Type 2 diabetes-induced neuronal pathology in the piriform cortex of the rat is reversed by the GLP-1 receptor agonist exendin-4
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Grazyna Lietzau1,3, Thomas Nyström1, Claes-Göran Östenson2, Vladimer Darsalia1 and Cesare Patrone1
1 Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden
2 Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden
3 Medical University of Gdansk, Department of Anatomy and Neurobiology, Gdansk, Poland
Grazyna Lietzau , email:
Vladimer Darsalia , email:
Cesare Patrone , email:
Keywords: diabetes, GLP-1R, Goto-Kakizaki rats, olfaction, piriform cortex
Received: October 28, 2015 Accepted: December 24, 2015 Published: January 05, 2016
Type 2 diabetes (T2D) patients often present olfactory dysfunction. However, the histopathological basis behind this has not been previously shown. Since the piriform cortex plays a crucial role in olfaction, we hypothesize that pathological changes in this brain area can occur in T2D patients along aging. Thus, we determined potential neuropathology in the piriform cortex of T2D rats, along aging. Furthermore, we determined the potential therapeutic role of the glucagon-like peptide-1 receptor (GLP1-R) agonist exendin-4 to counteract the identified T2D-induced neuropathology.
Young-adult and middle-aged T2D Goto-Kakizaki rats were compared to age-matched Wistars. Additional Goto-Kakizaki rats were treated for six weeks with exendin-4/vehicle before sacrifice. Potential T2D-induced neuropathology was assessed by quantifying NeuN-positive neurons and Calbindin-D28k-positive interneurons by immunohistochemistry and stereology methods. We also quantitatively measured Calbindin-D28k neuronal morphology and JNK phosphorylation-mediated cellular stress. PI3K/AKT signalling was assessed by immunohistochemistry, and potential apoptosis by TUNEL.
We show T2D-induced neuronal pathology in the piriform cortex along aging, characterized by atypical nuclear NeuN staining and increased JNK phosphorylation, without apoptosis. We also demonstrate the specific vulnerability of Calbindin-D28k interneurons. Finally, chronic treatment with exendin-4 substantially reversed the identified neuronal pathology in correlation with decreased JNK and increased AKT phosphorylation.
Our results reveal the histopathological basis to explain T2D olfactory dysfunction. We also show that the identified T2D-neuropathology can be counteracted by GLP-1R activation supporting recent research promoting the use of GLP-1R agonists against brain diseases. Whether the identified neuropathology could represent an early hallmark of cognitive decline in T2D remains to be determined.
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