Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII.
Insulin regulates blood glucose by promoting uptake by fat and muscle, and inhibiting production by liver. Insulin-stimulated glucose uptake is mediated by GLUT4, which translocates from an intracellular compartment to the plasma membrane. GLUT4 traffic and insulin secretion both rely on calcium-dependent, regulated exocytosis. Deletion of the voltage-gated potassium channel Kv1.3 results in constitutive expression of GLUT4 at the plasma membrane. Inhibition of channel activity stimulated GLUT4 translocation through a calcium dependent mechanism. The synaptotagmins (Syt) are calcium sensors for vesicular traffic, and Syt VII mediates lysosomal and secretory granule exocytosis. We asked if Syt VII regulates insulin secretion by pancreatic beta cells, and GLUT4 translocation in insulin-sensitive tissues mouse model. Syt VII deletion (Syt VII -/-) results in glucose intolerance and a marked decrease in glucose-stimulated insulin secretion in vivo. Pancreatic islet cells isolated from Syt VII -/- cells secreted significantly less insulin than islets of littermate controls. Syt VII deletion disrupted GLUT4 traffic as evidenced by constitutive expression of GLUT4 present at the plasma membrane of fat and skeletal muscle cells and unresponsiveness to insulin. These data document a key role for Syt VII in peripheral glucose homeostasis through its action on both insulin secretion and GLUT4 traffic.
Li
Yanyan
Y
Section of Nephrology, Department of Medicine, Yale University School of Medicine, 333 Cedar Street, LMP 2073, P.O. Box 208029, New Haven, CT 06520-8029, USA.
Wang
Peili
P
Xu
Jianchao
J
Gorelick
Fred
F
Yamazaki
Hanae
H
Andrews
Norma
N
Desir
Gary V
GV
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D050857:Synaptotagmins / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; C495692:SLC2A4 protein, human; D050857:Synaptotagmins; D002118:Calcium