Vol. 283, Issue 3, E403-E412, September 2002
INVITED REVIEW
Diabetes and insulin secretion: whither KATP?
C. G.
Nichols and
J. C.
Koster
Department of Cell Biology and Physiology, Washington
University School of Medicine, St. Louis, Missouri 63110
 |
ABSTRACT |
The critical involvement of ATP-sensitive
potassium (KATP) channels in insulin secretion is confirmed
both by the demonstration that mutations that reduce
KATP channel activity underlie many if not most cases of
persistent hyperinsulinemia, and by the ability of sulfonylureas, which
inhibit KATP channels, to enhance insulin secretion in type
II diabetics. By extrapolation, we contend that mutations that increase
-cell KATP channel activity should inhibit glucose-dependent insulin secretion and underlie, or at least predispose to, a diabetic phenotype. In transgenic animal models, this
prediction seems to be borne out. Although earlier genetic studies
failed to demonstrate a linkage between KATP mutations and
diabetes in humans, recent studies indicate significant association of
KATP channel gene mutations or polymorphisms and type II
diabetes. We suggest that further efforts to understand the involvement of KATP channels in diabetes are warranted.
ATP-sensitive potassium channels; pancreas; Kir6.2; SUR1
| |
METABOLITE REGULATION OF INSULIN SECRETION |
In the pancreas, the ATP-sensitive potassium
(KATP) channel is proposed to be a critical link in
glucose-induced insulin release from pancreatic -cells (Fig.
1A) (6, 10, 62).
According to this paradigm, during the fed state, when glucose
metabolism is increased, pancreatic KATP channels are
inhibited by a high intracellular ATP-to-ADP concentration ratio
([ATP]/[ADP]). This depolarizes the plasma membrane, which leads to
Ca2+ entry through voltage-dependent Ca2+
channels, or VDCC, thereby stimulating insulin secretion. A rise in
circulating serum insulin, in turn, leads to an increased glucose uptake in the periphery and a compensatory drop in blood glucose. Conversely, a falling intracellular [ATP]/[ADP] during the fasting state is presumed to relieve inhibition of KATP channels,
resulting in membrane hyperpolarization and cessation of insulin
release. Sulfonylurea drugs remain in use as major hypoglycemic agents in the treatment of type II diabetes (37). These agents
cause insulin secretion and act by inhibiting KATP channel
activity through the regulatory SUR1 subunit (2), which
emphasizes the central role of the KATP-dependent pathway
in regulation of insulin secretion. However, this pathway is
modulated by so-called KATP-independent mechanisms, and it
is important to bear in mind that glucose and other nutrient
metabolites, as well as incretins, act as "gain modulators" at
various additional stages of the insulin secretory process and thereby
can enhance the signal through the KATP-dependent pathway
(3).
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Fig. 1.
A: role of ATP-sensitive potassium
(KATP) channels in normal coupling of glucose levels to
insulin secretion. Increased blood glucose leads to a rise in -cell
[glucose] and hence increased [ATP]/[ADP]. This normally
(left) closes KATP channels, causing
depolarization of the cell, activation of calcium (Ca2+)
channels, Ca2+ entry, and insulin secretion. Decreased
glucose metabolism (due to decreased glucokinase activity) or
maintained KATP channel activity (due to ATP insensitivity
or increased channel density) would be expected to inhibit insulin
secretion. B: probable membrane topology of SUR1 and Kir6.2,
indicating mutations associated with type II diabetes. ATP inhibits
KATP channels by binding to the Kir6.2 subunit. Nucleotide
hydrolysis at the SUR1 nucleotide binding folds (NBFs) or MgADP binding
counteracts the inhibitory effect of ATP in channel activity.
C: steady-state [ATP] dependence of KATP
current (Irel) in -cell membranes from
wild-type and Kir6.2[ N30] transgenic mice (from Ref.
52). In transgenic mice, ATP sensitivity was decreased
~4-fold, and the curve was shallowed. D: as a consequence,
the relative current through transgenic channels is expected to be
significantly elevated within the physiological range of [ATP].
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According to the model, alterations in the metabolic signal, in the
responsiveness of the KATP channel to metabolites, or in
the number of active KATP channels should lead to altered
release of insulin. Increased metabolic flux, increased
KATP sensitivity to inhibitory nucleotides, or reduced
density of KATP channels should all lead to abnormally low
KATP activity and relative hyperinsulinism (HI).
Conversely, decreased metabolic flux, decreased KATP
sensitivity to inhibitory nucleotides, or increased density of
KATP channels should all lead to abnormally high
KATP activity and relative hypoinsulinism and a
predisposition to non-insulin-dependent diabetes mellitus (NIDDM) (Fig.
1A). The purpose of this prospective is to summarize the
clear picture that is emerging regarding the causal role of decreased
KATP channel activity in HI and to marshal the accumulating
evidence from both animal and human studies in support of the second
postulate, that relative KATP overactivity may be a potent
causal factor in NIDDM.
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MOLECULAR BASIS OF THE KATP CHANNEL |
KATP channels are generated as a complex of four
pore-forming Kir6.2 subunits, each of which is associated with a
sulfonylurea receptor (SUR1) subunit (Fig. 1B)
(7). Kir6.2 subunits surround the central ion-conducting
pore, and nucleotide inhibition results from the binding of ATP to
specific regions in the cytoplasmic domains of Kir6.2. However,
systematic mutagenesis of the Kir6.2 subunit has demonstrated that
residues throughout the subunit can affect the ATP sensitivity of the
channel allosterically (14, 18, 57, 85, 87, 94-96).
Although the native KATP channel is inhibited by micromolar
ATP, ATP sensitivity can be almost completely abolished by individual
point mutations. SUR1 is a member of the ATP binding cassette, or ABC,
family of membrane proteins, each of which contains two classical
nucleotide binding folds (NBFs) (39). Biochemical and
electrophysiological experiments have demonstrated that nucleotide
hydrolysis at both NBFs is involved in KATP channel
stimulation by MgADP and by potassium channel-opening drugs such as
diazoxide (8, 25, 86, 97). Thus, the net determinant of
physiological activity is the combined effect of ATP inhibition through
Kir6.2 and the counteracting effects of ATP hydrolysis and MgADP
binding in the NBFs of SUR1 (86) (Fig. 1B).
| |
KATP OVER- OR UNDERACTIVITY AS A CAUSAL MECHANISM OF
DIABETES AND HYPERINSULINISM |
Persistent hyperinsulinemia is caused by underactive
KATP channels.
The relatively rare but severe disease known as nesidioblastosis, or
persistent HI, results from maintained insulin secretion in the
face of low blood glucose (41). Untreated, this disease causes severe brain damage in neonates. Very few, and rather coarse, treatments are available, namely, glucose infusion, administration of
the drug diazoxide, and eventually 75-100% pancreatectomy, the
latter inevitably leading to later-onset diabetes (41). Recent efforts have defined mutations of SUR1 and
Kir6.2 subunits that are linked to HI (65, 66,
92), and most cases of HI involve defects in
SUR1 or Kir6.2 (84). These mutations
typically result in reduced or abolished channel activity, predicted to cause maintained -cell depolarization and persistent insulin secretion. These important advances establish a clear link between KATP channel defects and the HI disease, and the different
phenotypes that result from different mutations have begun to give some
insight into the variability of treatment efficacies, such as the
variable efficacy of the KATP channel-opening drug
diazoxide (65, 66).
Diabetes can be caused by relative KATP overactivity:
glucokinase mutations are causal in HI and diabetes.
One form of maturity onset diabetes of the young (MODY2) is frequently
associated with reduced glucokinase activity (16, 22, 29, 78,
100, 101). Glucokinase catalyzes the conversion of glucose to
glucose 6-phosphate, the first reaction of glycolysis, and reduced
glucokinase activity will reduce the glycolytic flux, hence lowering
[ATP]/[ADP], increasing KATP channel activity, and
thereby reducing insulin secretion (68, 77). In direct contrast, some forms of HI have been shown to result from an enhanced activity of glucokinase (23). Overactive glucokinase will
therefore increase glycolytic flux, providing a stronger inhibitory
signal (i.e., elevated [ATP]/[ADP]) to the KATP
channel, and hence increasing insulin secretion for a given glucose level.
Thus, in the case of glucokinase, it seems clear that human disease
mutations that render KATP channels underactive (reduced or
absent KATP channels themselves, or secondary to
glucokinase overactivity) cause HI as a result of uncontrolled insulin
secretion. Flipping the coin, there is also clear evidence that human
disease mutations that render KATP channels overactive
(secondary to glucokinase underactivity) in MODY2 cause diabetes as a
result of reduced insulin secretion. The missing piece in this
otherwise very simple yin-yang picture is a lack of evidence from early
studies for overactive KATP mutations causing diabetes.
However, as we will consider, animal studies suggest that even mildly
overactive KATP channels may significantly affect insulin
secretion, and from reconsideration of human patient studies there
clearly emerges a probable link.
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GENETIC MANIPULATION OF KATP IN MICE: MODELS OF HI AND
DIABETES? |
Knockout and dominant-negative models of hyperinsulinemia.
Although it is quite clear that underactive KATP channels
cause HI in humans, there has been variable success at generating mouse
models for HI by knockout of the SUR1 or Kir6.2
gene (61, 83). In particular, a lack of overt HI and
hypoglycemia has reduced their apparent relevance.
Miki et al. (61) first generated transgenic mice
expressing a dominant-negative mutant of Kir6.2
(Kir6.2[G132S]) in -cells under control of the insulin promoter.
This mutation abolishes KATP currents, causing elevation of
intracellular calcium concentration ([Ca2+]i). Neonatal transgenic mice exhibit
relatively high levels of serum insulin despite hypoglycemia, thus
resembling HI in humans, but they rapidly develop hyperglycemia and
reduced insulin secretion. Adult mice show enhanced -cell
apoptosis and reduced number of -cells. Both
Kir6.2 and SUR1 genes have subsequently been
knocked out by homologous recombination, and quite similar phenotypes result (60, 83). In both cases, the mice show a transient hypoglycemia as neonates, glucose-dependent insulin secretion is
greatly reduced or abolished, and older animals are glucose intolerant
(61, 83). Abnormally elevated insulin-to-glucose ratios
were really only observed in the 1st day of life for SUR1
/ mice,
and by day 5, the situation had reversed to a hyperglycemic phenotype. Certain incretins can bypass the KATP channel to
induce insulin secretion more directly, and even though glucose-induced insulin secretion is greatly reduced or abolished in these knockout animals, in each case there is minimal impairment of glucose tolerance, and blood glucose is normal in young animals.
Thus these various knockout animals reiterate the expected cellular
phenotypes (i.e., abolition of KATP channels and elevated [Ca2+]i) that are expected to underlie HI.
However, in no case was persistent HI observed, and rapid reversal of
any transient neonatal hypoglycemia resulted in a hyperglycemic or
diabetic phenotype. The reasons for the lack of correlation between the
mouse and human phenotypes with HI are not entirely clear. Although
temporally uncorrelated, there is evidence that HI patients may cross
over to a diabetic phenotype in later life, although this has generally been attributed to the near-total pancreatectomy that is acutely required to treat the neonatal symptoms (56). However,
there are recent studies indicating that nonsurgically treated HI
patients may become diabetic in later life (26, 40).
Conceivably, -cell death [as observed in mice expressing Kir6.2
dominant-negative Kir6.2 constructs (61)], coupled with a
decreased glucose-dependent insulin release [as demonstrated in both
knockout mice (60, 83) and in SUR1/ HI patients
(26)], may underlie a later-onset diabetes.
Severe diabetes in mice expressing overactive -cell
KATP channels with reduced ATP sensitivity.
KATP dependence of insulin secretion could be blocked
either by abolition of KATP channel activity (as we have
described) or by raising channel activity to a constant, unregulated
level. Mutations that make channel activity high may therefore be
expected to cause a primary hypoinsulinemic diabetes. To test this
prediction, we generated Kir6.2[N30]-green fluorescein protein
(GFP) transgenic mice (52). The transgene
construct contains a deletion of 30 amino acids from the
NH2 terminus and a COOH-terminal GFP tag. In cell lines,
the N30 deletion reduces the ATP sensitivity of the expressed
KATP channel by ~10-fold. The phenotype of the mice is
striking and appears to dramatically confirm a critical requirement for
KATP closure in order for insulin secretion to occur
(52). All progeny from four of the founders developed
severe hyperglycemia, hypoinsulinemia, and ketoacidosis. Almost all
died within the first 5 days of birth, most likely as a result of
dehydration combined with ketoacidosis. We attempted back-crossing onto
various mouse strains, but in all cases, neonatal lethality of the
transgene was observed.
KATP channels in transgenic -cells had reduced ATP
sensitivity (Fig. 1C) compared with control, and there were
no morphological abnormalities at the earliest stages of the disease.
Together, these results indicate that the single relevant defect is
likely to be a failure of insulin release due to increased
KATP channel activity. Most striking about this conclusion
is that the change in ATP sensitivity in isolated -cell channels is
only about fourfold. However, as illustrated in Fig. 1D, the
relevant region of the ATP-sensitivity curve is at the very foot of
activation (10), and in the physiological (i.e.,
millimolar) range of [ATP], the relative current through transgenic
channels is expected to be significantly elevated.
Mild impairment of glucose tolerance in mice expressing lower
levels of Kir6.2[N30] transgene: a window to a late-onset model of
KATP-induced diabetes?
In marked contrast to the four severely diabetic lines we have
described (52), progeny from a fifth (D-line) founder
carrying the Kir6.2[N30] transgene developed apparently normally,
with normal blood glucose levels, and were fertile (B. Marshall,
J. C. Koster, and C. G. Nichols, unpublished observations).
Analysis of isolated islets from these progeny mice reveals
undetectable levels of green fluorescence in most islet cells, but
invariably one or a few -cells (<2%) show an intense green
fluorescence. These fluorescing cells express KATP channels
with ATP insensitivity in the range expected for channels including
Kir6.2[N30] subunits. The extent of electrical coupling between
-cells is incompletely understood (50, 64), but it is
possible that expression of ATP-insensitive KATP channels
in only a few cells might contribute to suppression of excitability
throughout the islet. Glucose-dependent insulin secretion does not seem
to be significantly impaired in these mice; however, it is possible
that, under some conditions, residual KATP channel activity
of just a few -cells in the islet may suppress excitability. We
examined the possibility that this activity might be a latent
determinant of diabetes induced by diet. Paired transgenic and
nontransgenic D-line littermates were fed a high-fat diet for 12 mo.
Diabetogenicity of this regimen was significantly more severe in the
transgenic mice than in the littermate controls as assessed by more
significantly impaired glucose tolerance. Although the underlying
pancreatic defect remains to be clearly established, these data are an
indication that even very mild KATP overactivity may
actually predispose to a diabetic phenotype. Coupled with the severe
consequences of about fivefold reduction of ATP sensitivity of
KATP channels (52), it may be expected that
very subtle KATP overactivity in the human pancreas may
predispose to a diabetic phenotype (further discussion follows).
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OTHER EXPERIMENTAL MODELS OF INHERITED DIABETES AND HI: WHAT
EMERGES FROM GENETIC MODELS? |
NIDDM results from effective exhaustion of the pancreatic -cell
and nonresponsiveness to elevated glucose. This end result could be
caused by a whole host of factors, ensuring that no single therapeutic
approach would be successful for treatment and that no model for
induction would suffice to fully explain the disease process. Many
transgenic mice expressing different proteins under insulin promoter
control in -cells have now been generated to examine the specific
consequences of altered gene expression in -cells. Table
1 summarizes the results of a large
number of studies and illustrates some common traits that arise from
manipulation of gene expression in -cells. We can roughly group the
phenotypes of the mice into four classes: 1) progressive
-cell disappearance, often with lymphocyte infiltration, and
insulin-dependent diabetes mellitus; 2) HI and hypoglycemia;
3) mild phenotypes, often with normoglycemia; 4)
reduced insulin secretion without, or preceding, loss of -cells.
In many or most cases, the phenotype is readily explained by the known
actions of the proteins involved. There are actually few studies in
which transgene expression leads to nonspecific -cell destruction
and diabetes, and only three or four models (in class 4)
that reiterate the phenotype that we observed in Kir6.2[N30]-GFP
transgenic mice (52). Specifically, of all the studies
considered in Table 1, only homozygous glucokinase knockouts and
calmodulin-overexpressing mice show profound neonatal hyperglycemia and
hypoinsulinemia, with normal, or near-normal, morphology and insulin
content. Two separate glucokinase knockout mouse lines both showed
severe perinatal diabetes, with death occurring within 1 wk (27,
91). The study of Sakura et al. (77) demonstrated
that the electrical activity of isolated -cells from knockout
animals was completely normal, with the single exception that
inhibition of KATP channels and consequent generation
of action potentials (and hence insulin secretion) in response to elevated glucose were completely abolished. Given the
similarity of the HI disease resulting from either glucokinase
overactivity (23) or KATP underactivity
(47), the phenotypic identity between these glucokinase
knockout mice (77) and our Kir6.2[N30]-GFP mice
(52) provides important support for the argument that the profound neonatal diabetes, with normal islet architecture and insulin
content, is due to KATP channel overactivity and not to nonspecific protein overproduction.
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LINKAGE BETWEEN KATP MUTATIONS AND TYPE II
DIABETES? |
Numerous control-based genetic studies in the past five years have
focused on the possible association of polymorphisms in KATP and the development of type II (NIDDM) diabetes in
distinct human populations. Multiple initial linkage studies of highly polymorphic markers near the Kir6.2 and SUR1 gene
loci (located 4.5 kb apart on the human chromosome 11p15.1) failed to
implicate KATP as a primary diabetogene in various type II
diabetic populations (42, 43, 45, 89, 103). However, given
the multifactorial and complex nature of the disorder, a subordinate
role in a subgroup of type II diabetic subjects or in other ethnic
groups could not be precluded. More recently, numerous population-based
studies have investigated the association of genetic variants within
the Kir6.2 and SUR1 genes with an increased
susceptibility to type II diabetes in distinct ethnic subgroups. A
summary of the more common KATP variants identified and of
their linkage with type II diabetes is presented in Table
2.
SUR1 polymorphisms.
A majority of the identified polymorphisms (Table 2) map to the larger
SUR1 gene, with fewer localized to the pore-forming Kir6.2. These sequence variants include numerous missense
and silent mutations, an intronic nucleotide transversion, as well as
an intronic nucleotide insertion. Notably, linkage disequilibrium studies of the SUR1 gene have implicated the intronic nucleotide transversion [intron 16 (3t
c)] with an increased
susceptibility to type II diabetes in various cohorts (combined Utah
and United Kingdom group of Ref. 43) and in different
Caucasian (33, 59) and Japanese (67)
populations. Consistent with a possible role in -cell dysfunction,
the intron 16 (3tc) variant has recently been shown to
be associated with impaired second-phase insulin secretion during
hyperglycemic clamp in both normal and impaired glucose-tolerant Dutch
subjects (38). In addition, a combined at-risk genotype of
the intron 16 (3ct) variant and the missense mutation
in exon 18 T759T (ACC-ACT)
is coupled with a 50% reduction in serum C-peptide and a 40%
reduction in serum insulin responses upon tolbutamide injection in
normoglycemic subjects (36). Alone, the exon 18 T759T
silent mutation is also linked with type II diabetes as well as morbid
obesity in a French Caucasian cohort (34). Although not a
coding region mutation, these findings suggest that the intron 16 (3tc) variant, located in a splice acceptor site, is
associated with a functional change in the KATP channel in
the -cell, possibly through an effect on the stability or splicing
of the mRNA product. Alternatively, the polymorphism could be in
linkage disequilibrium with nearby sequence variants within the
SUR1 gene or flanking genes that directly underlie the
-cell dysfunction. The latter explanation now appears likely, as
both intron 16 (3tc) (34, 43, 59) and
(3ct) (24, 36, 38, 67, 76) transversions
have been shown to be significantly associated with type II diabetes in
various cohorts (43), RT-PCR analysis encompassing intron 16 showed no aberrant mRNA splicing, and the genotype does not uniformly cosegregate with type II diabetes in the various study populations, inconsistent with a role as a major diabetogenic polymorphism. Thus, as with the SUR1 silent mutation at exon
18 (T759T), the increased susceptibility to type II diabetes observed with the intron 16 (3tc) genotype likely reflects a
linkage disequilibrium with diabetogenic variant(s) located within the SUR1 gene or in flanking genes.
As we have outlined, the paradigm of glucose-induced insulin release
predicts that KATP overactivity (which would occur if the
channel had decreased sensitivity to inhibitory ATP or an increased
sensitivity to stimulatory MgADP) should lead to suppressed insulin
release due to impaired glucose sensing by the -cell. Missense
mutations, which change amino acid sequence, are of particular relevance with respect to channel function. Of the six missense mutations in SUR1 identified, three (exon 20 D811N, exon 21 R835C, and exon 33 S1369A) are localized to the NBFs of SUR1 (Fig.
1B, shown in bold in Table 2). Given the critical regulatory
role of the NBFs in KATP channel function (8, 25, 86,
97), these mutations are likely to alter channel activity.
However, neither the D811N nor the R835C mutations reportedly alter
sensitivity to inhibitory ATP or activation by metabolic inhibition
when expressed in transfected mammalian cells (67).
Although these data do not preclude subtle changes in channel function
that could underlie -cell dysfunction, they seem to indicate that
both the D811N and R835C mutations may be in linkage disequilibrium
with a genetic variant either at or near the SUR1 locus, a
disequilibrium that contributes to the inherited basis of type II diabetes.
Kir6.2 polymorphisms.
Mutations in the ATP-sensing Kir6.2 subunit that reduce sensitivity of
the channels to inhibitory ATP are predicted to maintain the
hyperpolarized membrane potential of the -cell despite an increased
[ATP/ADP] and, thereby, block the depolarization-dependent rise in
[Ca2+]i necessary to stimulate insulin
release. This is confirmed in the Kir6.2[N30] mouse model,
in which overactive KATP channels abolish insulin
secretion, leading to an overt diabetic phenotype (52). In
this case, the observation that a modest fourfold decrease in ATP
sensitivity of the channels can result in such a profound diabetic
phenotype raises the intriguing possibility that similarly ATP-insensitive mutants of KATP may underlie diabetes in
the human population.
As shown in Table 2, several linkage studies have identified both
missense and silent mutations in the Kir6.2 gene. Of these the E23K, I337V, and L270V have been shown to be significantly associated with type II diabetes, either alone [E23K in both a French
Caucasian population (33) and the UKPDS cohort
(42)] or in combination, as was observed with the
compound homozygous E23K/I337V with heterozygous L270V [Danish
Caucasian population (35)]. The point mutation (E23K),
originally considered a common polymorphism without association to
diabetes (35, 42, 79), is of particular interest. A
subsequent meta-analysis (33), combining all four studies
of various Caucasian populations and an independent study of UK
populations (24), reveals strong association of homozygous
E23K with type II diabetes (
2 = 12.9, P < 0.00033). Homozygous E23K (frequency in the
overall population = 12%) increases the odds ratio (the estimate
for the genotypic relative risk) to 2.14, thus accounting for 11% of
the disease (33). Even the heterozygous mutation has a
slight increase in susceptibility to the disease (odds ratio = 1.24), thereby accounting for another 9% (frequency in the overall
population = 47%) of type II diabetics.
Previous functional analyses failed to show a significant effect of any
one of the E23K, I337V, or L270V mutations on sensitivity of
reconstituted KATP channels expressed in Xenopus
oocytes to either metabolic inhibition or to the sulfonylurea
tolbutamide, suggesting that gross channel activity is unaltered
(79). However, detailed analyses of single-channel
properties and sensitivities to the regulatory nucleotides were not
made. Recent electrophysiological measurements have now demonstrated a
modest but significant effect of the Kir6.2 (E23K) mutation
on channel activity with respect to both open probability (i.e., the
percentage of the time the channel exists in an open state vs. a closed
state) and ATP sensitivity (82). When coexpressed with
SUR1, the Kir6.2 (E23K/E23K) genotype resulted in a halving
of the sensitivity to inhibitory ATP and an increase of open
probability (82). Because KATP channels operate physiologically at the very foot of the activation curve (Fig.
1D) (10), the net effect of such a shift in
sensitivity will be to increase current by about fourfold at 500 µM
ATP, thereby potentially significantly shifting the physiological
glucose dependence of activity to higher glucose concentrations, and to
inhibit insulin secretion.
Given our findings that similarly overactive -cell KATP
channels underlie profound neonatal hyperglycemia in a transgenic mouse
model of diabetes (52), these data raise the intriguing possibility that the K/K genotype may contribute to impaired insulin secretion in human populations. Thus the transgenic animal studies and
the electrophysiological studies of E23K imply a compelling mechanism
by which inherited changes in KATP activity can contribute to development of the disorder.
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PERSPECTIVES AND PROSPECTS |
Although more studies are necessary to establish a direct effect
on insulin secretion, recent work suggests that mutations in
KATP or regulatory proteins that result in subtle increase of channel activity can cause diabetes in animals and may contribute to
an increased susceptibility to type II diabetes in human populations. Relative KATP channel overactivity could be generated
either by changing the nucleotide responsiveness of channels, by
changing the metabolic signal itself, or simply by increasing the
density of otherwise normal KATP channels. Only very
recently have noncoding regions of these genes begun to be examined for
possible diabetes association (24), and significant
regions of the genes have yet to be examined. Undoubtedly, the etiology
of type II diabetes is likely to involve a complex contribution of both
environmental and genetic factors and may differ between populations.
Nevertheless, there are significant unexplored possible mechanisms by
which genetic mutations of KATP genes or the chromosomal
regions controlling KATP expression may contribute causally
to diabetes.
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ACKNOWLEDGEMENTS |
Our own experimental work has been supported by National Institute
of Diabetes and Digestive and Kidney Diseases Grant DK-55282 (to
C. G. Nichols) and by the Washington University Diabetes Research and Training Center.
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FOOTNOTES |
Address for reprint requests and other correspondence:
C. G. Nichols, Dept. of Cell Biology and Physiology,
Washington Univ. School of Medicine, St. Louis, MO 63110 (E-mail:
cnichols{at}cellbio.wustl.edu).
10.1152/ajpendo.00168.2002
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