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. [email hidden]
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. [email hidden]
[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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