In humans and rodents the development of the endocrine pancreas is under the control of tightly regulated, cross-interacting transcription factors. Two of them, paired box gene-4 (PAX4) and aristaless-related homeobox gene (ARX), play a central role in the allocation of endocrine progenitors towards β-cell and α-cell specification, respectively. Of note, in adulthood in both species, the expression of PAX4 has been shown to contribute to reprogramming of exocrine cells and α-cells into insulin-producing β-cells; induction of ARX expression in β-cells leads them to reprogramming into α-cells. We recently discovered that diabetic cats have an increased number of cells in the exocrine pancreas that stain positive for a marker of proliferation (proliferating cell nuclear antigen; PCNA), in particular nearby islets. Because proliferation increases reprogramming efficiency in rodents, we hypothesized that these cells may anticipate reprogramming in cats. Aim of the study was to test if diabetic cats have an increased number of cells in the endocrine and exocrine pancreas expressing developmental markers of β- and α-cells, suggesting reprogramming.
In 9 diabetic and 9 well-matched control cats, the pancreas was collected within 1 hour from death, formalin-fixed and paraffin-embedded for immunohistochemistry. Tissue sections were stained for insulin, glucagon, PAX4 and ARX. The number of cells positive for each marker and double-positive for any of their combination were counted in 5 images at 400x magnification in the exocrine pancreas and islets. Results were compared between groups with non-parametric tests.
As expected, compared to controls diabetic cats had less insulin-positive cells in the islets (median: 14.8, range: 2.4-51 vs. median: 64, range: 33.4-71.4; p=0.001) and scattered in the exocrine pancreas (median: 5, range: 1.8-14.6 vs. median: 10, range: 4.4-19; p=0.038); the number of glucagon-positive cells did not differ. Diabetic cats had more insulin/glucagon double-positive cells in the islets than controls (median: 0.2, range: 0-11 vs. median: 0, range: 0-0.4; p=0.024). In the islets, diabetic cats had more PAX4-positive cells (median: 9.6, range: 0-29.6 vs. median: 2.2, range: 0.2-6.4; p=0.038) and more PAX4/insulin double-positive cells (median: 4.4, range: 0-12 vs. median: 0.2, range: 0-1; p=0.027). The percentage of PAX4/insulin double-positive relative to the number of insulin-positive cells was 50-fold higher in diabetic cats (p=0.019); 7 of 9 cats had >5% of cells double-positive while none of the controls (78 vs. 0%, p=0.002). Diabetic cats had more ARX/glucagon double-positive cells in the exocrine pancreas than controls (median: 0, range: 0-0.8 vs. median: 0, range: 0-0; p=0.029). None of the markers or their combination differed between groups in the exocrine pancreas.
In the islets of diabetic cats, the decreased number of insulin-positive cells along with the increased number of PAX4-positive and PAX4/insulin double-positive cells suggest that some β-cells may change to an earlier stage of differentiation or that new β-cells are formed. The increased number of islet cells double-positive for insulin and glucagon in diabetic cats may indicate that α-cells are transforming into β-cells or vice versa, however the absolute number of these cells was very low. Collectively, these data suggest that histological evidence for reprogramming of cells is present in diabetic cats and that this event occurs in the islets and not in the exocrine pancreas. The reason behind the increased number of ARX/glucagon double-positive cells in the exocrine pancreas of diabetic cats is unclear.
Utrecht University & University of Zurich
Lune Dagmar Geurts BSc Short Resume
Address: Salamancapad 25, 3584 DX Utrecht, The Netherlands
Phone: +31 6 48 5432 91
January 2017 - now
o Master of Clinical Sciences of Companion Animals
January 2017 – May 2017
o Master - Research Project
University of Zurich & Utrecht University
o BSc – Bachelor of Veterinary Medicine
September 2013 – December 2016
o Bachelor of Veterinary Medicine
September 2012 – August 2013
o Bachelor of Veterinary Medicine
University of Antwerp
o VWO-diploma (Pre-university education)
A-level/Profile: Nature & health (Natuur & Gezondheid)
• Dutch: Native Language
• English: Fluent
• French: Basic
• German: Basic
• Spanish: Basic
September 2016 – September 2017
o Faculty Council – Student Body (vice-president)
October 2015 – October 2017
o Board Member – Veterinary Sub-society of Veritas Student Association (Veterinair Dispuut Veritas, VDV)
September 2015 – September 2016
o Cohort Education Monitoring – Student Body Member
Thursday, June 14
10:45 AM – 11:00 AM
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