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Limitation of glucotoxicity-induced beta-cell dedifferentiation and alpha-cell transition following Nkx6.1 overexpression

Lookup NU author(s): Sarah Armour, Professor James Shaw, Dr Michael White

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Abstract

Aims and Objectives: Beta-cell dedifferentiation and alpha-cell reprogramming is becoming an increasingly recognized mechanism of beta-cell dysfunction and hyperglucagonemia in type 2 diabetes. Characterised by the loss of key transcription factors, beta- to alpha-cell conversion following dedifferentiation may result from loss of repression of the alpha-cell program. The beta-cell transcription factor, Nkx6.1, helps repress alpha-cell genes through recruitment of co-repressor proteins, includingtransducin-like enhancer of split 3 (Tle3). We sought to determine whether loss of Nkx6.1 is involved in glucotoxicity-induced beta-to alpha-cell conversion. Methods: Gene expression and functional studies (Glucose Stimulated Insulin Secretion (GSIS)) were undertaken in INS1E cells cultured for 48 hours in normal (11 mM) or high (25 mM) glucose. For overexpression studies, cells were preincubated with either B-gal or Nkx6.1 adenoviral vectors for 1 hour prior to normal / glucotoxic culture. Results: Following 48 hours’ glucotoxicity, beta-cell-associated genes (Ins1, Ins2, Nkx6.1, PDX-1 and Tle3) were significantly reduced compared to normoglycaemic culture. These changes were associated with reduced insulin storage (60% decrease vs 11mM culture) and beta-cell function (GSIS index (n=3±SEM): 1.9±SEM (25 mM) vs 4.3±SEMx.x (11mM); p<0.05). Glucagon gene expression and protein content was significantly increased. Viral over-expression of Nkx6.1 under glucotoxic conditions returned glucagon and Tle3 expression levels to that of normoglycaemic conditions. These changes were associated with improved insulin storage / beta-cell function. Conclusions: - Glucotoxicity drives beta-cell dedifferentiation, dysfunction and transition towardsds alpha-cell phenotype. -Restoration of Nkx6.1 expression limits glucotoxicity-induced beta- to alpha-cell conversion, potentially via recruitment of the glucagon repressor, Tle3.


Publication metadata

Author(s): Armour SL, Shaw JA, White MG

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: Diabetes UK Professional Conference

Year of Conference: 2016

Pages: 20-22

Online publication date: 01/03/2016

Acceptance date: 01/03/2016

ISSN: 0742-3071

Publisher: Wiley-Blackwell

URL: https://doi.org/10.1111/dme.8_13047

DOI: 10.1111/dme.8_13047

Series Title: Diabetic Medicine


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