K(ATP) channels and islet hormone secretion: new insights and controversies

Abstract

ATP-sensitive potassium channels (K(ATP) channels) link cell metabolism to electrical activity by controlling the cell membrane potential. They participate in many physiological processes but have a particularly important role in systemic glucose homeostasis by regulating hormone secretion from pancreatic islet cells. Glucose-induced closure of K(ATP) channels is crucial for insulin secretion. Emerging data suggest that K(ATP) channels also play a key part in glucagon secretion, although precisely how they do so remains controversial. This Review highlights the role of K(ATP) channels in insulin and glucagon secretion. We discuss how K(ATP) channels might contribute not only to the initiation of insulin release but also to the graded stimulation of insulin secretion that occurs with increasing glucose concentrations. The various hypotheses concerning the role of K(ATP) channels in glucagon release are also reviewed. Furthermore, we illustrate how mutations in K(ATP) channel genes can cause hyposecretion or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, and how defective metabolic regulation of the channel may underlie the hypoinsulinaemia and the hyperglucagonaemia that characterize type 2 diabetes mellitus. Finally, we outline how sulphonylureas, which inhibit K(ATP) channels, stimulate insulin secretion in patients with neonatal diabetes mellitus or type 2 diabetes mellitus, and suggest their potential use to target the glucagon secretory defects found in diabetes mellitus.

Figure 1. K_ATP channel modulation of β-cell electrical activity.

Insulin secretion is a | inhibited at low glucose concentrations and b | stimulated at high glucose levels. c | Schematic illustrating the changes in membrane potential (V), intracellular Ca²⁺ ([Ca²⁺]_i), cytosolic [ATP]_i/[ADP]_i ratio and whole-cell K_ATP current produced by increasing glucose concentrations. At 5 mM glucose, K_ATP channels are active because of the low [ATP]_i/[ADP]_i ratio, which keeps the membrane hyperpolarized and prevents electrical activity. At 10 mM glucose, via stimulation of glucose metabolism, the [ATP]_i/[ADP]_i ratio increases, resulting in a reduced K_ATP current. When K_ATP channel activity is sufficiently low, the membrane depolarizes initiating electrical activity and Ca²⁺ influx. Elevation of [Ca²⁺]_i activates ATP-consuming Ca²⁺-pumps, causing a fall in the [ATP]_i/[ADP]_i ratio, reactivation of K_ATP channels, membrane repolarization and temporary termination of electrical activity. Elevated [Ca²⁺]_i also opens Ca²⁺-activated K⁺-channels, which contributes to the membrane repolarization (not shown). In the hyperpolarized state, Ca²⁺ influx ceases, [Ca²⁺]_i returns to basal, ATP consumption falls, the [ATP]_i/[ADP]_i ratio is restored, K_ATP and Ca²⁺-activated K⁺ channels close and electrical activity is reinitiated. Horizontal lines indicate the fall in ATP ([ATP]_i/[ADP]_i) needed to activate K_ATP channels to the level (K_ATP channel activity) required to initiate repolarization of the burst. Thus, the oscillations in the [ATP]_i/[ADP]_i are phase shifted (θ) with respect to changes in intracellular Ca²⁺, K_ATP channel activity and action potential firing (vertical lines). At 20 mM glucose, ATP production is high enough to compensate for the increased ATP consumption. Consequently, the [ATP]_i/[ADP]_i ratio is maintained at a sufficiently high level to keep K_ATP channels closed, resulting in continuous electrical activity. Abbreviation: K_ATP channels, ATP-sensitive potassium channels.

Figure 2. Patch clamping enables the activity of one or more ion channels to be recorded from single cells or isolated membrane patches with high precision.

a | In the cell-attached configuration, the patch electrode is sealed to the surface of an intact cell, allowing channel activity in the patch of membrane under the electrode tip to be studied under physiological conditions. If the pipette is withdrawn from the cell surface, an excised membrane patch is produced, spanning the pipette tip, which has its b | intracellular surface (inside-out patch), or c | extracellular surface (outside-out patch) exposed to the bath solution. Inside-out patches are used to test the effects of intracellular modulators on channel activity (for example, ATP). The whole-cell configuration measures the summed activity of the many ion channels in the membrane of the whole cell. d | The standard whole-cell method is obtained by forming a cell-attached patch and then destroying the patch membrane with strong suction to gain electrical access to the cell interior. The intracellular solution then dialyses with that in the patch (so, for example, ATP is lost or the intracellular solution can be manipulated). e | The perforated patch method preserves cellular metabolism and intracellular second messenger systems by using a pore-forming antibiotic (such as amphotericin B) to provide electrical access to the cell interior. Parts a to e adapted from Prog. Biophys. Mol. Biol., 54 (2), Ashcroft, F. M. & Rorsman, P. Electrophysiology of the pancreatic β-cell, 87143, ©1989, with permission from Elsevier.

Figure 3. K_ATP channel modulation of α-cell electrical activity.

a | Glucagon secretion is stimulated at low glucose levels and b | inhibited at high glucose levels. c | Schematic illustrating the changes in membrane potential (V), whole-cell K_ATP current and glucagon secretion produced by increasing glucose levels from 1 mM to 6 mM or by hyperactivation of the K_ATP channel using the K_ATP-channel activator diazoxide (far left). K_ATP channels are under strong tonic inhibition (99%) at low glucose levels, so that the membrane is depolarized sufficiently to elicit electrical activity, which consists of large-amplitude action potentials. Electrical activity is associated with activation of voltage-gated Na⁺ channels and voltage-gated Ca²⁺ channels, and Ca²⁺ influx through the latter triggers glucagon secretion. Increasing glucose levels to 6 mM closes K_ATP channels completely, further depolarizing the membrane. As in β cells, membrane depolarization increases action potential frequency. However, it also reduces α-cell spike amplitude, due to inactivation of voltage-gated Na⁺ channels, which leads to less activation of the P/Q-type Ca²⁺ channels linked to exocytosis and thus to reduced glucagon secretion. Abbreviation: K_ATP channels, ATP-sensitive potassium channels.

Figure 4. Relationship between K_ATP channel activity and hormone release.

a | Sigmoidal relationship between β-cell K_ATP channel activity and insulin release. The green circle indicates channel activity at normal glycaemic levels in humans (~4–5 mM), where insulin secretion is slightly stimulated. Hyperglycaemia decreases K_ATP channel activity and stimulates insulin secretion. Hypoglycaemia increases K_ATP channel activity and inhibits insulin release. b | Bell-shaped relationship between α-cell K_ATP channel activity and glucagon release. Hyperglycaemia decreases K_ATP channel activity and inhibits glucagon secretion. Hypoglycaemia increases K_ATP channel activity and stimulates glucagon release. c | In β cells from patients with type 2 diabetes mellitus (T2DM), K_ATP channel activity is enhanced (either because of impaired metabolism or activating K_ATP channel variants or mutations). Hypoglycaemia supresses insulin secretion further. Hyperglycaemia increases insulin secretion but not as much as in nondiabetic β cells. Closure of K_ATP channels by sulphonylureas (SU) reduces channel activity at normal glycaemic levels and so boosts insulin secretion in both normoglycaemia and hypoglycaemia. The pink circle shows that in neonatal diabetes mellitus (NDM) K_ATP channel activity is so much enhanced that insulin secretion is abolished. The orange circle shows that in congenital hyperinsulinism (HI) there is little or no K_ATP channel activity, which causes persistent insulin secretion. d | In α cells from patients with T2DM, K_ATP channel activity is enhanced. Because of the bell-shaped relationship, reduced K_ATP channel activity in response to hyperglycaemia leads to increased glucagon secretion whereas hypoglycaemia causes reduced glucagon secretion. The orange circle illustrates the situation in severe HI and the pink circle in NDM. Abbreviation: K_ATP channels, ATP-sensitive potassium channels.