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Reduced expression of the co-regulator TLE1 in type 2 diabetes is associated with increased islet α-cell number

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

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2020.

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Abstract

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.


Publication metadata

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

Journal: Endocrinology

Year: 2020

Volume: 161

Issue: 4

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

URL: https://doi.org/10.1210/endocr/bqaa011

DOI: 10.1210/endocr/bqaa011


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