Journal article
Carbohydrate response element-binding protein (ChREBP) plays a pivotal role in beta cell glucotoxicity
Diabetologia, Vol.55(6), pp.1783-1796
06/01/2012
DOI: 10.1007/s00125-012-2506-4
PMCID: PMC4010252
PMID: 22382520
Abstract
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.
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 (also known as ) in mice.
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 overexpression is sufficient to phenocopy the glucotoxicity manifestations of hyperglycaemia in mice in vivo.
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.
Details
- Title: Subtitle
- Carbohydrate response element-binding protein (ChREBP) plays a pivotal role in beta cell glucotoxicity
- Creators
- N. Poungvarin - Baylor College of MedicineJ. K. Lee - Baylor College of MedicineV. K. Yechoor - Baylor College of MedicineM. V. Li - Baylor College of MedicineT. Assavapokee - Baylor College of MedicineP. Suksaranjit - Baylor College of MedicineJ. J. Thepsongwajja - Baylor College of MedicineP. K. Saha - Baylor College of MedicineK. Oka - Baylor College of MedicineL. Chan - Baylor College of Medicine
- Resource Type
- Journal article
- Publication Details
- Diabetologia, Vol.55(6), pp.1783-1796
- Publisher
- Springer Nature
- DOI
- 10.1007/s00125-012-2506-4
- PMID
- 22382520
- PMCID
- PMC4010252
- ISSN
- 0012-186X
- eISSN
- 1432-0428
- Number of pages
- 14
- Grant note
- Betty Rutherford Chair for Diabetes Research from St Luke's Episcopal Hospital T.T. & W.F. Chao Global Foundation HL R01-51586 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL051586 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) P30-DK079638 / Diabetes & Endocrinology Research Center at BCM P30DK079638 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 06/01/2012
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359689102771
Metrics
12 Record Views