Role of calcium in insulin dependent glucose uptake in cell
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Biochemical and biophysical research communications
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Regulation of insulin secretion and GLUT4 tra3cking by the calcium sensor synaptotagmin VII ☆
Yanyan Li, Peili Wang, [...], and Gary V. Desir
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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 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.
Keywords: Insulin, Glucose, Diabetes, Insulin resistance
Intracellular calcium plays a key role in glucose metabolism with respect to insulin secretion and glucose uptake. Insulin is the most important hormone for regulation of peripheral glucose metabolism. It is released into the circulation by pancreatic β cells in response to changes in blood glucose. The mechanism of release is well understood and initiated by glucose entry into the β cell through the glucose transporter GLUT2 [1]. Intracellular glucose is phosphorylated by the enzyme glucokinase and subsequently metabolized to generate ATP. The subsequent increase in ATP:ADP ratio inhibits the ATP-gated potassium channel (KATP), resulting in membrane depolarization, activation of voltage-gated calcium (Cav) channels, and in increased intracellular calcium [Ca]i. The rise in [Ca]i then stimulates the exocytosis of insulin containing vesicles.
Once in circulation, insulin binds to membrane receptors in liver to decrease glucose production, and in fat and skeletal muscle to increase glucose uptake. The transport of glucose into these cells is mediated by GLUT4. The transporter is stored in intracellular vesicles that are translocated to the plasma membrane after insulin-receptor activation. Insulin may also activate GLUT4 that is present on the cell surface [2]. While the molecular details are complex and some aspects are still poorly understood, it appears that [Ca]i plays an important role in the final step of vesicle fusion with the plasma membrane [3].
Members of the synaptotagmin family of membrane proteins emerged recently as strong candidates for Ca2+ sensors during exocytosis [4–8]. Synaptotagmins have long cytoplasmic regions containing two C2 domains, homologous to the regulatory C2-region of protein kinase C (PKC). Similar to what has been shown for PKC, synaptotagmin C2 domains mediate Ca2+ and phosphatidylserine (PS) binding activity, and are thought to promote exocytosis by facilitating the formation of SNARE complexes [9]. The brain-specific isoform Syt I is localized on neuronal synaptic vesicles, and extensive genetic and biochemical evidence indicates that it functions as a Ca2+ sensor for fast, synchronous neurotransmitter release [10–12]. The ubiquitous isoform Syt VII is localized on lysosomes of many cell types, and also on non-synaptic secretory granules of PC12 and pancreatic β cells, where it regulates Ca2+-triggered exocytosis [4–8,13]. Recent in vitro reconstitution experiments have directly demonstrated that both Syt I and Syt VII, in the absence of any other proteins, can confer Ca2+ sensitivity to SNARE-mediated membrane fusion [14,15].
The detection of Syt VII on pancreatic β cell granules, where it appears to regulate insulin secretion [5,13], prompted us to explore the role of Syt VII in glucose homeostasis in Syt VII−/− mice [16]. We find that Syt VII−/− mice are glucose intolerant, due to abnormalities not only in insulin secretion, but also in GLUT4 traffic.
Author Manuscript
HHS Public Access
Regulation of insulin secretion and GLUT4 tra3cking by the calcium sensor synaptotagmin VII ☆
Yanyan Li, Peili Wang, [...], and Gary V. Desir
Additional article information
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 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.
Keywords: Insulin, Glucose, Diabetes, Insulin resistance
Intracellular calcium plays a key role in glucose metabolism with respect to insulin secretion and glucose uptake. Insulin is the most important hormone for regulation of peripheral glucose metabolism. It is released into the circulation by pancreatic β cells in response to changes in blood glucose. The mechanism of release is well understood and initiated by glucose entry into the β cell through the glucose transporter GLUT2 [1]. Intracellular glucose is phosphorylated by the enzyme glucokinase and subsequently metabolized to generate ATP. The subsequent increase in ATP:ADP ratio inhibits the ATP-gated potassium channel (KATP), resulting in membrane depolarization, activation of voltage-gated calcium (Cav) channels, and in increased intracellular calcium [Ca]i. The rise in [Ca]i then stimulates the exocytosis of insulin containing vesicles.
Once in circulation, insulin binds to membrane receptors in liver to decrease glucose production, and in fat and skeletal muscle to increase glucose uptake. The transport of glucose into these cells is mediated by GLUT4. The transporter is stored in intracellular vesicles that are translocated to the plasma membrane after insulin-receptor activation. Insulin may also activate GLUT4 that is present on the cell surface [2]. While the molecular details are complex and some aspects are still poorly understood, it appears that [Ca]i plays an important role in the final step of vesicle fusion with the plasma membrane [3].
Members of the synaptotagmin family of membrane proteins emerged recently as strong candidates for Ca2+ sensors during exocytosis [4–8]. Synaptotagmins have long cytoplasmic regions containing two C2 domains, homologous to the regulatory C2-region of protein kinase C (PKC). Similar to what has been shown for PKC, synaptotagmin C2 domains mediate Ca2+ and phosphatidylserine (PS) binding activity, and are thought to promote exocytosis by facilitating the formation of SNARE complexes [9]. The brain-specific isoform Syt I is localized on neuronal synaptic vesicles, and extensive genetic and biochemical evidence indicates that it functions as a Ca2+ sensor for fast, synchronous neurotransmitter release [10–12]. The ubiquitous isoform Syt VII is localized on lysosomes of many cell types, and also on non-synaptic secretory granules of PC12 and pancreatic β cells, where it regulates Ca2+-triggered exocytosis [4–8,13]. Recent in vitro reconstitution experiments have directly demonstrated that both Syt I and Syt VII, in the absence of any other proteins, can confer Ca2+ sensitivity to SNARE-mediated membrane fusion [14,15].
The detection of Syt VII on pancreatic β cell granules, where it appears to regulate insulin secretion [5,13], prompted us to explore the role of Syt VII in glucose homeostasis in Syt VII−/− mice [16]. We find that Syt VII−/− mice are glucose intolerant, due to abnormalities not only in insulin secretion, but also in GLUT4 traffic.
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