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Lookup NU author(s): Sarah Armour,
Dr Scott Anderson,
Dr Yuchun Ding,
Dr Christopher Carey,
Dr Rashmi Maheshwari,
Professor Natalio KrasnogorORCiD,
Professor James Shaw,
Dr Michael White
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2020.
For re-use rights please refer to the publisher's terms and conditions.
β-cell dysfunction in type 2 diabetes (T2D) is associated with loss of cellular identity and mis-expression of alternative islet hormones, including glucagon. The molecular basis for these cellular changes has been attributed to dysregulation of core β-cell transcription factors, which regulate β-cell identity through activating and repressive mechanisms. The TLE1 gene lies near a T2D susceptibility locus and, recently, the glucagon repressive actions of this transcriptional co-regulator have been demonstrated in vitro. We investigated whether TLE1 expression is disrupted in human T2D, and whether this is associated with increased islet glucagon-expressing cells. Automated image analysis following immunofluorescence in donors with (n=7) and without (n=7) T2D revealed that T2D was associated with higher islet α/β cell ratio (Control: 0.7±0.1 vs T2D: 1.6±0.4; P<0.05) and an increased frequency of bi-hormonal (insulin+/glucagon+) cells (Control: 0.8±0.2% vs T2D: 2.0±0.4%, p<0.05). In non-diabetic donors, the majority of TLE1-positive cells were mono-hormonal β-cells (insulin+/glucagon-: 98.2±0.5%; insulin+/glucagon+: 0.7±0.2%; insulin-/glucagon+: 1.1±0.4%; p<0.001). TLE1 expression was reduced in T2D (Control: 36±2.9% vs T2D: 24±2.6%; p<0.05). Reduced islet TLE1 expression was inversely correlated with α/β cell ratio (r=-0.55; p<0.05). TLE1 knockdown in EndoC-βH1 cells was associated with a 2.5-fold increase in glucagon gene mRNA and mis-expression of glucagon in insulin-positive cells. These data support TLE1 as a putative regulator of human β-cell identity, with dysregulated expression in T2D associated with increased glucagon expression potentially reflecting β- to- α-cell conversion.
Author(s): Armour SL, Anderson SJ, Richardson SJ, Ding Y, Carey C, Lyon J, Maheshwari RR, Al-Jahdami N, Krasnogor N, Morgan NG, MacDonald P, Shaw JAM, White MG
Publication type: Article
Publication status: Published
Print publication date: 01/04/2020
Online publication date: 17/02/2020
Acceptance date: 27/01/2020
Date deposited: 18/02/2020
ISSN (print): 0013-7227
ISSN (electronic): 1945-7170
Publisher: Oxford University Press
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