TY - JOUR
T1 - Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes
AU - Gunton, Jenny E.
AU - Kulkarni, Rohit N.
AU - Yim, SunHee
AU - Okada, Terumasa
AU - Hawthorne, Wayne J.
AU - Tseng, Yu Hua
AU - Roberson, Russell S.
AU - Ricordi, Camillo
AU - O'Connell, Philip J.
AU - Gonzalez, Frank J.
AU - Kahn, C. Ronald
N1 - Funding Information:
This work was supported by the Mary K. Iacocca Professorship and NIH grants RO1 DK33201 (C.R.K.), the Diabetes Genome Anatomy Project (DGAP) Grant DK60837-02, and the NCRR Islet Cell Resource (RR016603). J.E.G. was supported by a C.J. Martin fellowship from the National Health and Medical Research Council of Australia and the Royal Australasian College of Physicians Servier Award. R.N.K. was supported by NIH grants K08 DK02885 and R01 DK67536. We would like to thank Laureen Mazzola for managing the ARNT mouse colony; Scott Lannon for assistance with cRNA preparation; Jiang Hu for immunohistochemistry; Professor Gordon Weir, Mr. J. O’Neil, Mrs. A. Patel, Ms. S. Walters, and Ms. R. Stokes for assistance with preparation of pancreatic islets; and Dr. Andrew Dwyer for helpful comments on the manuscript.
PY - 2005/8/12
Y1 - 2005/8/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2005.05.027
DO - 10.1016/j.cell.2005.05.027
M3 - Article
C2 - 16096055
AN - SCOPUS:23744439083
SN - 0092-8674
VL - 122
SP - 337
EP - 349
JO - Cell
JF - Cell
IS - 3
ER -