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-dep...

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Veröffentlicht in:Biochemical and biophysical research communications 2007-10, Vol.362 (3), p.658-664
Hauptverfasser: Li, Yanyan, Wang, Peili, Xu, Jianchao, Gorelick, Fred, Yamazaki, Hanae, Andrews, Norma, Desir, Gary V.
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container_issue 3
container_start_page 658
container_title Biochemical and biophysical research communications
container_volume 362
creator Li, Yanyan
Wang, Peili
Xu, Jianchao
Gorelick, Fred
Yamazaki, Hanae
Andrews, Norma
Desir, Gary V.
description 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 β 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.
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subjects Adipose Tissue - metabolism
Animals
Calcium - metabolism
Crosses, Genetic
Diabetes
Gene Expression Regulation
Glucose
Glucose Tolerance Test
Glucose Transporter Type 4 - metabolism
Insulin
Insulin - metabolism
Insulin resistance
Insulin Secretion
Islets of Langerhans - metabolism
Male
Mice
Mice, Inbred C57BL
Models, Biological
Muscle, Skeletal - metabolism
Synaptotagmins - metabolism
title Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII
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