Abstract
PTEN, a negative regulator of the phosphatidylinositol-3-kinase/AKT pathway, is an important modulator of insulin signaling. To determine the metabolic function of pancreatic Pten, we generated pancreas-specific Pten knockout (PPKO) mice. PPKO mice had enlarged pancreas and elevated proliferation of acinar cells. They also exhibited hypoglycemia, hypoinsulinemia, and altered amino metabolism. Notably, PPKO mice showed delayed onset of streptozotocin (STZ)-induced diabetes and sex-biased resistance to high-fat-diet (HFD)-induced diabetes. To investigate the mechanism for the resistance to HFD-induced hyperglycemia in PPKO mice, we evaluated AKT phosphorylation in major insulin-responsive tissues: the liver, muscle, and fat. We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver. The phosphorylation of AKT and its downstream substrate GSK3β was increased in the liver of PPKO mice, while PTEN level was decreased without detectable excision of Pten allele in the liver of PPKO mice. Proteomics analysis revealed dramatically decreased level of 78-kDa glucose-regulated protein (GRP78) in the liver of PPKO mice, which may also contribute to the lower blood glucose level of PPKO mice fed with HFD. Together, our findings reveal a novel response in the liver to pancreatic defect in metabolic regulation, adding a new dimension to understanding diabetes resistance.
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Abbreviations
- STZ:
-
(streptozotocin)
- HFD:
-
(high-fat diet)
- X-Gal:
-
(5-bromo-4-chloro-3-indolyl β-D-galactoside)
- ALT:
-
(alanine aminotransferase)
- AST:
-
(aspartate aminotransferase)
- BUN:
-
(blood urea nitrogen)
- 2D-PAGE:
-
(two-dimensional polyacrylamide gel electrophoresis)
- ER:
-
(endoplasmic reticulum)
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Acknowledgements
This research was supported by grants from the Ministry of Education (705001), National Basic Research Program of China (973 Program 2009CB941200), National Natural Science Foundation of China (30830061 and 30421004), and a 111 project to H Deng. We thank Dr Tak Wah Mak (University of Alberta, Canada) for kindly providing the Ptenflox/flox mice, Dr Guoqiang Gu (Vanderbilt University, USA) for kindly providing the plasmid of Pdx1-Cre, and Dr C Wright (Vanderbilt University, USA) for the PDX1 antibody. We thank the Model Animal Research Center of Nanjing University for B6; 129-Gt(ROSA)26Sortm1Sho/J mice and the Research Center for Proteome Analysis for proteomics analysis. We thank Dr Matt Stremlau, Dr Hui Zhang, Jun Cai, Han Qin, Jian Li, Yan Shi, Haisheng Zhou, and Fei Ye for their critical reading of the manuscript. We also thank Wei Jiang, Yushan Guo, Jie Yang, Chengyan Wang, Hui Zhang, and other colleagues in our laboratory for providing technical assistance and advice during the experiments.
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Supplementary information
Supplementary information, Figure S1
Increased pancreas weight and acinar cell proliferation in one month old PPKO mice. (PDF 2269 kb)
Supplementary information, Figure S2
Extensive ductar complexes in the pancreas of six month old PPKO mice. (PDF 2834 kb)
Supplementary information, Figure S3
Glucose and insulin tolerance tests of PPKO and control mice. (PDF 311 kb)
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Tong, Z., Fan, Y., Zhang, W. et al. Pancreas-specific Pten deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling. Cell Res 19, 710–719 (2009). https://doi.org/10.1038/cr.2009.42
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DOI: https://doi.org/10.1038/cr.2009.42
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