Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes

Jenny E. Gunton, Rohit N. Kulkarni, SunHee Yim, Terumasa Okada, Wayne J. Hawthorne, Yu Hua Tseng, Russell S. Roberson, Camillo Ricordi, Philip J. O'Connell, Frank J. Gonzalez, C. Ronald Kahn

Research output: Contribution to journalArticle

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Abstract

β cell dysfunction is a central component of the pathogenesis of type 2 diabetes. Using oligonucleotide microarrays and real-time PCR of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls, we identified multiple changes in expression of genes known to be important in β cell function, including major decreases in expression of HNF4α, insulin receptor, IRS2, Akt2, and several glucose-metabolic-pathway genes. There was also a 90% decrease in expression of the transcription factor ARNT. Reducing ARNT levels in Min6 cells with small interfering RNA (siRNA) resulted in markedly impaired glucose-stimulated insulin release and changes in gene expression similar to those in human type 2 islets. Likewise, β cell-specific ARNT knockout mice exhibited abnormal glucose tolerance, impaired insulin secretion, and changes in islet gene expression that mimicked those in human diabetic islets. Together, these data suggest an important role for decreased ARNT and altered gene expression in the impaired islet function of human type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)337-349
Number of pages13
JournalCell
Volume122
Issue number3
DOIs
StatePublished - Aug 12 2005

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Medical problems
Islets of Langerhans
Gene expression
Type 2 Diabetes Mellitus
Gene Expression
Glucose
Genes
Insulin
Glucose Intolerance
Insulin Receptor
Microarrays
Metabolic Networks and Pathways
Oligonucleotide Array Sequence Analysis
Knockout Mice
Oligonucleotides
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Transcription Factors

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Gunton, J. E., Kulkarni, R. N., Yim, S., Okada, T., Hawthorne, W. J., Tseng, Y. H., ... Kahn, C. R. (2005). Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell, 122(3), 337-349. https://doi.org/10.1016/j.cell.2005.05.027

Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. / Gunton, Jenny E.; Kulkarni, Rohit N.; Yim, SunHee; Okada, Terumasa; Hawthorne, Wayne J.; Tseng, Yu Hua; Roberson, Russell S.; Ricordi, Camillo; O'Connell, Philip J.; Gonzalez, Frank J.; Kahn, C. Ronald.

In: Cell, Vol. 122, No. 3, 12.08.2005, p. 337-349.

Research output: Contribution to journalArticle

Gunton, JE, Kulkarni, RN, Yim, S, Okada, T, Hawthorne, WJ, Tseng, YH, Roberson, RS, Ricordi, C, O'Connell, PJ, Gonzalez, FJ & Kahn, CR 2005, 'Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes', Cell, vol. 122, no. 3, pp. 337-349. https://doi.org/10.1016/j.cell.2005.05.027
Gunton, Jenny E. ; Kulkarni, Rohit N. ; Yim, SunHee ; Okada, Terumasa ; Hawthorne, Wayne J. ; Tseng, Yu Hua ; Roberson, Russell S. ; Ricordi, Camillo ; O'Connell, Philip J. ; Gonzalez, Frank J. ; Kahn, C. Ronald. / Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. In: Cell. 2005 ; Vol. 122, No. 3. pp. 337-349.
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