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Modeling of the gap junction of pancreatic β -cells and the robustness of insulin secretion

View Article: PubMed Central - PubMed

ABSTRACT

Pancreatic β-cells are interconnected by gap junctions, which allow small molecules to pass from cell to cell. In spite of the importance of the gap junctions in cellular communication, modeling studies have been limited by the complexity of the system. Here, we propose a mathematical gap junction model that properly takes into account biological functions, and apply this model to the study of the β-cell cluster. We consider both electrical and metabolic features of the system. Then, we find that when a fraction of the ATP-sensitive K+ channels are damaged, robust insulin secretion can only be achieved by gap junctions. Our finding is consistent with recent experiments conducted by Rocheleau et al. Our study also suggests that the free passage of potassium ions through gap junctions plays an important role in achieving metabolic synchronization between β-cells.

No MeSH data available.


Effect of ḡK(ATP) variation. Original ḡK(ATP) value is 40000 pS. Note that K value is slightly higher than 95 mM here.
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f15-6_37: Effect of ḡK(ATP) variation. Original ḡK(ATP) value is 40000 pS. Note that K value is slightly higher than 95 mM here.

Mentions: Recently, Rocheleau et al.22 conducted an interesting experiment by blocking the ATP-sensitive K+ channels and gap junctions. They used transgenic mice and showed that the robust control of the insulin secretion can be achieved by the gap junctions. Following their experiment, we conducted a numerical experiment in which Ge = 2 mM. To simulate their experiment, we reduced the conductance of the ATP-sensitive K+ channels by decreasing the value of ḡK(ATP) from the original value of 40000 pS to 10000 pS in a single β-cell. In this case, the insulin secretion is prompted as shown in Fig. 15. This corresponds to the case where the gap junction is disconnected (case in Fig. 6(c)). If the ATP-sensitive K+ channels are fully functional, no insulin secretion should be observed when Ge = 2 mM as shown in Fig. 13. However, when the gap junction is opened (case in Fig. 6(b)), insulin secretion ceases, as shown in Fig. 7(b). This robustness of the insulin secretion is consistent with the experiments of Rocheleau et al. To clarify the detailed mechanism of this robustness, we show the ATP-sensitive potassium current IK(ATP) and the gap currents IG(K) and IK(Ca) in Fig. 8. When the ATP-sensitive potassium channels of both cells are not blocked, the gap currents are negligibly small. However, when one of two cells is blocked, IG(K) and IK(ATP) of the normal cell are significantly increased (see Figs. 8(b), 8(c)). Figure 8(d) shows that minus IG(K) is nearly equal to the IK(ATP) of the blocked cell plus IG(K). Besides, both values are roughly equal to IK(ATP) in equilibrium state in Fig. 8(a). This means that a significant increase of IK(ATP) of the normal cell is brought about mostly by the outward gap current IG(K) from the blocked cell. This increase of IG(K) brings the intracellular potassium density of the blocked cell back to the normal level, and the insulin secretion ceases. Namely, the intercellular collaboration of ATP-sensitive potassium channels via gap junctions is a key of this robustness. Here the positive direction of IK(ATP) is outward from the cell.


Modeling of the gap junction of pancreatic β -cells and the robustness of insulin secretion
Effect of ḡK(ATP) variation. Original ḡK(ATP) value is 40000 pS. Note that K value is slightly higher than 95 mM here.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5036665&req=5

f15-6_37: Effect of ḡK(ATP) variation. Original ḡK(ATP) value is 40000 pS. Note that K value is slightly higher than 95 mM here.
Mentions: Recently, Rocheleau et al.22 conducted an interesting experiment by blocking the ATP-sensitive K+ channels and gap junctions. They used transgenic mice and showed that the robust control of the insulin secretion can be achieved by the gap junctions. Following their experiment, we conducted a numerical experiment in which Ge = 2 mM. To simulate their experiment, we reduced the conductance of the ATP-sensitive K+ channels by decreasing the value of ḡK(ATP) from the original value of 40000 pS to 10000 pS in a single β-cell. In this case, the insulin secretion is prompted as shown in Fig. 15. This corresponds to the case where the gap junction is disconnected (case in Fig. 6(c)). If the ATP-sensitive K+ channels are fully functional, no insulin secretion should be observed when Ge = 2 mM as shown in Fig. 13. However, when the gap junction is opened (case in Fig. 6(b)), insulin secretion ceases, as shown in Fig. 7(b). This robustness of the insulin secretion is consistent with the experiments of Rocheleau et al. To clarify the detailed mechanism of this robustness, we show the ATP-sensitive potassium current IK(ATP) and the gap currents IG(K) and IK(Ca) in Fig. 8. When the ATP-sensitive potassium channels of both cells are not blocked, the gap currents are negligibly small. However, when one of two cells is blocked, IG(K) and IK(ATP) of the normal cell are significantly increased (see Figs. 8(b), 8(c)). Figure 8(d) shows that minus IG(K) is nearly equal to the IK(ATP) of the blocked cell plus IG(K). Besides, both values are roughly equal to IK(ATP) in equilibrium state in Fig. 8(a). This means that a significant increase of IK(ATP) of the normal cell is brought about mostly by the outward gap current IG(K) from the blocked cell. This increase of IG(K) brings the intracellular potassium density of the blocked cell back to the normal level, and the insulin secretion ceases. Namely, the intercellular collaboration of ATP-sensitive potassium channels via gap junctions is a key of this robustness. Here the positive direction of IK(ATP) is outward from the cell.

View Article: PubMed Central - PubMed

ABSTRACT

Pancreatic β-cells are interconnected by gap junctions, which allow small molecules to pass from cell to cell. In spite of the importance of the gap junctions in cellular communication, modeling studies have been limited by the complexity of the system. Here, we propose a mathematical gap junction model that properly takes into account biological functions, and apply this model to the study of the β-cell cluster. We consider both electrical and metabolic features of the system. Then, we find that when a fraction of the ATP-sensitive K+ channels are damaged, robust insulin secretion can only be achieved by gap junctions. Our finding is consistent with recent experiments conducted by Rocheleau et al. Our study also suggests that the free passage of potassium ions through gap junctions plays an important role in achieving metabolic synchronization between β-cells.

No MeSH data available.