Rab27a: a new face in beta cell metabolism-secretion coupling

Abstract

In pancreatic beta cells, not only insulin exocytosis per se, but translocation of beta granules toward the plasma membrane--an event upstream of exocytosis--are under the control of glucose. However, the molecular basis of this translocation has been poorly understood. Rab27a-mediated translocation of glucose-induced beta granules is reported in this issue of the JCI. Rab27a or its effector molecule may constitute a novel pharmacological target because potentiation of the Rab27a pathway is expected to restore beta cell glucose competency in patients with diabetes mellitus.

Figure 1

Metabolism-secretion coupling within the pancreatic β cell. (A and B) Elevation of ATP and ATP/ADP is the starting point for K_ATP channel–dependent signaling, which has been well elucidated, as shown here (6). Owing to [Ca²⁺]_i elevation, fusion of β granules in the RRP and the plasma membrane takes place, and this results in the first phase of glucose-induced insulin secretion. The molecular basis for K_ATP channel–independent signaling (B) is not fully characterized. The end point of this signaling is expansion and/or replenishment of the RRP, after which a second phase occurs in which insulin release gradually increases. Upon glucose stimulation, K_ATP channel–dependent and –independent events take place. When an experimental protocol to detect time-dependent potentiation is employed (16, 17), expansion of the RRP can be quantified. Membrane fusion of the β granules in the RRP is required and sufficient for first-phase insulin release, and, in addition, expansion and/or replenishment of the RRP is required for second phase release (see Figure 2). As shown in A, as a result of anaplerosis (2), increased citrate flux (2) and/or activation of acetyl-CoA carboxylase (ACC) (3) occurs, which results in expansion and/or replenishment of the RRP via the series of events indicated (10–12). Cytosolic flux of glutamate, by virtue of its uptake by β granules, sensitizes the granules for fusion (15). Activation of phospholipase C (PLC), PKC, or an increase in inositol trisphosphate (IP₃) (4) and liberation of stored Ca²⁺ (13) also yield expansion and/or replenishment. ATP itself (14) and elevation of ATP/ADP (9) are also involved in this process. In this issue of the JCI, Kasai et al. (1) report that Rab27a plays a critical role in replenishment of the RRP. CPT1, carnitine palmitoyl transferase 1; L-VDCC, L-type voltage-dependent Ca²⁺ channel.

Figure 2

A schematic presentation of glucose-induced biphasic insulin secretion by islet β cells. Stimulation by a high concentration of glucose elicits a rapid increase in insulin secretion within 1–2 minutes (first phase). Within 10 minutes, in the presence of the same stimulatory concentration of glucose, the secretion rate is decreased, and it gradually begins to increase again thereafter (second phase). Second-phase insulin release is more prominent in rat and human than in mouse β cells. First-phase insulin release is generated by fusion of β granules already in the RRP and the plasma membrane, which is called triggering. For the second phase, granules translocate from the RP to the RRP, which yields expansion and/or replenishment of the RRP. The first and second phases of insulin secretion are due to K_ATP channel–dependent and –independent glucose signaling, respectively, as outlined in Figure 1.