PTP1B deficiency increases glucose uptake in neonatal hepatocytes: involvement of IRA/GLUT2 complexes.
The contribution of the liver to glucose utilization is essential to maintain glucose homeostasis. Previous data from protein tyrosine phosphatase (PTP) 1B-deficient mice demonstrated that the liver is a major site for PTP1B action in the periphery. In this study, we have investigated the consequences of PTP1B deficiency in glucose uptake in hepatocytes from neonatal and adult mice. The lack of PTP1B increased basal glucose uptake in hepatocytes from neonatal (3-5 days old) but not adult (10-12 wk old) mice. This occurs without changes in hexokinase, glucokinase, and glucose 6-phosphatase enzymatic activities. By contrast, the glucose transporter GLUT2 was upregulated at the protein level in neonatal hepatocytes and livers from PTP1B-deficient neonates. These results were accompanied by a significant increase in the net free intrahepatic glucose levels in the livers of PTP1B(-/-) neonates. The association between GLUT2 and insulin receptor (IR) A isoform was increased in PTP1B(-/-) neonatal hepatocytes compared with the wild-type. Indeed, PTP1B deficiency in neonatal hepatocytes shifted the ratio of isoforms A and B of the IR by increasing the amount of IRA and decreasing IRB. Moreover, overexpression of IRA in PTP1B(-/-) neonatal hepatocytes increased the amount of IRA/GLUT2 complexes. Conversely, hepatocytes from adult mice only expressed IRB. Since IRA plays a direct role in the regulation of glucose uptake in neonatal hepatocytes through its specific association with GLUT2, we propose the increase in IRA/GLUT2 complexes due to PTP1B deficiency as the molecular mechanism of the increased glucose uptake in the neonatal stage.
Instituto de Investigaciones Biomédicas Alberto Sols, C/ Arturo Pérez Duperier 4, 28029 Madrid, Spain.
Agueda
A
González-Rodriguez
Carmen
C
Nevado
Fernando
F
Escrivá
Giorgio
G
Sesti
Cristina M
CM
Rondinone
Manuel
M
Benito
Angela M
AM
Valverde
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D051273:Glucose Transporter Type 2 / Q000502:physiology*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism; D051379:Mice; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency*; D011972:Receptor, Insulin / Q000502:physiology*
D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; C495678:Slc2a1 protein, mouse; C495682:Slc2a2 protein, mouse; D006593:Hexokinase; D005941:Glucokinase; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D005952:Glucose-6-Phosphatase; D005947:Glucose