In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 6 ( 2002-03-19), p. 3818-3823
Kurzfassung:
Defects in pancreatic β-cell function contribute to the development of type 2 diabetes, a polygenic disease that is characterized by insulin resistance and compromised insulin secretion. Hepatocyte nuclear factors (HNFs) -1α, -3β, -4α, and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in β-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1 α +/− , Hnf-3 β +/− , or Hnf-4 α +/− , causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on β-cell activity in vivo , we generated mice with the following combined heterozygous mutations: Pdx-1 +/− / Hnf-1α +/− , Pdx-1 +/− / Hnf-3β +/− , Pdx-1 +/− / Hnf-4α +/− , Hnf-1α +/− / Hnf-4α +/− , and Hnf-3β +/− / Hnf-4α +/− . The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1α ( Pdx-1 +/− / Hnf-1α +/− ), or Pdx-1 and Hnf-3β ( Pdx-1 +/− / Hnf-3β +/− ). Both double mutants develop progressively impaired glucose tolerance and acquire a compromised first- and second-phase insulin secretion profile in response to glucose compared with Pdx-1 +/− mice alone. The loss in β-cell function in Pdx-1 +/− / Hnf-3β +/− mice was associated with decreased expression of Nkx-6.1, glucokinase (Gck), aldolase B ( aldo-B ), and insulin, whereas Nkx2.2, Nkx-6.1, Glut-2, Gck, aldo-B, the liver isoform of pyruvate kinase, and insulin expression was reduced in Pdx-1 +/− / Hnf-1α +/− mice. The islet cell architecture was also abnormal in Pdx-1 +/− / Hnf-3β +/− and Pdx-1 +/− / Hnf-1α +/− mice, with glucagon-expressing cells scattered throughout the islet, a defect that may be connected to decreased E-cadherin expression. Our data suggest that functional interactions between key islet regulatory factors play an important role in maintaining islet architecture and β-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to β-cell dysfunction in diabetes.
Materialart:
Online-Ressource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.062605899
Sprache:
Englisch
Verlag:
Proceedings of the National Academy of Sciences
Publikationsdatum:
2002
ZDB Id:
209104-5
ZDB Id:
1461794-8
SSG:
11
SSG:
12
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