standard chelation regimens will probably not work in FA, as
>these patients do not exhibit gross iron-loading. Considering
>that there is no effective treatment for FA, it is essential
>that the therapeutic potential of iron chelators that target
>mitochondrial iron pools is assessed experimentally.
>
>
>PMID: 12556217
>
>
>-------------------------------------------------------------
>--------------
>------
>
>Who loves ya. Tom
>
>Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com Man
>Is A Herbivore!
>http://pages.ivillage.com/ironjustice/manisaherbivore DEAD
>PEOPLE WALKING
>http://pages.ivillage.com/ironjustice/deadpeoplewalking

[Mattlb]

doe wrote:
>
> It seems iron accumulation destroys beta cells leading to ..
> diabetes .. Jeez .. have we heard of that somewhere ..
> before ..?

I hope you realise that the abstracts you cited both deal
with abnormal cells, either through deliberate modification
or inherited disease and therefore have no significance to
normal cells.

Dietary iron has no effect on mitochondrial iron (apart from
severe deficiencies), and mitochondrial iron only builds up
due to a defect in the recycling process which means
mitochondria can't make the haem they need. This means they
can't make ATP, which means the (beta) cells die. The fact
that iron promotes free radical formation and therefore
damage to the mitochondria just speeds things up a bit. In
people without a frataxin deficiency there's no iron buildup,
so normal levels of iron don't cause diabetes.

MattLB

[Doe]

>Subject: Re: Diabetes / iron accumulation / beta cell
>destruction From: MattLB mattlb@FAKEBITangelfire.com Date:
>6/2/2004 6:43 AM Mountain Daylight Time Message-id:
><40BDCB8B.7DAA5F00@FAKEBITangelfire.com>
>
>doe wrote:
>>
>> It seems iron accumulation destroys beta cells leading to
>> .. diabetes .. Jeez .. have we heard of that somewhere ..
>> before ..?
>
>I hope you realise that the abstracts you cited both deal
>with abnormal cells, either through deliberate modification
>or inherited disease and therefore have no significance to
>normal cells.
>
> Dietary iron has no effect on mitochondrial iron (apart from
> severe deficiencies), and mitochondrial iron only builds up
> due to a defect in the recycling process which means
> mitochondria can't make the haem they need. This means they
> can't make ATP, which means the (beta) cells die. The fact
> that iron promotes free radical formation and therefore
> damage to the mitochondria just speeds things up a bit. In
> people without a frataxin deficiency there's no iron
> buildup, so normal levels of iron don't cause diabetes.
>
>MattLB

So the cause of type 1 is something 'other' .. than .. iron ..

Eh ..

In this case .. it .. IS .. iron ..

But in .. other .. cases .. it .. is .. not ..

Eh ..

Even though .. they have shown .. that the diabetes .. type 1
.. IS .. caused by 'something' .. that .. EITHER oxidizes /
rusts ..or .. ?

Who loves ya. Tom Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com Man Is A Herbivore!
http://pages.ivillage.com/ironjustice/manisaherbivore DEAD
PEOPLE WALKING
http://pages.ivillage.com/ironjustice/deadpeoplewalking

[Doe]

>Subject: Re: Diabetes / iron accumulation / beta cell
>destruction From: MattLB mattlb@FAKEBITangelfire.com Date:
>6/2/2004 6:43 AM Mountain Daylight Time Message-id:
><40BDCB8B.7DAA5F00@FAKEBITangelfire.com>
>
>doe wrote:
>>
>> It seems iron accumulation destroys beta cells leading to
>> .. diabetes .. Jeez .. have we heard of that somewhere ..
>> before ..?
>
>I hope you realise that the abstracts you cited both deal
>with abnormal cells, either through deliberate modification
>or inherited disease and therefore have no significance to
>normal cells.
>
> Dietary iron has no effect on mitochondrial iron (apart from
> severe deficiencies), and mitochondrial iron only builds up
> due to a defect in the recycling process which means
> mitochondria can't make the haem they need. This means they
> can't make ATP, which means the (beta) cells die. The fact
> that iron promotes free radical formation and therefore
> damage to the mitochondria just speeds things up a bit. In
> people without a frataxin deficiency there's no iron
> buildup, so normal levels of iron don't cause diabetes.
>
>MattLB
>
>

It seems .. ageing .. causes .. mitochondrial iron
accumulation .. ?

<<snip>> Because aging subcortical astrocytes may exhibit
both enhanced MAO-B activity and abundant mitochondrial iron
(5) <<snip>>

http://www.mcmaster.ca/inabis98/juurlink/schipper0139/two.html

Who loves ya. Tom Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com Man Is A Herbivore!
http://pages.ivillage.com/ironjustice/manisaherbivore DEAD
PEOPLE WALKING
http://pages.ivillage.com/ironjustice/deadpeoplewalking