Pancreas-specific Pten deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling.
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 GSK3beta 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.
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China.
Zan
Z
Tong
Yan
Y
Fan
Weiqi
W
Zhang
Jun
J
Xu
Jing
J
Cheng
Mingxiao
M
Ding
Hongkui
H
Deng
D000818:Animals; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006360:Heat-Shock Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D010179:Pancreas / Q000201:enzymology*; D010766:Phosphorylation; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D004041:Dietary Fats; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007328:Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse