Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass.
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.
Ristow
Michael
M
German Institute of Human Nutrition, Department Klinische Ernährung, 114 Arthur-Scheunert-Strasse, D-14558 Bergholz-Rehbrücke, Germany. mristow@mristow.org
Mulder
Hindrik
H
Pomplun
Doreen
D
Schulz
Tim J
TJ
Müller-Schmehl
Katrin
K
Krause
Anja
A
Fex
Malin
M
Puccio
Helene
H
Müller
Jörg
J
Isken
Frank
F
Spranger
Joachim
J
Müller-Wieland
Dirk
D
Magnuson
Mark A
MA
Möhlig
Matthias
M
Koenig
Michel
M
Pfeiffer
Andreas F H
AF
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D018076:DNA, Complementary / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D005091:Exons; D005838:Genotype; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism*; D008280:Magnetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D017382:Reactive Oxygen Species; D013997:Time Factors; D014018:Tissue Distribution; D000096923:Frataxin
D018076:DNA, Complementary; D007328:Insulin; D033862:Iron-Binding Proteins; D017382:Reactive Oxygen Species; D000096923:Frataxin