DOI: 10.1073/pnas.062605899. Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1 , Hnf-1 α, and Hnf-3 β

Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1 , Hnf-1 α, and Hnf-3 β

10.1073/pnas.062605899

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

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.

Bibliography

Shih, D. Q., Heimesaat, M., Kuwajima, S., Stein, R., Wright, C. V. E., & Stoffel, M. (2002). Profound defects in pancreatic Î²-cell function in mice with combined heterozygous mutations in Pdx-1 , Hnf-1 Î±, and Hnf-3 Î². Proceedings of the National Academy of Sciences, 99(6), 3818â3823.

Authors 6

David Q. Shih (first)
Markus Heimesaat (additional)
Satoru Kuwajima (additional)
Roland Stein (additional)
Christopher V. E. Wright (additional)
Markus Stoffel (additional)

References 27 Referenced 81

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:37 a.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 3:07 p.m.)
Indexed	5 months ago (April 3, 2025, 9:43 a.m.)
Issued	23 years, 5 months ago (March 19, 2002)
Published	23 years, 5 months ago (March 19, 2002)
Published Online	23 years, 5 months ago (March 19, 2002)
Published Print	23 years, 5 months ago (March 19, 2002)

Funders 0

None

BibTeX

@article{Shih_2002, title={Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1 , Hnf-1 α, and Hnf-3 β}, volume={99}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.062605899}, DOI={10.1073/pnas.062605899}, number={6}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Shih, David Q. and Heimesaat, Markus and Kuwajima, Satoru and Stein, Roland and Wright, Christopher V. E. and Stoffel, Markus}, year={2002}, month=mar, pages={3818–3823} }

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To investigate the possible functional relationships between these transcription factors on \u03b2-cell activity\n            <jats:italic>in vivo</jats:italic>\n            , we generated mice with the following combined heterozygous mutations:\n            <jats:italic>Pdx-1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            /\n            <jats:italic>Hnf-1\u03b1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            ,\n            <jats:italic>Pdx-1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            /\n            <jats:italic>Hnf-3\u03b2</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            ,\n            <jats:italic>Pdx-1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            /\n            <jats:italic>Hnf-4\u03b1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            ,\n            <jats:italic>Hnf-1\u03b1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            /\n            <jats:italic>Hnf-4\u03b1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            , and\n            <jats:italic>Hnf-3\u03b2</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            /\n            <jats:italic>Hnf-4\u03b1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            . The greatest loss in function was in combined heterozygous null alleles of\n            <jats:italic>Pdx-1</jats:italic>\n            and\n            <jats:italic>Hnf-1\u03b1</jats:italic>\n            (\n            <jats:italic>Pdx-1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            /\n            <jats:italic>Hnf-1\u03b1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            ), or\n            <jats:italic>Pdx-1</jats:italic>\n            and\n            <jats:italic>Hnf-3\u03b2</jats:italic>\n            (\n            <jats:italic>Pdx-1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            /\n            <jats:italic>Hnf-3\u03b2</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            ). 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\n            <jats:italic>Pdx-1</jats:italic>\n            <jats:sup>+/\u2212</jats:sup>\n            mice alone. 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