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Diabetologia. 2012 Jun;55(6):1783-96. doi: 10.1007/s00125-012-2506-4. Epub 2012 Mar 3.

Carbohydrate response element-binding protein (ChREBP) plays a pivotal role in beta cell glucotoxicity.

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1
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, R614, Houston, TX 77030, USA.

Abstract

AIMS/HYPOTHESIS:

This study was aimed at the elucidation of the pathogenesis of glucotoxicity, i.e. the mechanism whereby hyperglycaemia damages pancreatic beta cells. The identification of pathways in the process may help identify targets for beta cell-protective therapy. Carbohydrate response element-binding protein (ChREBP), a transcription factor that regulates the expression of multiple hyperglycaemia-induced genes, is produced in abundance in pancreatic beta cells. We hypothesise that ChREBP plays a pivotal role in mediating beta cell glucotoxicity.

METHODS:

We assessed the role of ChREBP in glucotoxicity in 832/13 beta cells, isolated mouse islets and human pancreas tissue sections using multiple complementary approaches under control and high-glucose-challenge conditions as well as in adeno-associated virus-induced beta cell-specific overexpression of Chrebp (also known as Mlxipl) in mice.

RESULTS:

Under both in vitro and in vivo conditions, ChREBP activates downstream target genes, including fatty acid synthase and thioredoxin-interacting protein, leading to lipid accumulation, increased oxidative stress, reduced insulin gene transcription/secretion and enhanced caspase activity and apoptosis, processes that collectively define glucotoxicity. Immunoreactive ChREBP is enriched in the nucleuses of beta cells in pancreatic tissue sections from diabetic individuals compared with non-diabetic individuals. Finally, we demonstrate that induced beta cell-specific Chrebp overexpression is sufficient to phenocopy the glucotoxicity manifestations of hyperglycaemia in mice in vivo.

CONCLUSIONS/INTERPRETATION:

These data indicate that ChREBP is a key transcription factor that mediates many of the hyperglycaemia-induced activations in a gene expression programme that underlies beta cell glucotoxicity at the molecular, cellular and whole animal levels.

PMID:
22382520
PMCID:
PMC4010252
DOI:
10.1007/s00125-012-2506-4
[Indexed for MEDLINE]
Free PMC Article
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