Am J Physiol Endocrinol Metab 293: E880–E889, 2007.
First published July 24, 2007; doi:10.1152/ajpendo.00348.2007.
Invited Review
THE WALTER B. CANNON PHYSIOLOGY IN PERSPECTIVE LECTURE, 2007
ATP-sensitive K⫹ channels and disease: from molecule to malady
Frances M. Ashcroft
Henry Wellcome Centre for Gene Function, University of Oxford, Oxford, United Kingdom
Kir6.2; SUR1; neonatal diabetes; hyperinsulinism
WALTER BRADFORD CANNON (1871–1945) was an eminent American physiologist who pioneered the concept of homeostasis.
In his seminal text, The Wisdom of the Body, he described it
as “the coordinated physiological reactions which maintain
most of the steady states in the body.” Among these steady
states, one of the most important is that of the blood glucose
concentration. In nondiabetic individuals, the fasting blood
glucose level is at 4 –5 mM. If glucose drops below ⬃1–2
mM, the brain is starved of fuel, causing cognitive impairment and ultimately loss of consciousness. Long-term elevation of the blood glucose concentration (⬎7 mM) is also
dangerous, as it results in glycation of membrane proteins
and gives rise to a host of complications that include retinopathy, nephropathy, peripheral neuropathy, and cardiac disease.
Glucose homeostatic mechanisms ensure that the blood glucose fluctuations which occur inevitably after every carbohydrate meal are only transient. When these mechanisms fail, the
result is diabetes mellitus or its converse, hyperinsulinism. This
essay is based on the American Physiological Society’s 2007
lecture in honor of Walter B. Cannon and takes as its theme
glucose homeostasis in health and disease.
Insulin plays a crucial role in blood glucose homeostasis
because it is the only hormone capable of reducing the blood
glucose level; in contrast, many hormones can increase blood
glucose levels. Diabetes mellitus results if insufficient insulin
is produced to meet the needs of the body. The term refers to
a range of conditions all of which are characterized by an
elevated blood glucose level but which may have different
etiologies. Several different forms of the disease are recognized.
Address for reprint requests and other correspondence: F. M. Ashcroft,
Henry Wellcome Centre for Gene Function, Dept. of Physiology, Anatomy and
Genetics, Univ. of Oxford, Parks Road, Oxford OX1 3PT, UK (e-mail: frances.
[email protected]).
E880
Type 1 diabetes typically presents in childhood as an autoimmune attack on the pancreatic ␤-cells that results in their
complete destruction; consequently, the patient must take insulin for the rest of their life. It accounts for more than 10% of
all diabetes and will not be considered further here. Type 2
diabetes, which is reaching epidemic proportions in Western
societies and is predicted to affect 300 million people worldwide by 2025, is a very different disease (42). It is normally
associated with both inadequate insulin secretion and impaired
insulin action. Type 2 diabetes is a polygenic disease that
results from a combination of gene variants in many different
genes, each of which individually has only a small effect. Some
of these genes have recently been identified by genome-wide
scans (20, 80, 90). There are also several different forms of
monogenic diabetes that result from single gene mutations (22,
24, 32, 76). These disorders are rare, but their study has
provided important insights into insulin secretion in both health
and disease and led to identification of some of the genes that
contribute to type 2 diabetes.
This essay focuses on the ATP-sensitive potassium
(KATP) channel, which plays a key role in blood glucose
homeostasis. Mutations in the genes that encode this channel can lead to neonatal diabetes or congenital hyperinsulinism. There are many excellent and comprehensive recent
reviews on the KATP channel and its role in human disease
(3, 13, 32, 39, 54, 58). In this essay, therefore, I have taken
a different approach and instead provide a personal perspective of how we reached our current state of understanding of
KATP channel function. The story of the KATP channel is a
long one. More than 20 years elapsed between the discovery
that it regulates insulin secretion and the introduction of a
new therapy for children with neonatal diabetes. Translational research, no matter how fast the final stages may
appear, usually takes a long time.
0193-1849/07 $8.00 Copyright © 2007 the American Physiological Society
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Ashcroft FM. ATP-sensitive K⫹ channels and disease: from molecule to
malady. Am J Physiol Endocrinol Metab 293: E880 –E889, 2007. First published
July 24, 2007; doi:10.1152/ajpendo.00348.2007.—This essay is based on a lecture
given to the American Physiological Society in honor of Walter B. Cannon, an
advocate of homeostasis. It focuses on the role of the ATP-sensitive potassium K⫹
(KATP) channel in glucose homeostasis and, in particular, on its role in insulin
secretion from pancreatic ␤-cells. The ␤-cell KATP channel comprises pore-forming
Kir6.2 and regulatory SUR1 subunits, and mutations in either type of subunit can
result in too little or too much insulin release. Here, I review the latest information
on the relationship between KATP channel structure and function, and consider how
mutations in the KATP channel genes lead to neonatal diabetes or congenital
hyperinsulinism.
Invited Review
THE WALTER B. CANNON LECTURE
KATP Channels: the Early Days
through voltage-gated Ca2⫹ channels in the plasma membrane.
In the unstimulated ␤-cell, KATP channels are open, and K⫹
efflux through these channels keeps the membrane potential at
a negative level where voltage-gated Ca2⫹ channels are closed.
When the plasma glucose concentration rises, glucose uptake
and metabolism by the pancreatic ␤-cell are enhanced, leading
to closure of the KATP channels. This causes a membrane
depolarization that triggers opening of voltage-gated Ca2⫹
channels and Ca2⫹-dependent electrical activity. The consequent Ca2⫹ influx stimulates insulin release.
Sulfonylurea drugs were soon shown to stimulate insulin
secretion by closing KATP channels directly, thereby bypassing
the metabolic steps in stimulus-secretion coupling (27, 87).
Despite the fact that their target was unknown, these drugs had
been used to treat type 2 diabetes since the 1950’s—and they
are still used today. The story of their serendipitous discovery
has been told elsewhere (34).
For many years, the product of glucose metabolism that
regulates KATP channel activity was hotly contested. While it
was very clear that ATP shut the channel in inside-out patches,
the ATP sensitivity was so high that in the intact ␤-cell the
KATP channel should always be closed (5, 10). This did not
agree with the observation that the channel was open in ␤-cells
exposed to glucose-free solution (4). This suggested the presence of additional channel regulators. In fact, the regulation of
KATP channel turned out to be extremely complex. It is the
target for numerous cytosolic compounds, including nucleotides (5, 10, 14, 40), lipids such as phosphatidylinositol
bisphosphate (9, 17, 79), and long-chain acyl-CoAs (26, 48).
Of particular importance is MgADP, which stimulates channel
activity and can reactivate channels closed by ATP (14, 40).
In the early days, many biochemists had a certain resistance
to the idea that ATP could act as a signaling molecule—
reasonably enough, because in most cells ATP levels are very
stable. We now know, however, that ATP levels in ␤-cells do
change in response to glucose metabolism: from about 2 mM
to 4 mM when glucose is increased from 0 to 10 mM (11, 84).
Thus, it is now generally believed that changes in adenine
nucleotide concentrations are largely responsible for mediating
the effects of glucose metabolism on KATP channel activity. At
low glucose concentrations, where metabolism is low, the
stimulatory effects of MgADP predominate, whereas when
glucose metabolism is stimulated the inhibitory action of ATP
is favored.
Fig. 1. Role of ATP-sensitive K⫹ (KATP)
channels in insulin secretion. A: when metabolism is low, KATP channels are open, keeping the membrane hyperpolarized and voltage-gated Ca2⫹ channels closed, so that
[Ca2⫹]i remains low and insulin secretion is
prevented. B: when metabolism increases,
ATP increases and MgADP falls, so that
KATP channels shut. This triggers depolarization of the ␤-cell membrane potential, opening of voltage-gated Ca2⫹ channels, Ca2⫹
influx, and exocytosis of insulin granules.
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In 1983, when I first entered the field, it was well established
that glucose metabolism was required to stimulate insulin
release (7). It was also known that Ca2⫹-dependent ␤-cell
electrical activity was essential, as this led to an influx of
calcium that was the trigger for insulin secretion (63). Technically demanding studies in which sharp microelectrodes were
used to record from ␤-cells within isolated islets had shown
that in the absence of glucose the ␤-cell was electrically silent,
with a resting potential of around ⫺70 mV and that glucose
produced a gradual membrane depolarization that triggered
electrical activity (reviewed in Refs. 6 and 35). What was not
so clear was how glucose initiated this depolarization. However, there was a clue: work by Janove Sehlin and Inge-Bert
Taljedal (74) and subsequently by Jean-Claude Henquin (33)
had revealed that glucose metabolism reduced efflux of 86Rb (a
congener for K⫹), suggesting that closure of a K⫹ channel was
involved.
The advent of the high-resolution patch clamp technique in
1981 (31) enabled this K⫹ channel to be identified, and I used
this method on single ␤-cells dispersed from pancreatic islets
(4). As we were looking for a channel regulated by glucose
metabolism, we used cell-attached membrane patches to ensure
that ␤-cell metabolism remained intact. We also added glucose
to the bath solution, so that any effect of glucose on the activity
of ion channels in the patch of membrane under the recording
pipette had to be mediated via an intracellular route. Finally,
we filled the pipette with a high K⫹ solution to shift the K⫹
equilibrium potential and enable single K⫹ channel currents to
be recorded at the resting potential of the ␤-cell. Our studies
led to discovery of a K⫹ channel that was active at the resting
potential and closed by glucose metabolism (4).
Intriguingly, the single-channel conductance and kinetics of
this K⫹ channel were very similar to those of a K⫹ channel
identified in cardiac myocytes the previous year that was
blocked by elevation of intracellular ATP (61). A similar KATP
channel had also just been described by Dan Cook and Nick
Hales in inside-out patches excised from pancreatic ␤-cells
(10). Within a year of its discovery, Patrik Rorsman and Gerd
Trube had shown the glucose-sensitive K⫹ channel was identical to the KATP channel (70).
Thus, by 1985, there was a consensus model for glucosedependent insulin secretion (Fig. 1). This postulated that insulin release is initiated by elevation of the intracellular Ca2⫹
concentration ([Ca⫹]i), which is mediated by Ca2⫹ influx
E881
Invited Review
E882
THE WALTER B. CANNON LECTURE
Current View of KATP Channel Structure and Function
Cloning of the genes encoding Kir6.2 (KCNJ11) and SUR1
(ABCC8) enabled the relationship between the structure and
function of the KATP channel to be addressed by electrophysiological or biochemical analysis of heterologously expressed
wild-type and mutant KATP channels.
Such studies revealed that the KATP channel is an octameric
complex of four Kir6.2 subunits and four SUR1 subunits (38).
Neither subunit can reach the plasma membrane in the absence
of its partner, because each possesses an endoplasmic reticulum (ER) retention motif that must be masked by the other
subunit (91). This ensures that only fully functional KATP
channels are trafficked to the surface membrane. We serendipitously discovered, however, that deletion of the last 35 or so
residues of Kir6.2 enables it to be expressed at the membrane
surface in the absence of SUR1 (88) [it deletes the ER retention
signal (91)]. This allowed the intrinsic properties of Kir6.2 to
be distinguished from those conferred by SUR1 (88).
Specific functions could then be assigned to the individual
subunits. Metabolic regulation of KATP channel activity was
found to be mediated by both Kir6.2 and SUR1 subunits. The
site to which ATP binds to close the channel lies on Kir6.2
(88), whereas MgADP binding to SUR1 stimulates channel
activity (28, 59, 88). Although MgATP can also stimulate
KATP channel activity via interaction with SUR1 (29), it
appears that it must first be hydrolyzed to MgADP (92). SUR
thus functions as a second metabolic sensor, endowing the
KATP channel with an exquisite sensitivity to changes in
adenine nucleotide concentrations. It also serves as a target for
the inhibitory sulfonylurea drugs and the stimulatory K channel
openers, both of which act by binding to SUR and thereby
influence opening and closing (gating) of the Kir6.2 pore
(1, 88).
AJP-Endocrinol Metab • VOL
A key question is: where are the binding sites for drugs and
nucleotides on the KATP channel and how does ligand binding
lead to changes in channel gating? A mechanistic understanding of this question would be greatly facilitated by knowledge
of the atomic structure of the channel. Unfortunately, this is not
yet available. Currently, there is only a low-resolution structure
of the purified complex (53). This reveals that the KATP
channel assembles as a central tetrameric Kir6.2 pore surrounded by four SUR1 subunits, but sheds no light on the
binding sites.
Some information on the location of the binding sites can,
however, be gleaned from homology modeling and mutagenesis studies. Like other ABC proteins, SUR1 has two large
cytosolic domains that have consensus sequences for ATP
binding and hydrolysis. Mutations in these nucleotide-binding
domains (NBDs) impair radiolabeled ATP binding (51) and
channel activation by Mg-nucleotides (28). The high conservation of amino acid sequence and overall folds of the NBDs
across ABC proteins suggests that homology models of the
NBDs of SUR1 based on ABC crystal structures may be a
reasonable approximation to reality. However, the transmembrane domains of SUR1 are too divergent to model accurately.
Shozeb Haider, Mark Sansom, and I have produced a homology model of Kir6.2 (2) based on the crystal structures of
the transmembrane domains of a bacterial Kir channel (47) and
the cytosolic domain of a eukaryotic Kir channel (60). We then
used automated docking to probe for the ATP-binding site (2).
The putative binding pocket lies at the interface between the
cytosolic domains of adjacent Kir6.2 subunits, with residues in
the COOH terminus of one subunit forming the main binding
pocket and residues in the NH2 terminus of the adjacent
subunit also contributing. This location is in agreement with a
substantial body of mutagenesis data. It later turned out that
many Kir6.2 mutations which cause neonatal diabetes lie
within the putative ATP-binding site (3, 23, 50, 77, 82), which
adds further strength to our argument that this region is
involved in ATP binding.
Identification of Disease-Causing KATP Channel Mutations
The discovery of mutations in the KATP channel subunits
SUR1 and Kir6.2 that cause congenital hyperinsulinism of
infancy (CHI) followed rapidly upon cloning of the genes (57,
86). This disorder affects about 1 in 50,000 live births and is
characterized by continuous and unregulated insulin secretion
in the face of very low blood glucose levels (13). Patients with
this disorder usually present at birth or shortly afterwards. In
some cases, their blood glucose levels fall so low that they
suffer brain damage as a consequence.
More than 100 CHI mutations in SUR1 have now been
described, distributed throughout the whole protein, and several mutations in Kir6.2 (13, 24). Many of these mutations
result in the total loss of KATP channels in the plasma membrane due to abnormalities in gene expression, protein synthesis, maturation, assembly, or membrane trafficking. Other
SUR1 mutations impair the ability of the channel to respond to
metabolic activators such as MgADP; consequently the channels are always closed. All CHI mutations are therefore lossof-function mutations that result in permanent depolarization
of the ␤-cell membrane and thereby continuous Ca2⫹ influx
and insulin secretion.
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The KATP channel dominates the ␤-cell resting potential, and
there is a highly nonlinear relationship between the KATP
channel conductance and the ␤-cell membrane potential (85).
This means that, close to the threshold for electrical activity,
very small changes in KATP conductance have marked effects
on electrical activity and insulin secretion. It was therefore
evident right from the start that tiny changes in KATP conductance resulting from mutations in KATP channel genes, or from
impaired metabolic regulation of KATP channel activity, would
result in altered insulin secretion. Demonstration that this was
the case, however, had to await the cloning of genes encoding
the KATP channel.
This took time; indeed, it was not until 10 years after its
discovery that the ␤-cell KATP channel was cloned. One reason
it was unusually difficult was that it turned out that the KATP
channel is, in fact, a complex of two different proteins (37, 71).
The pore-forming subunit, known as Kir6.2, is a member of the
inwardly rectifying K⫹ channel family (37, 71). This associates in a 4:4 complex (38) with a much larger regulatory
subunit, the sulfonylurea receptor SUR1, which belongs to the
ABCC family of ATP-binding cassette transporters (1). Cloning of Kir6.2 was hard enough, but cloning of SUR1 by Joe
Bryan and colleagues was a tour de force, requiring purification of the protein itself followed by NH2-terminal sequencing
and screening of cDNA libraries (1). These were the heroic
days when one could not simply order the clone!
Invited Review
THE WALTER B. CANNON LECTURE
Mouse models have traditionally been used to probe
the molecular mechanism of human disorders. The KATP
channel is no exception, and both gain- and loss-offunction models have been generated, mainly by Susumu
Seino, Colin Nichols, and their colleagues (54). These
have yielded important insights into human diabetes and
CHI.
That gain-of-function KATP channel mutations cause
severe neonatal diabetes was first described in mice (44),
four years before it was shown in humans (23). Because
the mutant Kir6.2 transgene was targeted to the ␤-cell,
extrapancreatic symptoms (such as those found in some
patients with Kir6.2 mutations) were absent. No change
in insulin content or ␤-cell number was observed, but
serum insulin levels were extremely low, as expected
from the reduced ATP sensitivity of the KATP channel
(44). Interestingly, mice in which the mutant transgene
was targeted to the heart had no obvious cardiac symptoms (43), as was subsequently found for patients with
gain-of-function KATP channel mutations (3, 23). Mice in
which the mutant transgene was expressed at much lower
levels usually exhibited impaired glucose tolerance
rather than diabetes (46). Thus, as in humans (3, 32), mice
exhibit a spectrum of diabetes phenotypes that correlates
with extent of KATP channel activity.
As predicted, the pancreatic ␤-cells of mice lacking
functional KATP channels were depolarized and had elevated basal [Ca2⫹]i (45, 55, 56, 73). Glucose-stimulated
insulin secretion from isolated islets was absent, confirming that KATP channels are crucial for insulin release.
But the mouse models also produced some surprises.
Animals in which the KATP channel was functionally
inactivated by a dominant negative Kir6.2 mutation
(Kir6.2G132S) exhibited hypoglycemia and hyperinsulinemia as neonates but subsequently developed hyperglycemia due to substantial ␤-cell loss (56). Similarly,
when either Kir6.2 or SUR1 was genetically deleted,
adult mice had reduced insulin secretion and were normoglycemic (55, 73). Remarkably, however, mice expressing
a different dominant negative Kir6.2 mutation exhibited
hyperinsulinism as adults (45) and showed no ␤-cell loss.
It was hypothesized that the very different phenotype of
these mice might be because KATP channel activity was
only partially suppressed (30% of ␤-cells were unaffected). Most patients with severe CHI undergo sub-total
pancreatectomy as infants to control their hyperinsulinism, but nonsurgically treated patients sometimes
progress to glucose intolerance or diabetes (36). The
mouse models suggest that this may reflect a gradual
␤-cell loss, which happens more slowly if suppression of
KATP channel activity is less severe.
Current Understanding of the Role of KATP Channels in
Neonatal Diabetes
It is also clear from Fig. 1 that gain-of-function mutations in
KATP channel genes would be expected to decrease insulin
release and lead to diabetes. Such mutations were looked for in
patients with type 2 diabetes as soon as the gene was cloned,
Neonatal diabetes (ND) is now defined as diabetes presenting within the first six months of life (15). It affects about 1 in
200,000 live births and is characterized by severe hyperglycemia, which may be either permanent or transient. Why some
patients show neonatal diabetes that subsequently remits and
may later relapse again (19, 21, 32) is not understood. Neonatal
diabetes is sometimes accompanied by mental and motor
developmental delay, epilepsy, and muscle weakness, a condition known as DEND syndrome (32). Patients with intermediate DEND (iDEND) syndrome have neonatal diabetes coupled
with delayed speech and walking and may also show muscle
weakness (32).
Neonatal diabetes is caused by mutations in a number of
different genes, but studies over the last three years have
shown that the commonest mutations are in KCNJ11 (Kir6.2)
and ABCC8 (SUR1) (3, 8, 16, 19, 23, 32, 65). Patients with
ND-Kir6.2 mutations are all heterozygotes (3, 32) whereas
ND-SUR1 mutations are genetically more heterogeneous, with
heterozygotes, homozygotes, and compound heterozygotes all
being described (8, 16, 65). In the case of Kir6.2 mutations,
there is a reasonable correlation between genotype and the
clinical phenotype (3, 32). It is still too early to know whether
this is also the case for SUR1 mutations.
To date, over 30 gain-of-function mutations in Kir6.2 associated with neonatal diabetes have been identified, the most
prevalent being at residues R201 and V59 (19, 32). These
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and as early as 1996 we identified a commonly occurring
variant at residue 23 of Kir6.2 (E23K) (72). Excitingly, the K
variant occurred with a greater frequency in the diabetic
population, but in our studies the difference was not significant
(the sample of 100 patients was far too small), so no conclusion
could be drawn. It is now known that this polymorphism does
indeed convey an increased risk of type 2 diabetes. However,
the increase in risk is modest—the odds ratio is 1.2—and it
required large population studies involving thousands of patients and controls to demonstrate the association (25, 90).
It was obvious, even when we were genotyping type 2
diabetic patients for mutations in Kir6.2, that we were really
looking at the wrong population. Type 2 diabetes typically
develops late in life, whereas a severe monogenic disorder
would be expected to manifest at birth, like CHI. However, at
that time, all the clinicians I consulted told me that neonatal
diabetes did not exist. Subsequently it turned out this was
wrong: such patients were extremely rare, and most clinicians
had simply not come across them.
Andrew Hattersley, however, knew that such patients existed despite their rarity. He also recognized that studies of
patients with monogenic diabetes could potentially identify
new genes that regulated insulin secretion and provide novel
insights into type 2 diabetes. He therefore set up an international collection of patients with neonatal diabetes and began
screening their DNA for mutations in candidate genes. I shall
never forget the telephone call I received from Andrew and
Anna Gloyn telling me they had found the first mutation in
Kir6.2 associated with neonatal diabetes. It was a truly exciting
day. Equally exciting was our subsequent discovery that the
mutation impaired ATP inhibition of the KATP channel (23).
Of Mice and Men: Mouse Models of Hyperinsulinism
and Diabetes
AJP-Endocrinol Metab • VOL
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Invited Review
E884
THE WALTER B. CANNON LECTURE
All Kir6.2 and SUR1 ND mutations that have been functionally analyzed to date are gain-of-function mutations that
produce an increase in the resting whole cell KATP current.
This is predicted to reduce glucose-dependent depolarization of
the ␤-cell membrane, thus preventing activation of Ca2⫹ currents, electrical activity, Ca2⫹ influx, and insulin secretion (76).
Functional Effects of Kir6.2 Mutations Causing
Neonatal Diabetes
mutations cluster around the putative ATP-binding site or lie in
regions of the protein involved in channel gating, such as the
slide helix, the cytosolic mouth of the channel, or the gating
loops that link the ATP-binding site to the slide helix (Fig. 2).
They may also affect residues involved in intrasubunit interactions. Functional analysis of ND-Kir6.2 mutations has provided useful insights into the working of the KATP channel.
More recently, gain-of-function mutations have been also identified in the SUR1 subunit (8, 16, 65). These are dispersed
throughout the protein sequence but are particularly concentrated in the first five transmembrane helices and connecting
loops, the third cytosolic linker, and in NBD2.
Fig. 3. ATP sensitivity correlates with disease severity.
For neonatal diabetes caused by Kir6.2 mutations, disease
severity correlates with the extent of unblocked KATP
current measured in inside-out patches at 3 mM MgATP.
Different phenotypes can be produced by the same molecular mechanism: i.e., impaired ATP binding (purple
stars) or changes in gating (green stars). For those mutations without stars, no single-channel kinetics have been
measured and the molecular mechanism is unclear.
DEND, DEND syndrome (developmental delay, epilepsy
and neonatal diabetes). iDEND, intermediate DEND syndrome. The number of patches varies from 6 to 9. Data
are taken from Refs. 32, 50, 64, 67, 68, 77, 78, 82.
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Fig. 2. Location of disease-causing mutations in Kir6.2. Model of the Kir6.2
tetramer viewed from the side. For clarity, the transmembranes of only 2
subunits and the intracellular domains of 2 separate subunits are illustrated.
ATP is docked into its binding sites. Residues that are mutated in neonatal
diabetes are shown in ball-and-stick format.
The effects of more than 20 ND-Kir6.2 mutations on KATP
channel properties have been explored by heterologous expression of recombinant channels (3, 21, 32, 50, 64, 67, 68, 77, 82).
Because all patients are heterozygotes, the heterozygous state
has been simulated by coexpression of wild-type and mutant
Kir6.2 with SUR1. The increase in KATP current caused by
ND-Kir6.2 mutations results from an impaired ability of
MgATP to close the KATP channel. ATP concentration-response curves reveal that Kir6.2 mutations may shift the ATP
concentration at which channel inhibition is half-maximal to
higher ATP concentrations and/or may lead to some KATP
current remaining unblocked even at saturating ATP concentrations. In all cases, however, the magnitude of the KATP
current at physiologically relevant ATP concentrations (i.e.,
that expected in the presence of glucose) is increased. All
ND-Kir6.2 mutations increase the KATP current at 3 mM
MgATP at least 20-fold, and those mutations that cause DEND
syndrome have the greatest effect (Fig. 3). There appears to be
no clear correlation, however, between the magnitude of the
KATP current and whether the mutation causes permanent or
relapsing-remitting neonatal diabetes.
Neonatal diabetes mutations that lie within the putative
ATP-binding site of Kir6.2 are considered to impair channel
inhibition at Kir6.2 by interfering with nucleotide binding (3,
32, 50, 64, 77). While the electrophysiological data are entirely
consistent with this view, this has yet to be demonstrated in
biochemical studies. Many mutations, however, appear to affect ATP inhibition indirectly by altering KATP channel gating
(21, 64, 67, 68). These mutations stabilize the intrinsic open
state of the channel (i.e., that in the absence of ATP), which
shifts the gating equilibrium in the presence of ATP towards
channel opening and thus indirectly reduces the channel ATP
Invited Review
THE WALTER B. CANNON LECTURE
sensitivity. Such gating mutations are found in regions of
Kir6.2 considered to be involved in opening and closing of the
pore (30).
SUR1-ND mutations also act by a variety of molecular
mechanisms. They may stabilize the open state of the KATP
channel and thereby indirectly impair ATP inhibition at Kir6.2
(65). Other mutations, however, do not alter the inhibitory
effect of ATP but instead enhance the stimulatory effect of
Mg-nucleotides (8).
Extrapancreatic Effects of ND Mutations
Implications for Therapy of ND Patients
Before the discovery that ND can be caused by mutations in
the KATP channel, it was assumed these patients suffered from
an unusually early onset form of type 1 diabetes. Thus they
were treated with insulin. The discovery that ND patients
possess gain-of-function mutations in KATP channel genes
immediately suggested another therapy: sulfonylureas should
stimulate insulin secretion in these patients by closing their
KATP channels (Fig. 4). Andrew Hattersley’s group were the
first to introduce sulfonylurea therapy for patients with Kir6.2
mutations that cause neonatal diabetes (23) and have now
shown that over 90% of these “insulin-dependent” patients can
be managed by sulfonylureas alone (62). Importantly, not only
is their quality of life enhanced but there is also a significant
improvement in their blood glucose control. Fluctuations in
blood glucose are reduced (93), and there is a marked decrease
in their HbA1C levels (which provides a measure of their
average blood glucose level during the proceeding weeks) (62).
The improvement in blood glucose would be expected to
reduce the risk of diabetic complications (12, 89).
As in nondiabetics, oral glucose is much more effective than
intravenous glucose at eliciting insulin secretion in patients
treated with sulfonylureas (62). This is because oral glucose
triggers the release of incretins such as glucagon-like peptide-1
(GLP-1) and gastrointestinal peptide (GIP) from the gut. These
hormones are unable to elicit insulin secretion alone, because
they do not close KATP channels. However, if intracellular
Ca2⫹ has been elevated by closure of KATP channels, they are
able to amplify insulin secretion (6). As expected, incretins
have no effect in ND patients with KATP channel mutations
prior to sulfonylurea therapy, because blood glucose levels do
not shut KATP channels (62) (Fig. 4A). Following sulfonylurea
treatment and KATP channels closure, however, they are able to
amplify insulin secretion (Fig. 4B).
Sulfonylureas are very effective at treating patients with
Kir6.2 mutations that cause neonatal diabetes without neurological complications. Functional analysis has shown that the
mutations these patients carry have little effect on sulfonylurea
block on KATP channels (62, 93). In contrast, sulfonylureas
were not effective in patients with Kir6.2 mutations that cause
Fig. 4. Sulfonylureas stimulate insulin secretion in neonatal diabetes due to KATP channel mutations. A: gain-of-function mutations in KATP channel subunits
prevent the channel from closing in response to metabolically generated changes in adenine nucleotides. Consequently, the ␤-cell membrane remains
hyperpolarized even when blood glucose levels are elevated, thereby keeping voltage-gated Ca2⫹ channels closed and preventing insulin secretion. Incretins are
ineffective as intracellular Ca2⫹ levels are low. B: sulfonylureas bypass the metabolic steps and bind directly to the KATP channel, causing it to close. This triggers
depolarization of the ␤-cell membrane potential, opening of voltage-gated Ca2⫹ channels, Ca2⫹ influx, and insulin secretion in patients with gain-of-function
mutations in KATP channels. Incretins are also now effective.
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Kir6.2 is widely expressed throughout the body, being found
in heart, skeletal muscle, various endocrine cells, peripheral
axons, and multiple types of brain neurons (37, 41, 71).
Gain-of-function mutations in Kir6.2 are therefore expected to
reduce the electrical excitability of these cells. This can account for the neurological and motor defects found in DEND
patients: the epilepsy can be explained as a result of reduced
activity of inhibitory neurons.
That much larger KATP currents appear to be required to
affect extrapancreatic tissues may reflect differences both in
cell metabolism and in the complement of ion channels that
regulate the cell membrane potential. The ␤-cell is unusual in
that KATP channel activity dominates the resting membrane
potential and in that channel activity is sensitive to changes in
extracellular glucose (in many cell types, KATP channels open
only during ischemia).
Although Kir6.2 is expressed in the heart (37, 71) and forms
the pore of the cardiac KATP channel (18), no obvious cardiac
abnormalities have been reported in patients carrying Kir6.2
mutations. Similarly, mice engineered to carry gain-of-function
Kir6.2 mutations that are expressed only in the heart are not
substantially affected (43). This conundrum may be explained
by the fact that coexpression of mutant Kir6.2 with the cardiac
type of SUR (SUR2) produces a very much smaller increase in
the KATP current at physiologically relevant ATP concentrations than coexpression with SUR1 (83). This seems to be
because Mg-nucleotide activation is enhanced by SUR1 but not
SUR2A (49, 52, 83).
E885
Invited Review
E886
THE WALTER B. CANNON LECTURE
DEND syndrome, presumably because these particular mutations strongly impaired the ability of sulfonylureas to block the
KATP channel (62).
Although it is still early days, there are an increasing number
of cases in which sulfonylureas have been able to ameliorate
the muscle weakness found in patients with iDEND syndrome
and, to a variable extent, their motor and mental developmental
delay (78, 81). Thus, while insulin cannot ameliorate the
extrapancreatic effects of ND mutations, sulfonylureas may be
able to do so because they can close overactive KATP channels
in all tissues to which they have access.
KATP Channels and Glucose Homeostasis: a Question
of Balance
Beyond the Frontiers
Twenty-three years on from the discovery that the KATP
channel is important in insulin secretion, many key questions
remain unanswered and there is much to do. The atomic
structure of the individual subunits, Kir6.2 and SUR1, have
still to be resolved, something that is essential if we are to
unequivocally identify the binding sites for drugs and nucleotides. The structure of the whole octameric KATP channel
complex would be even more valuable as this might help
clarify how interaction of Mg-nucleotides or drugs with SUR1
is transmitted to Kir6.2 to modulate K⫹ flux through the
channel pore.
Precisely how most SUR1 mutations that cause neonatal
diabetes influence KATP channel activity is yet to be discovered. Likewise, how the E23K polymorphism in Kir6.2
enhances the risk of type 2 diabetes is still unclear. Functional studies have yielded conflicting results, with both a
decrease (75) and an increase (69) in ATP inhibition being
reported. Furthermore, it is puzzling that the reported reduction in ATP sensitivity (75) is similar to that found for mutations
that cause permanent neonatal diabetes (67, 77, 82).
At the clinical level, it is important to determine the extent
to which sulfonylureas can ameliorate the extrapancreatic
symptoms of patients with iDEND and DEND syndrome.
There is also a question of the choice of sulfonylurea: it seems
logical that a SUR1-specific drug might be advisable for
patients with SUR1 mutations, but would it also be beneficial
in patients with Kir6.2 mutations? Why older PNDM patients
respond less well to sulfonylurea therapy requires elucidation,
as does the mechanism by which severe Kir6.2 mutations lead
to motor and mental developmental delay, muscle weakness,
and epilepsy. No doubt, mice carrying disease-causing mutations will be helpful in this respect.
AJP-Endocrinol Metab • VOL
ACKNOWLEDGMENTS
I thank the many brilliant students and post-docs who have enlivened my
life and my research over the years. I also thank my wonderful colleagues and
collaborators for much stimulating debate and criticism. It is invidious to single
out individuals, but I particularly wish to thank Stephen Ashcroft for introducing me to the world of the ␤-cell (and no, he is no relation despite his
name), Patrik Rorsman for over 20 years of stimulating collaboration and
friendship, Andrew Hattersley for a wonderfully productive collaboration—
and for choosing us to work with on the KATP channel mutations he identified,
and Mark Sansom for our recent fruitful and enjoyable collaboration. I also
thank the Wellcome Trust, the Royal Society, Diabetes UK, and the European
Union for supporting my research, and the Royal Society for a Research
Professorship. Finally, I emphasize that this is very much my own perspective
on the history of the KATP channel; others in the field may, of course, see it in
a different light.
REFERENCES
1. Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP 4th, Boyd
AE 3rd, Gonzalez Herrerasosa H, Nguy K, Bryan J, Nelson DA.
Cloning of the beta-cell high-affinity sulphonylurea receptor: a regulator
of insulin secretion. Science 268: 423– 425, 1995.
2. Antcliff JF, Haider S, Proks P, Sansom MSP, Ashcroft FM. Functional
analysis of a structural model of the ATP-binding site of the KATP channel
Kir6.2 subunit. EMBO J 24: 229 –239, 2005.
3. Ashcroft FM. ATP-sensitive potassium channelopathies: focus on insulin
secretion. J Clin Invest 115: 2047–2058, 2005.
4. Ashcroft FM, Harrison DE, Ashcroft SJH. Glucose induces closure of
single potassium channels in isolated rat pancreatic ␤-cells. Nature 312:
446 – 448, 1984.
5. Ashcroft FM, Kakei M. ATP-sensitive K-channels: modulation by ATP
and Mg2⫹ ions. J Physiol 416, 349 –367, 1989.
6. Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic ␤-cell.
Prog Biophys Mol Biol 54: 87–143, 1989.
7. Ashcroft SJ. Glucoreceptor mechanisms and the control of insulin release
and biosynthesis. Diabetologia 18: 5–15, 1980.
8. Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann
R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating
mutations in the ABCC8 gene in neonatal diabetes mellitus. New Engl
J Med 355: 456 – 466, 2006.
9. Baukrowitz T, Fakler B. KATP channels: Linker between phospholipid
metabolism and excitability. Biochem Pharmacol 60: 735–740, 2000.
10. Cook DL, Hales CN. Intracellular ATP directly blocks K⫹ channels in
pancreatic ␤-cells. Nature 311: 271–273, 1984.
11. Detimary P, Dejonghe S, Ling Z, Pipeleers D, Schuit F, Henquin JC.
The changes in adenine nucleotides measured in glucose-stimulated rodent
islets occur in beta cells but not in alpha cells and are also observed in
human islets. J Biol Chem 273: 33905–33908, 1998.
12. Diabetes Control, and Complications Trial Research Group. The
effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med 329: 977–986, 1993.
13. Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley
KJ. Hyperinsulinism in infancy: from basic science to clinical disease.
Physiol Rev 84: 239 –275, 2004.
14. Dunne MJ, Petersen OH. Intracellular ADP activates ATP-sensitive K⫹
channels in an insulin-secreting cell line. FEBS Lett 208: 59 – 62, 1986.
15. Edghill EL, Gloyn AL, Gillespie KM, Lambert AP, Raymond NT,
Swift PG, Ellard S, Gale EA, Hattersley AT. Activating mutations in the
KCNJ11 gene encoding the ATP-sensitive K⫹ channel subunit Kir6.2 are
rare in clinically defined type 1 diabetes diagnosed before 2 years.
Diabetes 5:2998 –3001, 2004.
16. Ellard E, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish
A, Edghill EL, Mackay DJG, Proks P, Shimomura K, Haberland H,
Carson DJ, Shield JPH, Hattersley AT, Ashcroft FM. Permanent
neonatal diabetes caused by dominant, recessive or compound heterozy-
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In summary, KATP channel activity makes an important
contribution to glucose homeostasis. When these channels are
shut, insulin is secreted, and when they are open, insulin
release is prevented. KATP channel activity is tightly regulated
by the ␤-cell metabolism, and if this coupling is disturbed,
insulin secretion is perturbed. Thus, diabetes results when
KATP channels fail to close in response to enhanced metabolism, and congenital hyperinsulinism results when KATP channels remain open even when plasma glucose levels fail. Very
small changes in KATP channel activity are sufficient to produce marked changes in insulin secretion. As Walter Cannon
reminds us, homeostasis is a finely balanced affair.
These are but a few of the many questions in the field.
Answering them may take another 20 years, but it is bound to
be an exciting journey. For young scientists looking for a
discipline that embraces both basic and clinical science, the
KATP channel has much to offer.
Invited Review
THE WALTER B. CANNON LECTURE
17.
18.
19.
20.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
AJP-Endocrinol Metab • VOL
36. Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft Laakso M
FM. A new subtype of autosomal dominant diabetes due to the E1506K
substitution in the sulfonylurea receptor 1 gene. Lancet 361: 301–307, 2003.
37. Inagaki N, Gonoi T, Clement IVJP, Namba N, Inazawa J, Gonzalez G,
Aguilar-Bryan L, Seino S, Bryan J. Reconstitution of IKATP: An inward
rectifier subunit plus the sulfonylurea receptor. Science 270: 1166 –1169,
1995.
38. Inagaki N, Gonoi T, Seino S. Subunit stoichiometry of the pancreatic
beta-cell ATP-sensitive K⫹ channel. FEBS Lett 409: 232–236, 1997.
39. Kane GC, Liu XK, Yamada S, Olson TM, Terzic A. Cardiac KATP
channels in health and disease. J Mol Cell Cardiol 38: 937– 43, 2005.
40. Kakei M, Kelly RP, Ashcroft SJH, Ashcroft FM. The ATP-sensitivity
of K⫹ channels in rat pancreatic ␤-cells is modulated by ADP. FEBS Lett
208: 63– 66, 1986.
41. Karschin C, Ecke C, Ashcroft FM, Karschin A. Overlapping distribution of KATP channel-forming Kir6.2 subunit and the sulfonylurea receptor
SUR1 in rodent brain. FEBS Lett 401: 59 – 64, 1997.
42. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–
2025: prevalence, numerical estimates, and projections. Diabetes Care 21:
1414 –1431, 1998.
43. Koster JC, Knopp A, Flagg TP, Markova KP, Sha Q, Enkvetchakul D,
Betsuyaku T, Yamada KA, Nichols CG. Tolerance for ATP-insensitive
K-ATP channels in transgenic mice. Circ Res 89: 1022–1029, 2001.
44. Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG. Targeted
overactivity of beta cell KATP channels induces profound neonatal diabetes. Cell 100: 645– 654, 2000.
45. Koster JC, Remedi MS, Flagg TP, Johnson JD, Markova KP, Marshall BA, Nichols CG. Hyperinsulinism induced by targeted suppression
of beta cell KATP channels. Proc Natl Acad Sci USA 99: 16992–16997,
2002.
46. Koster JC, Remedi MS, Masia R, Patton B, Tong A, Nichols CG.
Expression of ATP-insensitive KATP channels in pancreatic beta-cells
underlies a spectrum of diabetic phenotypes. Diabetes 55: 2957–2964,
2006.
47. Kuo AL, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J,
Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA. Crystal structure of
the potassium channel KirBac1.1 in the closed state Science 300: 1922–
1926, 2003.
48. Larsson O, Deeney JT, Bränström R, Berggren PO, Corkey BE.
Activation of the ATP-sensitive K⫹ channels by long chain acyl-CoA.
J Biol Chem 271: 10623–10626, 1996.
49. Masia R, Enkvetchakul D, Nichols CG. Differential nucleotide regulation of KATP channels by SUR1 and SUR2A. J Mol Cell Cardiol 39:
491–501, 2005.
50. Masia R, Koster JC, Tumini S, Chiarelli F, Colombo C, Nichols CG,
Barbetti F. An ATP-binding mutation (G334D) in KCNJ11 is associated
with a sulfonylurea-insensitive form of developmental delay, epilepsy, and
neonatal diabetes. Diabetes 56: 328 –336, 2007.
51. Matsuo M, Tanabe K, Kioka N, Amachi T, Ueda K. Different binding
properties and affinities for ATP and ADP among sulfonylurea receptor
subtypes, SUR1, SUR2A, and SUR2B. J Biol Chem 275: 28757–28763,
2002.
52. Matsuoka T, Matsushita K, Katayama Y, Fujita A, Inageda K,
Tanemoto M, Inanobe A, Yamashita S, Matsuzawa Y, Kurachi Y.
C-terminal tails of sulfonylurea receptors control ADP-induced activation
and diazoxide modulation of ATP-sensitive K⫹ channels. Circ Res 87:
873– 880, 2000.
53. Mikhailov MV, Campbell JD, de Wet H, Shimomura K, Zadek B,
Collins RF, Sansom MSP, Ford RC, Ashcroft FM. 3-D structural and
functional characterization of the purified KATP channel complex Kir6.2SUR1. EMBO J 24: 4166 – 4175, 2005.
54. Miki T, Seino S. Roles of KATP channels as metabolic sensors in acute
metabolic changes. J Mol Cell Cardiol 38: 917–925, 2005.
55. Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto
A, Gonoi T, Iwanaga T, Miyazaki J, Seino S. Defective insulin secretion
and enhanced insulin action in KATP channel-deficient mice. Proc Natl
Acad Sci USA 95: 10402–10406, 1998.
56. Miki T, Tashiro F, Iwanaga T, Nagashima K, Yoshitomi H, Aihara H,
Nitta Y, Gonoi T, Inagaki N, Miyazaki J, Seino S. Abnormalities of
pancreatic islets by targeted expression of a dominant-negative KATP
channel. Proc Natl Acad Sci USA 94: 11969 –71193, 1997.
57. Nestorowicz A, Inagaki N, Gonoi T, Schoor KP, Wilson BA, Glaser B,
Landau H, Stanley CA, Thornton PS, Seino S, Permutt MA. A
nonsense mutation in the inward rectifier potassium channel gene, Kir6.2,
293 • OCTOBER 2007 •
www.ajpendo.org
Downloaded from http://ajpendo.physiology.org/ by 10.220.33.1 on June 16, 2017
21.
gous SUR1 mutations with opposite functional effects. Am J Hum Genetics. 81:375–382, 2007.
Fan Z, Makielski JC. Anionic phospholipids activate ATP-sensitive
potassium channels. J Biol Chem 272: 5388 –5395, 1997.
Flagg TP, Nichols CG. Sarcolemmal KATP channels: what do we really
know? J Mol Cell Cardiol 39: 61–70, 2005.
Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT. Mutations in
ATP-sensitive K⫹ channel genes cause Transient Neonatal Diabetes and
Permanent Diabetes in Childhood or Adulthood. Diabetes 56: 1930 –1937,
2007.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM,
Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B,
Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM,
Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin
MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I,
Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman
GA, Palmer CN, Doney AS, Morris AD, Davey-Smith G, The Wellcome Trust Case Control Consortium; Hattersley AT, McCarthy MI.
A common variant in the FTO gene is associated with body mass index
and predisposes to childhood and adult obesity. Science 316: 889 – 894,
2007.
Girard C, Shimomura K, Proks P, Absalom N, de Nanclares PG,
Ashcroft FM. Functional analysis of six Kir6.2 (KCNJ11) mutations
causing neonatal diabetes. Pflügers Arch 453: 323–332, 2006.
Gloyn AL. Glucokinase (GCK) mutations in hyper- and hypoglycemia:
maturity-onset diabetes of the young, permanent neonatal diabetes, and
hyperinsulinemia of infancy. Hum Mut 22: 353–362, 2003.
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining JG, Slingerland AS, Howard N, Srinivasan S, Silva JMCL, Molnes J, Edghill EL,
Frayling TM, Temple IK, Deborah Mackay D, Shield JPH, Sumnik Z,
van Rhijn A, Wales JKH, Clark P, Gorman S, Aisenberg J, Ellard S,
Njølstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the
gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and
permanent neonatal diabetes. N Engl J Med 350: 1838 –1849, 2004.
Gloyn AL, Siddiqui J, Ellard S. Mutations in the genes encoding the
pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1
(ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mut 27: 220 –
231, 2006.
Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman
G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI,
Hattersley AT, Frayling TM. Large-scale association studies of variants
in genes encoding the pancreatic ␤-cell KATP channel subunits Kir6.2
(KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is
associated with type 2 diabetes Diabetes 52: 568 –572, 2003.
Gribble FM, Proks P, Corkey BE, Ashcroft FM. Mechanism of cloned
KATP channel activation by oleyol-CoA. J Biol Chem 273: 26383–26387,
1998.
Gribble FM, Reimann F. Sulphonylurea action revisited: the postcloning era. Diabetologia 46: 875– 891, 2003.
Gribble FM, Tucker SJ, Ashcroft FM. The essential role of the Walker
A motifs of SUR1 in KATP channel activation by Mg-ADP and diazoxide.
EMBO J 16: 1145–1152, 1997.
Gribble FM, Tucker SJ, Haug T, Ashcroft FM. MgATP activates the
beta cell KATP channel by interaction with its SUR1 subunit. Proc Natl
Acad Sci USA 95: 7185–7190, 1998.
Haider S, Antcliff JF, Proks P, Sansom MSP, Ashcroft FM. Focus on
Kir6.2: a key component of the ATP-sensitive potassium channel. J Mol
Cell Cardiol 38: 927–936, 2005.
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved
patch-clamp techniques for high-resolution current recording from cells
and cell-free membrane patches. Pflügers Arch 391: 85–100, 1981.
Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new
therapy. Diabetes 54: 2503–2513, 2005.
Henquin JC. D-Glucose inhibits potassium efflux from pancreatic islet
cells. Nature 271: 271–273, 1978.
Henquin JC. The fiftieth anniversary of hypoglycaemic sulphonamides.
How did the mother compound work? Diabetologia 35: 907–912, 1992.
Henquin JC, Meissner HP. Significance of ionic fluxes and changes in
membrane potential for stimulus-secretion coupling in pancreatic ␤-cells.
Experientia 40: 1043–1052, 1984.
E887
Invited Review
E888
58.
59.
60.
61.
62.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
is associated with familial hyperinsulinism. Diabetes 46: 1743–1748,
1997.
Nichols CG. KATP channels as molecular sensors of cellular metabolism.
Nature 440: 470 – 476, 2006.
Nichols CG, Shyng SL, Nestorowicz A. Adenosine diphosphate as an
intracellular regulator of insulin secretion. Science 272: 1785–1787, 1996.
Nishida M, MacKinnon R. Structural basis of inward rectification:
cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8Å
resolution. Cell 111: 957–965, 2002.
Noma A. ATP-regulated K⫹ channels in cardiac muscle. Nature 305:
147–148, 1983.
Pearson ER, Flechtner I, Njølståd PR, Neonatal Diabetes International Collaborative Group, Malecki MT, Flanagan S, Larkin B,
Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J,
Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley
AT. The successful transfer of insulin treated patients with diabetes due to
Kir62 (KCNJ11) mutations to sulphonylurea tablets. N Eng J Med 355:
467– 477, 2006.
Prentki M, Matschinsky FM. Ca2⫹, cAMP, and phospholipid-derived
messengers in coupling mechanisms of insulin secretion. Physiol Rev 67:
1185–1248, 1987.
Proks P, Antcliff JF, Lippiat J, Gloyn A, Hattersley AT, Ashcroft FM.
Molecular basis of Kir6.2 mutations associated with neonatal diabetes or
neonatal diabetes plus neurological features. Proc Natl Acad Sci USA 101:
17539 –17544, 2004.
Proks P, Arnold A, Bruining J, Girard C, Flanagan SE, Larkin B,
Colclough K, Hattersley AT, Ashcroft FM, Ellard SE. A heterozygous
activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes
neonatal diabetes. Hum Mol Genet 15: 1793–1800, 2006.
Proks P, Girard C, Ashcroft FM. Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol
Genet 14: 2717–2726, 2005.
Proks P, Girard C, Bvre H, Njolstad PR, Ashcroft FM. Functional
effects of mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11),
causing neonatal diabetes, and response to sulphonylurea therapy. Diabetes 55: 1731–1737, 2006.
Proks P, Girard C, Haider S, Gloyn AL, Hattersley AT, Sansom MSP,
Ashcroft FM. A novel gating mutation at the internal mouth of the Kir6.2
pore is associated with DEND syndrome. EMBO Rep 6: 470 – 475, 2005.
Riedel MJ, Boora P, Steckley D, de Vries G, Light Kir6 PE.2.
polymorphisms sensitize beta-cell ATP-sensitive potassium channels to
activation by acyl CoAs: a possible cellular mechanism for increased
susceptibility to type 2 diabetes? Diabetes 52: 2630 –2635, 2003.
Rorsman P, Trube G. Glucose dependent K⫹-channels in pancreatic
beta-cells are regulated by intracellular ATP. Pflügers Arch 405: 305–309,
1985.
Sakura H, Ämmalä C, Smith PA, Gribble FM, Ashcroft FM. Cloning
and functional expression of the cDNA encoding a novel ATP-sensitive
potassium channel subunit expressed in pancreatic beta cells, brain, heart
and skeletal muscle. FEBS Lett 377: 338 –344, 1995.
Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM.
Sequence variations in the human Kir6.2 gene, a subunit of the ␤-cell
ATP-sensitive K-channel: no association with non-insulin dependent diabetes in white Caucasian subjects or evidence of abnormal function when
expressed in vitro. Diabetologia 39: 1233–1237, 1996.
Seghers V, Nakazaki M, DeMayo F, Aguilar-Bryan L, Bryan J. Sur1
knockout mice. A model for KATP channel-independent regulation of
insulin secretion. J Biol Chem 275: 9270 –9277, 2000.
Sehlin J, Taljedal IB. Glucose-induced decrease in Rb⫹ permeability in
pancreatic beta cells. Nature 253: 635– 636, 1975.
Schwanstecher C, Meyer U, Schwanstecher M. K(IR)6.2 polymorphism
predisposes to type 2 diabetes by inducing overactivity of pancreatic
beta-cell ATP-sensitive K⫹ channels. Diabetes 51: 875– 879, 2002.
Shih DQ, Stoffel M. Molecular etiologies of MODY and other early-onset
forms of diabetes. Curr Diab Rep 2: 125–134, 2002.
Shimomura K, Girard CAJ, Proks P, Nazim J, Lippiat JD, Cerutti F,
Lorini R, Ellard S, Hattersely A, Barbetti F, Ashcroft FM. Mutations
at the same residue (R50) of Kir6.2 (KCNJ11) produce different functional
effects. Diabetes 55: 1705–1712, 2006.
Shimomura K, Hörster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, Wolf NI, Ashcroft FM, Ebinger F. A novel mutation causing
DEND syndrome—a treatable channelopathy of pancreas and brain. Neurology 2007 [Published on-line July 25, PMID 17652641].
AJP-Endocrinol Metab • VOL
79. Shyng SL, Nichols CG. Membrane phospholipid control of nucleotide
sensitivity of KATP channels. Science 282: 1138 –1141, 1998.
80. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P,
Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G,
Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI,
Balding DJ, Meyre D, Polychronakos C, Froguel P. A genome-wide
association study identifies novel risk loci for type 2 diabetes. Nature 445:
881– 885, 2007.
81. Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ. Improved motor development and good long-term glycaemic
control with sulfonylurea treatment in a patient with the syndrome of
intermediate developmental delay, early-onset generalised epilepsy and
neonatal diabetes associated with the V59M mutation in the KCNJ11
gene. Diabetologia 49: 2559 –2563, 2006.
82. Tammaro P, Girard C, Molnes J, Njølstad PR, Ashcroft Kir6 FM.2.
mutations causing neonatal diabetes provide new insights into Kir6.2SUR1 interactions. EMBO J 24: 2318 –2330, 2005.
83. Tammaro P, Proks P, Ashcroft FM. Functional effects of naturally
occurring KCNJ11 mutations causing neonatal diabetes on cloned cardiac
KATP channels. J Physiol 571: 3–14, 2006.
84. Tarasov A, Dusonchet J, Ashcroft FM. Metabolic regulation of the
pancreatic B-cell KATP channel: a pas de deux. Diabetes 53: S123–S127,
2004.
85. Tarasov A, Welters HJ, Senkel S, Ryffel GU, Hattersley AT, Morgan
NG, Ashcroft Kir6 FMA.2. mutation causing neonatal diabetes impairs
electrical activity and insulin secretion from INS-1 beta cells. Diabetes 55:
3075–3082, 2006.
86. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W,
Aguilar-Bryan L, Gagel RF, Bryan J. Mutations in the sulfonylurea
receptor gene in familial persistent hyperinsulinemic hypoglycemia of
infancy. Science 268: 426 – 429, 1995.
87. Trube G, Rorsman P, Ohno-Shosaku T. Opposite effects of tolbutamide
and diazoxide on the ATP-dependent K⫹ channel in mouse pancreatic
beta-cells. Pflügers Arch 407: 493– 499, 1986.
88. Tucker SJ, Gribble FM, Zhao C, Trapp S, Ashcroft Truncation of
Kir6 FM.2. produces ATP-sensitive K channels in the absence of the
sulphonylurea receptor. Nature 387: 179 –181, 1997.
89. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 352: 837– 853, 1998.
90. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS,
Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett
JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini
JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris
AD, Doney AS; Wellcome Trust Case Control Consortium (WTCCC),
Burton PR, Clayton DG, Craddock N, Deloukas P, Duncanson A,
Kwiatkowski DP, Ouwehand WH, Samani NJ, Todd JA, Donnelly P,
Davison D, Easton D, Evans D, Leung HT, Spencer CC, Tobin
MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley
JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE,
Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones
RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St
Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK,
Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G,
Moskvina V, Nikolov I, O’donovan MC, Owen MJ, Collier DA, Elkin
A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball
SG, Balmforth AJ, Barrett JH, Bishop DT, Iles MM, Maqbool A,
Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S,
Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond
H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM,
Onnie CM, Prescott NJ, Sanderson J, Mathew CG, Barbour J,
Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings
FR, Jewell DP, Webster J, Brown MJ, Lathrop GM, Connell J,
Dominiczak A, Braga Marcano CA, Burke B, Dobson R, Gungadoo J,
Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M,
Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre
S, Gilbert PD, Hider SL, Hinks AM, John SL, Potter C, Silman AJ,
Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B,
Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA,
Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA,
Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman
N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M,
Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwil-
293 • OCTOBER 2007 •
www.ajpendo.org
Downloaded from http://ajpendo.physiology.org/ by 10.220.33.1 on June 16, 2017
63.
THE WALTER B. CANNON LECTURE
Invited Review
THE WALTER B. CANNON LECTURE
liam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S,
Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ,
Ferreira T, Pereira-Gale J, Hallgrimsdóttir IB, Howie BN, Su Z, Teo
YY, Vukcevic D, Bentley D, Compston A, Ouwehand NJ, Samani MR,
Isaacs JD, Morgan AW, Wilson GD, Ardern-Jones A, Berg J, Brady
A, Bradshaw N, Brewer C, Brice G, Bullman B, Campbell J, Castle B,
Cetnarsryj R, Chapman C, Chu C, Coates N, Cole T, Davidson R,
Donaldson A, Dorkins H, Douglas F, Eccles D, Eeles R, Elmslie F,
Evans DG, Goff S, Goodman S, Goudie D, Gray J, Greenhalgh L,
Gregory H, Hodgson SV, Homfray T, Houlston RS, Izatt L, Jackson
L, Jeffers L, Johnson-Roffey V, Kavalier F, Kirk C, Lalloo F, Langman C, Locke I, Longmuir M, Mackay J, Magee A, Mansour S,
Miedzybrodzka Z, Miller J, Morrison P, Murday V, Paterson J,
Pichert G, Porteous M, Rahman N, Rogers M, Rowe S, Shanley S,
E889
Saggar A, Scott G, Side L, Snadden L, Steel M, Thomas M, Thomas
S, McCarthy MI, Hattersley AT. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science
316: 1336 –1341, 2007.
91. Zerangue N, Schwappach B, Jan YN, Jan LY. A new ER trafficking
signal regulates the subunit stoichiometry of plasma membrane KATP
channels. Neuron 22: 537–548, 1999.
92. Zingman LV, Alekseev AE, Bienengraeber M, Hodgson D, Karger
AB, Dzeja PP, Terzic A. Signaling in channel/enzyme multimers:
ATPase transitions in SUR module gate ATP-sensitive K⫹ conductance.
Neuron 31: 233–245, 2001.
93. Zung A, Glaser B, Nimri R, Zadik Z. Glibenclamide treatment in
permanent neonatal diabetes mellitus due to an activating mutation in
Kir6.2. J Clin Endocrinol Metab 89: 5504 –5507, 2004.
Downloaded from http://ajpendo.physiology.org/ by 10.220.33.1 on June 16, 2017
AJP-Endocrinol Metab • VOL
293 • OCTOBER 2007 •
www.ajpendo.org