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Review
. 2013 Nov;9(11):660-9.
doi: 10.1038/nrendo.2013.166. Epub 2013 Sep 17.

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

Frances M Ashcroft  1 , Patrik Rorsman
Affiliations
Review

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

Frances M Ashcroft et al. Nat Rev Endocrinol. 2013 Nov.

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.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1
Figure 1. KATP 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 KATP current produced by increasing glucose concentrations. At 5 mM glucose, KATP 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 KATP current. When KATP 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 KATP 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, KATP 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 KATP channels to the level (KATP 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+, KATP 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 KATP channels closed, resulting in continuous electrical activity. Abbreviation: KATP channels, ATP-sensitive potassium channels.
Figure 2
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
Figure 3. KATP 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 KATP current and glucagon secretion produced by increasing glucose levels from 1 mM to 6 mM or by hyperactivation of the KATP channel using the KATP-channel activator diazoxide (far left). KATP 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 KATP 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: KATP channels, ATP-sensitive potassium channels.
Figure 4
Figure 4. Relationship between KATP channel activity and hormone release.
a | Sigmoidal relationship between β-cell KATP 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 KATP channel activity and stimulates insulin secretion. Hypoglycaemia increases KATP channel activity and inhibits insulin release. b | Bell-shaped relationship between α-cell KATP channel activity and glucagon release. Hyperglycaemia decreases KATP channel activity and inhibits glucagon secretion. Hypoglycaemia increases KATP channel activity and stimulates glucagon release. c | In β cells from patients with type 2 diabetes mellitus (T2DM), KATP channel activity is enhanced (either because of impaired metabolism or activating KATP channel variants or mutations). Hypoglycaemia supresses insulin secretion further. Hyperglycaemia increases insulin secretion but not as much as in nondiabetic β cells. Closure of KATP 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) KATP 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 KATP channel activity, which causes persistent insulin secretion. d | In α cells from patients with T2DM, KATP channel activity is enhanced. Because of the bell-shaped relationship, reduced KATP 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: KATP channels, ATP-sensitive potassium channels.
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