Controlling Insulin Secretion: An Exciting TASK

The β-cells of the pancreatic islets of Langerhans secrete insulin in response to metabolic fuels and neurohormonal inputs after a meal. The proper regulation of insulin secretion is critical for the maintenance of glucose homeostasis. An absolute or relative impairment of insulin secretion in the face of insulin resistance underlies the pathophysiology of type 2 diabetes. Accordingly, some of the key antidiabetes agents promote increased insulin secretion from islets, including the newer incretin-based therapeutics and the sulfonylurea class of drugs. The consensus mechanism for glucose-stimulated insulin secretion was elucidated almost 30 years ago and has remained largely unchanged since. A glucose-dependent increase in the intracellular ATP to ADP ratio closes ATP-sensitive potassium (KATP) ion channels (1, 2), themselves the target of the sulfonylurea drugs (3). This results in depolarization of the β-cell membrane and the firing of action potentials, which allows the activation of voltage-gated Ca2+ channels and a rise in intracellular Ca2+ that triggers insulin release (4). It is well-recognized, however, that a diverse array of additional ion channels contribute to β-cell excitability, and only recently have we begun to understand the roles and molecular identities of the many key channels that shape the electrical response in these cells. Although the outward flux of K+ mediated by KATP channels dominates the electrical conductance of the β-cell membrane in the resting condition, holding the membrane potential of these cells near the equilibrium potential for K+ (∼−70 mV), closure of KATP channels upon glucose stimulation is not in itself sufficient to depolarize the cell. For the β-cell to depolarize, an inward depolarizing leak current is required to push the membrane potential toward a more positive equilibrium (or plateau, Figure 1) sufficient to allow the activation of the voltage-gated Na+, Ca2+, and K+ channels that mediate regenerative action potential firing (5). This depolarizing force is likely mediated by channels that mainly allow the inward leak of Na+ (and possibly Ca2+) such as the transient receptor potential (TRP) family of channels (6) and/or the muscarinic-activated nonselective Na+-leak channel (NALNC) (7). Additional currents, such as those mediated by the small-conductance Ca2+-sensitive K+ (SK) channels (8) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (9), contribute to the oscillatory nature of the electrical activity that characterizes β-cell electrical function. In the presence of stimulatory glucose, when most KATP channels are closed, the characteristic electrical response of pancreatic β-cells consists of slow waves of membrane depolarization to a plateau potential (red dashed line) upon which action potentials are superimposed. The plateau potential is set by a balance of depolarizing inward leak currents that push the membrane potential upward (ie, more positive) and a counterbalancing outward leak current, which Dadi et al (10) have shown in this issue to be mediated by the 2-pore-domain K+ channel TASK-1. Although required for membrane depolarization after glucose stimulation, these inward leak currents pose a problem of their own: the equilibrium potential for Na+ and Ca2+ is much too positive (>+50 mV) to allow the rhythmic opening and closing of voltage-dependent ion channels required for action potential firing. What this means is that upon KATP channel closure in response to elevated glucose or sulfonylurea, the inward leak currents could depolarize the β-cell too much, unless a counterbalancing outward leak is also present. In the present issue of Endocrinology, Dadi et al (10) present evidence to suggest that this key outward leak current is mediated by TASK-1, a member of the 2-pore-domain K+ (K2P) channel family shown to be expressed at the mRNA level in human β-cells only very recently (11, 12) and suggested previously as a target of inhaled anesthetics (13) and for the treatment of multiple sclerosis (14), T cell-mediated autoimmunity (15), and cardiac arrhythmia (16) among other conditions. Using cell-type–specific knockout mice and a selective TASK-1 inhibitor, the authors demonstrate that this channel mediates a background K+ current in mouse and human β-cells that limits membrane depolarization. Inhibition or knockout of TASK-1 (but not the related TASK-3) enhanced membrane depolarization and, at least in mice, increased insulin secretion. The inherent glucose dependence of this mechanism is intriguing, and supported by the findings that in vivo fasting glycaemia and in vitro insulin secretion at low glucose are unaffected by β-cell–specific TASK-1 knockout. Although suggestive that TASK-1 inhibition might be useful in type 2 diabetes, Dadi et al (10) correctly suggest that further study is required to determine whether this would represent an appropriate therapeutic approach. A key limitation to targeting TASK-1 in diabetes raised by Dadi et al (10) is the role for this channel in vascular tone. TASK-1 inhibition may contribute to hypertension either by directly modulating human pulmonary artery smooth muscle cell tone (17) but also indirectly through the induction of hyperaldosteronism in mice (18) and possibly humans (19). These issues may in part be dealt with by further work focused on understanding tissue-selective mechanisms that regulate TASK-1 activity or subcellular targeting. Although TASK-1 mediates a background leak K+ current, its activity can be regulated. For example, the Gq-dependent regulation (20) alluded to by Dadi et al (10) may underlie TASK-1 inhibition by muscarinic receptor activation (21), which also promotes insulin secretion (22). Subcellular targeting of TASK-1 is also controlled, for example by the 14–3-3 family of proteins (23), which are key regulators of islet survival (24). As such, and given that many signals appear to control TASK-1 activity in neurons (25, 26), understanding the β-cell–selective control of TASK-1 activity may provide a route to tissue-specific modulation of TASK-1 in diabetes. Aside from the issue of tissue specificity, there remains much to be understood about the control of β-cell electrical function and the role of TASK-1 in mouse and human insulin secretion. Dadi et al (10) importantly confirm the presence of TASK-1–mediated currents in human β-cells and the ability of TASK-1 inhibition to increase the plateau potential and the intracellular Ca2+ response in human β-cells and islets. This may be particularly useful under conditions where glucose cannot efficiently depolarize the β-cell, either due to impaired ATP generation (27) or in the context of KATP channel polymorphisms that reduce the sensitivity of the channel to ATP (28). This is a slippery slope, however, and elevating the plateau potential in human β-cells may not always be a good idea. Notably, Dadi et al (10) show that TASK-1 inhibition reduced action potential peak amplitude by as much as 10 mV in human (but not mouse) β-cells. This is, as the authors suggest, in line with a more prominent role for voltage-gated Na+ channels in human β-cells (5). The effect these blunted action potentials will have on insulin secretion from human islets remains unclear, however, and the implications of a switch from Na+- to Ca2+-dependent action potentials in human β-cells is likely to be less straightforward than Dadi et al (10) suggest. As opposed to the voltage-gated L-type Ca2+ currents that (together with voltage-gated Na+ currents) contribute to the action potential upstroke in human β-cells, the exocytosis of insulin granules in human β-cells is closely coupled to Ca2+ entry through the voltage-gated P/Q-type Ca2+ channels (4, 5). These are activated at higher membrane voltages (>−30 mV) and are likely activated poorly, if at all, during a blunted action potential. Indeed, an ∼10-mV reduction in depolarization amplitude results in an ∼50% reduction in insulin exocytosis from human β-cells (5). As such, the increased Ca2+ observed in the human islets after TASK-1 inhibition may reflect an influx of Ca2+ through L-type Ca2+ channels that may be less efficient in promoting insulin secretion. A species-specific difference in the role of TASK-1 is possible, with the channel playing a positive role in humans by ensuring the appropriate recovery of Na+ channels from inactivation. Nonetheless, Dadi et al (10) have elucidated an important mechanism controlling β-cell excitability. Until now, the ionic current limiting the plateau depolarization in these cells has received little attention. The elucidation of a role for TASK-1 demonstrates that such currents are indeed very important contributors to islet electrical and Ca2+ regulation and can be potent modulators of insulin secretion and glucose homeostasis. Identification of additional hyperpolarizing leak channels and a fuller understanding of the regulation and consequences of TASK-1 inhibition in humans promises to reveal new and exciting mechanisms for the physiological (and potentially pharmacological) control of insulin secretion in health and diabetes. I thank my friend and colleague, the late Dr Matthias Braun, an outstanding contributor to the field of islet electrophysiology who provided the example membrane potential trace in Figure 1. P.E.M. is supported by a Scholarship from Alberta Innovates-Health Solutions and holds the Canada Research Chair in Islet Biology. Research on islet ion channels in P.E.M.'s laboratory is supported by an operating grant from the Canadian Institutes of Health Research. Disclosure Summary: The author has nothing to disclose.

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