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. 2007 Oct 26;362(3):658-64.
doi: 10.1016/j.bbrc.2007.08.023. Epub 2007 Aug 15.

Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII

Yanyan Li  1 , Peili Wang, Jianchao Xu, Fred Gorelick, Hanae Yamazaki, Norma Andrews, Gary V Desir
Affiliations

Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII

Yanyan Li et al. Biochem Biophys Res Commun. .

Abstract

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.

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Figures

Fig. 1
Fig. 1
Decreased insulin secretion in Syt VII−/− mice. (A) Abnormal glucose tolerance test in Syt VII−/−: WT (wild-type littermate, n = 4) compared to KO (Syt VII−/−, n = 4). Blood glucose measured at indicated times following intraperitoneal injection of glucose (2 g/kg body weight). Stars indicate p values less than 0.05. (B) Decreased glucose-stimulated insulin secretion in vivo in Syt VII−/−: WT (wild-type littermate, n = 4) compared to KO (Syt VII−/−, n = 4). Animals were subjected to a 4 h fast and plasma insulin measured at before and 30 min following intraperitoneal injection of glucose (2 g/ kg body weight). A star indicates a p value less than 0.05. (C) Insulin secretory responses of islets isolated from wild-type and Syt VII knockouts: Groups of 14–18 islets were isolated from wild type (closed circles) or Syt VII knockout mice and perifused for 30 min with 3 mM glucose (G3) to establish stable, basal rates of insulin release. They were then perifused for 30 min with 20 mM glucose (G20), onset indicated by the first vertical line. Mean values ± SEMs of at least six perifusions are shown. This figure has not been corrected for the dead space in the perifusion apparatus, 2.5 ml or approximately 2.5 min with a flow rate of 1 ml/min. A star indicates a p value less than 0.05.
Fig. 2
Fig. 2
Insulin resistance in Syt VII−/− adipocytes. (A) Insulin tolerance test: WT (wild-type littermate, n = 4) compared to KO (Syt VII−/−, n = 4). Blood glucose measured at indicated times following intraperitoneal injection of insulin (2.55 μg/kg body weight). (B) Insulin-stimulated glucose uptake in skeletal muscle: skeletal muscle isolated from WT (wild-type littermate, n = 4) compared to KO (Syt VII−/−, n = 4). WORT is wortmanin (100 nM). (C) Insulin-stimulated glucose uptake in adipocytes: Adipose tissue isolated from WT (wild-type littermate, n = 4) compared to KO (Syt VII−/−, n = 4). WORT is wortmanin (100 nM). A star indicates a p value less than 0.05.
Fig. 3
Fig. 3
Dysregulated GLUT4 traffic in Syt VII−/− mice. (A) GLUT4 traffic in WT and Syt VII−/− fat cells: GLUT4 distribution examined by confocal microscopy in adipocytes, isolated from wild-type littermate (WT, n = 3) and Syt VII−/−, (KO, n = 3), and maintained in primary culture. PBS is phosphate buffered saline. Insulin dose is 100 nM. Representative experiment shown. (B) Total GLUT4 content unaltered by Syt VII deletion: Unfractionated adipocyte proteins separated by SDS gel electrophoresis and total GLUT4 content measured by Western blotting. WT is wild-type littermate, and KO is Syt VII−/−. Representative experiment shown.
Fig. 4
Fig. 4
Colocalization of GLUT4, Syt VII, and Kv1.3. Unstimulated adipocytes isolated from wild-type mice, maintained in primary culture, and examined by confocal microscopy. Colocalization of (A) GLUT4 and Syt VII, (B) Kv1.3 and GLUT4, (C) Kv1.3 and Syt VII.
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