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    • br Transportation from TGN toward plasma membrane

    2022-09-07


    Transportation from TGN toward plasma membrane The insulin molecules are packaged along with other molecules such as C-peptides, amylin, Zn2+, ATP and GABA in synaptic-like macrovesicles (SLMVs, with the diameters of 50–100 nm) and large dense core vesicles (LDCVs, with the diameters of 200–500 nm) at TGN side (Fig. 7). The physiological role of SLMVs is not clear yet. The SLMVs may be utilized for ultrafast secretion of neurotransmitters such as glutamate, GABA and ATP or indirectly regulate the exocytosis of LDCVs (Kasai et al., 2014; Weiss et al., 2014). The secretory vesicles should deliver their cargo to plasma membrane along extensive networks of microtubules radiating from the perinuclear region of the β cell to the plasma membrane (Fig. 2). In vivo inactivation of kinesin-1 in pancreatic β-cells leads to insulin secretory deficiency (Cui et al., 2011). Accordingly, a proportion of insulin granules attach along the microtubules in the β-cells in vitro. Regarding to aforementioned findings and various similar observations such as axonal transport of the motor protein, the active movement of insulin containing granules may be achieved by kinesin-1 walking toward the positive end of a microtubule, hydrolysing ATP molecules as a power supply (Cui et al., 2011; Rutter and Hill, 2006) (Fig. 2). However, the majority of insulin containing granules remain in the standby state in cytoplasm, awaiting for the secretion-inducing signals. Approximately 9000–13,000 dense-core secretory vesicles are present in each rodent (mouse/rat) β-cells. Among them around 7% are docking at the plasma membrane, while 20% are localized within ~300 nm on the cell surface (Rutter and Hill, 2006).
    Induction of insulin release Following an elevation in concentration of blood glucose, glucose enters to the Ezetimibe of β cells, through class-I of facilitative glucose transporters (Gluts, family 2A of the solute carriers/SLC2A) in a passive transportation mode that facilitates glucose diffusion without need of energy input (Komatsu et al., 2013). Glut2 is the predominant glucose transporter in rodents, however the other three main types of glucose transporters (Glut1, 3 and 4) are also facilitate glucose influx in human β cells. Among them, the role of Glut1 is more notable in human (De Vos et al., 1995; van de Bunt and Gloyn, 2012; McCulloch et al., 2011). On the contrary with the mouse islets, a recent study suggests that GLUT1 and GLUT3 are predominantly transcribed in both human islets and β cells with more than two fold of expression than GLUT2 (Bae et al., 2010). In contrast to Glut4, the function of Glut1, 2 and 3 is insulin independent. The capacity of Glut2 for glucose transportation is high, while its affinity for glucose is remarkably low (with high Km value around 15–20 mM) to make sure that the glucose inflow is proportional to the extracellular glucose level (De Vos et al., 1995). Therefore, the role of Glut2 is more prominent in the postprandial state or elevation of glucose level in the blood stream or the environment of liver or islet cells. Contrarily, the affinity of Glut1 and Glut3 for glucose is higher (with lower Km value around 1 mM), which afford them an ability to maintain basal glucose uptake (less than 100 g/dl blood glucose) (De Vos et al., 1995). Immediately after entering to the cytosol, glucose is phosphorylated to produce glucose 6-phosphate (G6P) (Schuit et al., 1999) by two types of hexokinase isoenzymes, including glucokinase (GK) in the β-cells and hexokinases I-III (HK) in the other tissues, through hydrolyzing one ATP molecule per reaction. In contrast to hexokinase, glucokinase is prone to inhibition in a feedback negative reaction mode, to make sure that intracellular level of G6p is proportional to the extracellular level of glucose (Kasai et al., 2014; Komatsu et al., 2013; Xiong et al., 2017). In addition, glucokinase-mediated phosphorylation of glucose is an irreversible chemical reaction, trapping of G6p inside the cell (Fig. 4) (Komatsu et al., 2013; Weiss et al., 2014). The specific features of GK and Glut2 (in mice) make them specific cellular sensors for glucose (Schuit et al., 1999; Xiong et al., 2017). Nevertheless, the role of Glut2 in human islets is still vigorously debated and controversial (van de Bunt and Gloyn, 2012; Schuit et al., 1999).