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Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass
Michael Ristow, … , Michel Koenig, Andreas F.H. Pfeiffer
Michael Ristow, … , Michel Koenig, Andreas F.H. Pfeiffer
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):527-534. https://doi.org/10.1172/JCI18107.
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Article Metabolism

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

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Abstract

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing β cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic β 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 β 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 β cells. Hence, disruption of the frataxin gene in pancreatic β 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 β cell function observed in different subtypes of diabetes in humans.

Authors

Michael Ristow, Hindrik Mulder, Doreen Pomplun, Tim J. Schulz, Katrin Müller-Schmehl, Anja Krause, Malin Fex, Hélène Puccio, Jörg Müller, Frank Isken, Joachim Spranger, Dirk Müller-Wieland, Mark A. Magnuson, Matthias Möhlig, Michel Koenig, Andreas F.H. Pfeiffer

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Figure 4

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Increased levels of ROS, increased apoptosis, and decreased proliferatio...
Increased levels of ROS, increased apoptosis, and decreased proliferation precede reduction of β cell mass. (a) Readouts from ESR-based detection of superoxide in control islets (upper panel) and knockout islets (lower panel) from 6-week-old animals. Gray lines depict the raw signal with magnetic fields, and black lines depict the filtered signal. Circles indicate peaks and troughs used to determine the type of ROS, in this case specifically indicating the presence of superoxide. a.u., arbitrary units. (b) Fluorescence at 488 nm after loading of islets with H2DCF, showing higher levels of DCF, an oxidation product of H2DCF, in knockout islets in the presence of 11.1 mM glucose. Insets depict native islets. (c) Quantification of islet cells immunohistochemically positive for activated caspase-3, a marker of apoptosis, as well as Ki67 and BrdU, both markers for proliferation. Black bars, knockout animals; gray bars, control animals; error bars, SEM. **P < 0.005.

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