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Pdx1 restores β cell function in Irs2 knockout mice
Jake A. Kushner, … , Marc R. Montminy, Morris F. White
Jake A. Kushner, … , Marc R. Montminy, Morris F. White
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1193-1201. https://doi.org/10.1172/JCI14439.
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Categories: Article Endocrinology

Pdx1 restores β cell function in Irs2 knockout mice

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Abstract

The homeodomain transcription factor Pdx1 is required for pancreas development, including the differentiation and function of β cells. Mutations in Pdx1 or upstream hepatocyte nuclear factors cause autosomal forms of early-onset diabetes (maturity-onset diabetes of the young [MODY]). In mice, the Irs2 branch of the insulin/Igf signaling system mediates peripheral insulin action and pancreatic β cell growth and function. To investigate whether β cell failure in Irs2–/– mice might be related to dysfunction of MODY-related transcription factors, we measured the expression of Pdx1 in islets from young Irs2–/– mice. Before the onset of diabetes, Pdx1 was reduced in islets from Irs2–/– mice, whereas it was expressed normally in islets from wild-type or Irs1–/– mice, which do not develop diabetes. Whereas male Irs2–/–Pdx1+/+ mice developed diabetes between 8 and 10 weeks of age, haploinsufficiency for Pdx1 caused diabetes in newborn Irs2–/– mice. By contrast, transgenic expression of Pdx1 restored β cell mass and function in Irs2–/– mice and promoted glucose tolerance throughout life, as these mice survived for at least 20 months without diabetes. Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY.

Authors

Jake A. Kushner, Jing Ye, Markus Schubert, Deborah J. Burks, Matthew A. Dow, Carrie L. Flint, Sanjoy Dutta, Christopher V.E. Wright, Marc R. Montminy, Morris F. White

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Figure 2

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Characterization of progeny of Irs2+/–Pdx1+/– intercross. (a) Body weigh...
Characterization of progeny of Irs2+/–Pdx1+/– intercross. (a) Body weights of Irs2+/–Pdx1+/– intercross pups measured on P2.5. Results are reported as mean ± SEM of at least seven mice (except Irs2–/–Pdx1–/– mice, n = 3). **P < 0.01 compared with all other genotypes. (b) Blood glucose of Irs2+/–Pdx1+/– intercross pups measured on P2.5. Results are reported as mean ± SEM of at least seven mice, or three Irs2–/–Pdx1–/– mice. **P < 0.01 for Irs2–/–Pdx1+/– or Irs2–/–Pdx1–/– mice compared with all other genotypes. (c) Blood glucose values of wild-type, Irs2–/–, Pdx1+/–, and Irs2–/–Pdx1+/– mouse pups in the first 4 days of life. Results are reported as mean ± SEM of at least seven mice.
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