1 Department of Pediatrics, Kuopio University Hospital, Kuopio 70211; 3 Transplantation Laboratory, Haartman Institute and Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland 00014; 3Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland, Oregon 97201; and 4 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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ATP-sensitive potassium
(KATP) channels are inhibited by intracellular ATP and
activated by ADP. Nutrient oxidation in -cells leads to a rise in
[ATP]-to-[ADP] ratios, which in turn leads to reduced
KATP channel activity, depolarization, voltage-dependent Ca2+ channel activation, Ca2+ entry, and
exocytosis. Persistent hyperinsulinemic hypoglycemia of infancy (HI) is
a genetic disorder characterized by dysregulated insulin secretion and,
although rare, causes severe mental retardation and epilepsy if left
untreated. The last five or six years have seen rapid advance in
understanding the molecular basis of KATP channel activity
and the molecular genetics of HI. In the majority of cases for which a
genotype has been uncovered, causal HI mutations are found in one or
the other of the two genes, SUR1 and Kir6.2, that encode the
KATP channel. This article will review studies that have
defined the link between channel activity and defective insulin release
and will consider implications for future understanding of the
mechanisms of control of insulin secretion in normal and diseased states.
ATP-sensitive potassium; hyperinsulinemic hypoglycemia of infancy; pancreas; Kir6.2; diabetes; SUR1
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INTRODUCTION: THE INSULIN SECRETION PARADIGM |
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ATP-sensitive potassium (KATP)
channels are a unique class of potassium channels with the hallmark
physiological properties of being inhibited by intracellular ATP and
activated by ADP. Their role in regulation of insulin secretion from
the islets of Langerhans has long been recognized (5).
Decreased blood glucose leads to a fall in -cell glucose
concentration and, hence, a decreased [ATP]-to-[ADP] ratio. This
opens KATP channels, causing hyperpolarization of the cell
and consequent closure of calcium (Ca2+) channels, block of
Ca2+ entry, and suppression of insulin secretion (Fig.
1A). However, there have been
lingering arguments that this straightforward scenario cannot account
for the entire picture of insulin secretion. In particular, insulin
secretion occurs in two phases, an early transient phase and a
secondary sustained phase (24). In isolated pancreatic islets, maximal depolarization of the cells by exposure to
high [K+] causes only a transient insulin release; under
conditions in which KATP channels may be continuously
activated by diazoxide, a glucose-dependent release of insulin can
still be seen (18).
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Thus a concept is developing that KATP-dependent inhibition of Ca2+ entry and vesicle release is the major mechanism for regulating insulin secretion, but that KATP-independent mechanisms must modulate it or provide alternative pathways for controlling insulin secretion (4). In this regard, recent animal studies, in which the KATP channel proteins have been directly manipulated, have raised more questions than they have answered (see ANIMAL MODELS OF HI). Nevertheless, the weight of evidence from studies of the genetic basis of hypoglycemic hyperinsulinemia provides compelling evidence for a critical role of KATP in linking nutrient levels to insulin secretion. The purpose of this article is to review the extensive work of the last few years that has defined this link and to consider unanswered questions and implications for future understanding of the mechanisms of control of insulin secretion in normal and clinical conditions.
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CONGENITAL HYPERINSULINEMIA, OR PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA OF INFANCY: A BREAKDOWN IN THE REGULATION OF INSULIN SECRETION |
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Persistent hyperinsulinemic hypoglycemia of infancy (HI), also referred to as congenital hyperinsulinism, is a genetic disorder characterized by dysregulated insulin secretion (8) and is the most common cause of persistent and recurrent hypoglycemia in infancy. The typical incidence of the disease is estimated to be ~1:50,000 live births, but in some areas of high consanguinity, it is as high as 1:3,000 (10, 34, 36). The clinical phenotype is variable, but the disease can be a major cause of severe mental retardation and epilepsy if not treated properly (6, 37, 38). Due to the anabolic effect of insulin, the newborn with HI may be macrosomic at birth, thus resembling an infant of a diabetic mother and reflecting the prenatal hyperinsulinism; in most cases, symptoms of hypoglycemia (such as floppiness, jitteriness, poor feeding, and lethargy) appear during the first postnatal hours or days but in a few cases during the first year. The diagnosis of HI is based on the detection of 1) nonketotic hypoglycemia, 2) inappropriately high (measurable) insulin concentration and raised C-peptide at the point of hypoglycemia, and 3) increased glucose requirements to maintain normoglycemia. Low levels of serum free fatty acids and ketone bodies due to the antilipolytic effect of insulin at the time of hypoglycemia, as well as the glycemic response to glucagon administration, support the diagnosis of hyperinsulinism (7).
The KATP channel opener diazoxide, administered together
with chlorothiazide, is the mainstay of medical management of HI, and
hormones like somatostatin and glucagon are also of proven benefit.
However, some patients fail to respond to medical treatment, necessitating surgical removal of up to 95% of the pancreas to avoid
permanent neurological damage (7, 60). The responsivity of
some patients to drugs that activate KATP channels is
consistent with the proposed role of KATP channels in
controlling insulin secretion and with a relative deficiency of
KATP channel activity in these patients. Over the last five
years, there has been rapid advance in the molecular genetics of HI.
Although several mutations have been uncovered in genes encoding
metabolic enzymes (glucokinase, glutamate dehydrogenase), and the
molecular basis remains to be established in 50% of all cases, the
majority of causal mutations that have been uncovered are in the genes
encoding the KATP channel.
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HI MUTATIONS IN THE KATP CHANNEL GENES SUR1 AND KIR6.2: THE MOLECULAR BASIS OF THE DISEASE |
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Since the 1940s, it has been realized that binding of
sulfonylureas to a receptor in the -cell membrane can trigger
insulin secretion, and in the early 1980s it was demonstrated that
[3H]glibenclamide labeled an ~140-kDa protein in the
membranes of insulin-secreting cells. A subsequent determined
purification of the receptor resulted in the cloning of SUR1
(3), which generated KATP channels when
coexpressed with the cloned K channel subunit Kir6.2 (27)
(Fig. 1B). The channels are normally formed as an octamer
consisting of four Kir6.2 subunits that generate the pore and four SUR1
subunits (12, 28, 58). Although Kir6.2 tetramers can
generate channels in the absence of SUR1 (70), each
subunit carries an endoplasmic reticulum (ER) retention signal that is
shielded when complexed with the other subunit, allowing ER export and
the generation of channel activity at the surface membrane
(74). As we will consider, this multimeric nature of the
functional channel allows for the generation of complex
genotype-phenotype correlations when subunit mutations are present
heterozygously, as is likely in many HI patients.
Regulation of channel activity involves complex interactions with cytosolic nucleotides. Hallmark ATP inhibition occurs through nonhydrolytic interaction with the cytoplasmic domains of the Kir6.2 subunit (14, 32, 56, 63, 68-70) (Fig. 1C). Physiological activation probably results from the counteracting effect of ATP hydrolysis and MgADP binding occurring at SUR1 (5) (Fig. 1C). SUR1 is a member of the ATP binding cassette (ABC) family of membrane proteins, each of which contains two classical nucleotide binding folds (NBFs) (24a), capable of nucleotide binding and hydrolysis (75) (Fig. 1C). Examination of an HI disease-causing mutation (G1479R) in NBF2 (45) provided the first clue to the role of SUR1 in channel activation. This mutation selectively abolished MgADP (and diazoxide) stimulation of channel activity, with no effect on ATP inhibition. Similar results are obtained with multiple other introduced mutations in SUR1 (22, 57), consistent with nucleotide hydrolysis at the SUR NBFs being involved in channel stimulation by MgADP. Ueda et al. (71) showed that ATP binds to NBF1 and that this binding is stabilized by MgADP binding to NBF2 (72). Both NBFs of SUR2A are capable of hydrolyzing ATP (9), and mutations that reduce the ATPase activity produce channels with increased ATP sensitivity, consistent with a model whereby SUR acts as a "hypersensitivity switch" to modulate ATP sensitivity of channel activity (57, 75, 76), the hypersensitizing switch being turned off by ATP hydrolysis at the NBFs, with MgADP binding as a product analog, to stabilize the "activated" state (Fig. 1C).
Both SUR1 and Kir6.2 were localized to human chromosome 11p15.1, and
coincident with channel cloning efforts, a number of groups traced the
genetic locus of HI to the same region (3, 19, 66).
HI-associated SUR1 mutations were rapidly identified (67),
and more than 50 HI mutations have now been recognized in the SUR1 and
Kir6.2 genes (55). Most KATP channel defects resulting from HI mutations can be divided into two major functional categories: defects of expressed channel properties, and biosynthetic or trafficking defects that lead to lack of, or reduced, surface expression of channels. The first mutation shown to alter
KATP channel properties was an HI-associated missense
mutation (G1479R) in the NBF2 of SUR1 (45) (Fig.
1B). Recombinant channels encoded by this mutation in
hamster SUR1 behave essentially normally with respect to single channel
conductance and ATP sensitivity in inside-out membrane patches.
However, these channels do not respond to stimulation by MgADP,
rendering the channels "physiologically nonfunctional" because they
cannot open in response to a rise in [ADP] after glucose deprivation
(45). As a result, -cells are expected to remain
depolarized, and insulin secretion is expected to continue. Reduced
sensitivity to stimulation by MgADP is a defect of channels generated
by a number of HI-associated SUR1 mutations, including F591L, T1139M,
R1215Q, G1382S, and E1506K (25, 59) (Fig. 1B). These results suggest that a defective MgADP response is a common mechanism of HI and demonstrate the critical role of MgADP in activating KATP channels in physiological conditions.
Alteration of channel response to MgADP by HI mutations could be due to direct effects on nucleotide binding and hydrolysis at the NBFs or to defects in the subsequent coupling events that lead to channel opening. One HI mutation (SUR1[R1420C]) lowers the affinity of NBF2 for ATP and ADP and abolishes the cooperative binding between the two NBFs (36). Curiously, this biochemical defect was not immediately reflected in the EC50 for MgADP activation of channel activity when wild-type Kir6.2 was used for channel reconstitution, but because MgADP stimulates channel activity on one hand by interaction with SUR1, and inhibits channel activity on the other by interaction with Kir6.2, subtle difference in MgADP dose response may be masked. To separate these two opposing effects, Matsuo et al. (36) also examined SUR1 expressed with Kir6.2[R50G], a mutation that has greatly reduced sensitivity to ATP inhibition. Consistent with the biochemical data, the EC50 for MgADP activation of the SUR1[R1420C] + Kir6.2[R50G] mutant channel is about three times higher than that of wild-type SUR1 + Kir6.2[R50G] channels. Biochemical studies like this help map out the residues that are critical for direct nucleotide interaction and those that are involved in the functional coupling between SUR1 and Kir6.2.
A second major consequence of HI mutations in KATP subunits is reduced, or lack of, surface expression of channels. This is obvious for mutations that cause large truncation of SUR1 or Kir6.2 proteins. Mutations in the Kir6.2 gene, which is located five kilobases downstream of the SUR1 gene, actually seem to be relatively rare causes of HI, but the nonsense mutation Y12X, which leads to truncation of the protein after 12 amino acids, was detected in a single homozygous patient of a Palestinian Arab family (43). Two other recessively inherited HI-associated mutations in Kir6.2 have thus far been reported. A homozygous point mutation (L147P) is associated with a severe and drug-resistant form of HI in a patient of Iranian origin (65), and a third Kir6.2 mutation (W91R) was identified in a newborn of Palestinian descent with severe disease that required pancreatectomy (2). None of these mutations generated active KATP channels when coexpressed with wild-type SUR1. In the first case this is clearly due to lack of channel protein, but the mechanism of the latter two remains unknown, possibly reflecting altered trafficking or abolition of ion conductance. Two additional Kir6.2 mutations have recently been detected in one Finnish compound heterozygous patient (Huopio, H., unpublished observations). The first mutation is located before the translation start site and forms a new start codon and a frame shift. The other mutation causes an amino acid change from lysine to asparagine. The patient had a very severe form of HI and was treated with subtotal pancreatectomy at the age of 11 days.
A mutation in exon 35 of SUR1 causes a frame shift after R1437, resulting in a protein with an additional 23 extraneous amino acids and deletion of NBF2 (16). When coexpressed with Kir6.2 in COS cells, the mutant SUR1 again fails to generate active channels. One potential explanation is that truncation of NBF2 might cause defective trafficking of the channel complex, because it also removes an anterograde traffic signal encoded in the COOH terminus (54). However, Sakura et al. (48) reported that an SUR1 splice variant that introduced a frame shift after amino acid 1,330 did generate KATP current when coexpressed with Kir6.2 in Xenopus oocytes. In this case, NBF2 is also completely absent, but there is an addition of 25 novel amino acids after residue 1,330. The discrepancy between the two cases may be due to the nature of the additional amino acids introduced by the frame shift, but it is also possible that the requirements for trafficking and surface expression are different in Xenopus oocytes and mammalian cells.
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TRAFFICKING DEFECTS IN HI |
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A number of mutant proteins that do not express in mammalian cells
are expressed in Xenopus oocytes, an example being the common cystic fibrosis-causing mutation (F508) in the cystic fibrosis transmembrane regulator (CFTR), another ABC protein related to
SUR1 (15). Cartier et al. (11) recently
demonstrated that the mutation responsible for ~20% of Ashkenazi
Jewish HI (SUR1[
F1388]) causes both defective trafficking and lack
of surface expression of functional KATP channels and
altered channel function (Fig. 2A). The mutant protein
appears to be retained in the ER, like the CFTR[
F508] mutation.
Partridge et al. (47) subsequently reported that another
single amino acid mutation (R1394H) also causes defective trafficking
in mammalian cells, but rather than being retained in the ER, the
protein appears to accumulate in the Golgi. Interestingly, this defect
is also not observed when the mutant is expressed in Xenopus
oocytes.
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The finding that defective KATP channel trafficking is a
molecular basis of HI highlights the importance of understanding how
trafficking and surface expression of channels are regulated. Proper
cell surface expression of KATP channels is thought to be
under the control of a tripeptide ER retention signal (RKR) that is
present in both SUR1 and Kir6.2 subunits (74). When expressed independently, each protein is normally retained in the ER
due to exposure of the RKR signal; removal of the retention signal
allows either protein to escape the ER quality control mechanism and
express on the cell surface (70, 74). The association of
SUR1 and Kir6.2 is proposed to mutually shield the ER retention signals
and permit the channel complex to traffic to the cell surface. An
additional anterograde trafficking signal is present in the COOH
terminus of SUR1, and deletion of as few as seven amino acids from the
COOH terminus of SUR1 markedly reduces surface expression of
KATP channels (54). For such mutations,
manipulations that allow correction of the trafficking defects might be
of therapeutic value for the disease. Cartier et al. (11)
found that mutation of the RKR sequence to AAA leads to partial
expression of SUR1[F1388] mutant channels (Fig. 2A). In
this particular case, the now expressed channels also show the other
common HI defect and are still MgADP insensitive (Fig. 2B),
such that even if the trafficking defect were corrected, the mutant
channel would remain physiologically nonfunctional. Partridge et al.
(47) found that whereas lowering the temperature did not
improve surface expression of SUR1[R1394H], treatment with diazoxide
did, an effect that could be blocked by simultaneous treatment with
glibenclamide. It may be of potential therapeutic importance to
determine whether diazoxide treatment affects the expression efficiency
of wild-type channels and other trafficking mutant channels.
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EPIDEMIOLOGY OF HI: CLINICAL CORRELATIONS BETWEEN MUTATION AND DISEASE |
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Because KATP channels are formed as octamers,
consisting of four Kir6.2 and four SUR1 subunits, the degree of
dominance of any disease mutations is expected to correlate with the
degree of impairment of insulin release and severity of the HI disease that result. In heterozygous conditions, heteromeric channels will
predominate, and partial reductions of channel activity will be
expected. In cases where isolated -cells have been examined from HI
patients, complete inhibition of KATP channel activity leading to constitutive membrane depolarization, activation of voltage-gated Ca2+ channels, and inappropriate exocytosis
of insulin, regardless of the blood glucose levels, have been observed
(1, 29). In future studies, detailed analysis of
genotype-phenotype correlations for the wide range of different HI
mutations in KATP channel genes is likely to reveal a range
of phenotypic outcomes, given the low allelic frequencies of single
mutations and the fact that most patients with HI-associated mutations
are compound heterozygotes or have only a single identified mutation.
Patients from genetically isolated populations (like Ashkenazi Jews or
Finns) offer controlled cohorts for study of genotype-phenotype
correlations, and a database integrating the clinical, molecular
genetic, histopathological, and electrophysiological data of all
European patients is under development and will enable more detailed
correlation studies in the future (http://umd2.necker.fr:2007/).
One piece of evidence for genetic heterogeneity of HI is that specific
mutations in KATP channel genes may explain HI to varying degrees in different populations. For example, in the Japanese population, SUR1 mutations account for only ~20% of HI cases, whereas in Ashkenazi Jews, two single mutations account for 90% of all
cases (44, 64). The deletion of the codon for F1388 (F1388) was found to associate with 20% of the Ashkenazi Jewish HI-associated chromosomes (44). Homozygous
F1388 was
detected in only two patients, who both had a severe HI. The splice
site mutation 3992-9g
a, which has been detected in 70% of
Ashkenazi Jewish HI chromosomes, leads to variable phenotypic
expression of the disease (67): most patients who are
homozygous for this mutation have a severe drug-resistant form of the
disease, but others have mild HI and are clinically unaffected. The
clinical heterogeneity may be due to the effects of other genes or
exogenous factors that modify the phenotype, and individuals with
different phenotypes may express variable proportions of normal protein (44).
Two different founder mutations in the SUR1 gene are associated with
>50% of all HI cases in the Finnish population, and each mutation is
geographically clustered in distinct regions of the country (Fig.
3A). The recessively inherited
missense mutation V187D, located in a transmembrane domain of SUR1,
leads to severe early-onset HI (46). This disease is
geographically clustered in Central Finland (Fig. 3A), where
the incidence is as high as 1:3,200 births. Interestingly, the disease
phenotype is almost as severe in patients homozygous or heterozygous
for the mutation; even a single copy of the V187D mutation seems to
lead to a severe drug-unresponsive form of HI in compound
heterozygotes. However, carriers of this mutation (parents, siblings)
are asymptomatic and have normal insulin secretion, normal tissue
sensitivity to insulin, and no inappropriate insulin secretion during
hypoglycemia (26). Functional studies (intact cell
recordings, cell-free inside-out patches) of -cells isolated from an
HI patient homozygous for the V187D mutation, as well as the results of
recombinant KATP channel experiments, are consistent with
the phenotype and show that mutation SUR1[V187D] leads to a loss of
functional KATP channels that are not activated by
diazoxide or somatostatin.
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The dominantly inherited mutation SUR1(E1506K) (Fig. 3B) associates with a different phenotype (25). All patients have a mild form of HI that can usually be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of coexpression studies of recombinant wild-type (wt)-Kir6.2 and SUR1[E1506K]. Mutant channels are insensitive to metabolic inhibition, but a partial response to diazoxide is retained. Despite the dominant nature of SUR1[E1506K] in causing the disease, it does not exert a completely dominant negative effect when expressed together with the wild-type gene in Xenopus oocytes. Studies of glucose homeostasis in carriers of the SUR1[E1506K] mutation have indicated that this mutation leads to insulin deficiency and to development of diabetes mellitus in later life (25).
In roughly one-third of all cases, focal adenomatous hyperplasia (focal
HI), with somatic loss of maternal alleles in the imprinted chromosomal
region 11p15 along with paternally inherited KATP channel
mutations, leads to the HI phenotype (13, 17, 21, 73). The
focal form of HI may be genetically more homogenous than diffuse HI, as
it is linked to KATP channel gene mutations in almost
two-thirds of cases (17). The lost maternal region includes the nonimprinted SUR1 and Kir6.2 genes, the maternally imprinted tumor suppressor genes H19 and P57KIP2, and the
paternally imprinted insulin-like growth factor II, which plays a
central role in pancreatic tumorigenesis. The imbalance between the
tumor supressor genes and IGF-II leads to focal hyperplasia of
-cells, whereas the rest of the pancreas presents a normal histology
(53). Despite the differential genetic etiologies, the
clinical presentation of focal and diffuse forms of HI is similar, and
these two conditions can be distinguished only by selective venous
catheterization and perioperative microscopical examination of frozen
sections (52). In the case of focal HI, patients can be
treated by a partial resection of the focal lesion, whereas in the
diffuse form of the disease, subtotal pancreatectomy is often necessary
(33, 62).
Mutations in genes encoding the glucokinase (GK) and glutamate
dehydrogenase (GDH) enzymes are rare causes of HI. GK controls the
rate-limiting step of -cell glucose metabolism and is therefore critical in glucose-mediated insulin secretion (35).
Glaser et al. (20) described a unique autosomal dominant
missense mutation V455M in the GK gene that leads to increased glucose
affinity. The mutation was detected in a single family with five
affected individuals in three generations. All patients responded well to diazoxide treatment, consistent with the ability to bypass the
defect and activate KATP channels directly. Interestingly, insulin-deficient diabetes also developed later in life in the oldest
family member, suggesting that the mutation may cause gradual
-cell failure.
Hyperinsulinism-hyperammonemia (HIHA) is a syndrome caused by
dominantly inherited activating mutations in the GDH gene that simultaneously increase the release of insulin by pancreatic -cells and impair the detoxification of ammonia in the liver
(62). Most mutations are located in the allosteric
regulatory domain of the enzyme, but recent studies have described
mutations outside this region (41, 49, 61). Hypoglycemia
in patients with HIHA is generally less severe than in patients with
mutations in KATP channel genes. The clinical
manifestations of HIHA include normal birth weight, late onset of
hypoglycemia, diazoxide responsiveness, and protein-sensitive
hypoglycemia (62).
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ANIMAL MODELS OF HI |
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There has been variable success at generating mouse models for HI
by manipulation of the SUR1 or Kir6.2 genes (69, 70). Miki
et al. (40) first generated transgenic mice expressing a
dominant-negative mutant of Kir6.2 (Kir6.2[G132S]) in -cells under
control of the insulin promoter. The mutation alters the structure of
the K+ selectivity filter, rendering the channels either
nonfunctional or possibly slightly Na+ permeable
(42). KATP currents are significantly reduced
in isolated
-cells, and both resting membrane potential and basal intracellular calcium concentration ([Ca2+]i)
are consequently significantly higher than those of control mice.
Neonatal transgenic mice exhibit relatively high levels of serum
insulin despite hypoglycemia, resembling HI in humans, but the
transgenic mice rapidly develop hyperglycemia with reduced glucose-induced insulin secretion. Histological analysis reveals abnormal architecture of the islets of transgenic mice, with enhanced apoptosis and a marked decrease in the number of
-cells in
adult mice.
Miki et al. (39) subsequently knocked out the Kir6.2 gene
by homologous recombination to generate mice completely lacking KATP channels in -cells of homozygous (Kir6.2
/
)
mice, and again [Ca2+]i and membrane
potentials were elevated. The mice also show a transient hypoglycemia
as neonates similar to that of Kir6.2[G132S] transgenic mice. Again,
there is no glucose-dependent insulin secretion, and older animals are
glucose intolerant. Surprisingly, glucose tolerance is apparently
normal in young mice, and insulin tolerance is actually enhanced,
possibly a consequence of reduced KATP channel activity in
skeletal muscle cells.
Seghers et al. (50) generated SUR1 knockout mice. These
animals also completely lack KATP channels in -cells and
might reasonably be expected to provide the most appropriate HI model. First-phase insulin release is almost completely abolished, as in
Kir6.2
/
mice, and a second-phase insulin release is reduced compared with wild-type animals. Blood glucose levels are normal in
adult animals; however, consistent with an inability to "turn off"
insulin release by KATP channel activation, fasted
SUR1
/
mice did show statistically significant hypoglycemia relative to control SUR1+/+ mice (50). Nevertheless, frank
hypoglycemia and abnormally elevated insulin-to-glucose ratios were
really observed only in the 1st day of life for SUR1
/
mice,
and by day 5, the situation had reversed to a
hyperglycemic phenotype. Clearly, certain incretins can bypass the
KATP channel to more directly induce insulin secretion, and
even though glucose-induced insulin secretion is greatly reduced or
abolished in Kir6.2
/
and SUR1
/
mice, in each case there is
minimal impairment of glucose tolerance, and blood glucose is normal in
young animals. Insulin responses to either intraperitoneal glucose
loading or to meal ingestion are observed in Kir6.2
/
mice
(51), suggesting that mixed meal-induced insulin secretion
due to potentiating effects of incretins is retained (51).
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 hyperinsulinemia observed, and rapid
reversal of any transient neonatal hypoglycemia resulted in a
hyperglycemic, essentially diabetic, phenotype. The reasons for the
lack of correlation between the mouse phenotypes with HI in humans 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 been attributed to the near-total pancreatectomy that is acutely required to treat the neonatal symptoms (31).
However, as we have mentioned, there are recent studies indicating that nonsurgically treated HI patients may become diabetic in later life
(23, 25). Conceivably, -cell death [as observed in
mice expressing Kir6.2 dominant-negative Kir6.2 constructs
(40)], coupled with a decreased glucose-dependent insulin
release [as demonstrated in both knockout mice (39, 50)
and in SUR1
/
HI patients (23)] may underlie a later
onset of diabetes. In this context, it should be noted that, because
KATP-dependent insulin secretion requires dynamic
variations of KATP channel activity, dynamic control can be
abolished either by abolition of channel activity 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. In accord with this prediction, mice
expressing a gain-of-function Kir6.2[
N30] transgene that reduces
ATP sensitivity of expressed channels are dramatically hypoglycemic and
hyperinsulinemic as neonates, typically dying within 1 wk of birth
(30). It remains an open question whether any
gain-of-function KATP channel mutations underlie a MODY
(Maturity Onset Diabetes of the Young) or other non-type I diabetic
phenotype in humans.
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PERSPECTIVES |
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The last five or six years have seen dramatic elucidation of the molecular basis of KATP channel function and the role of KATP channels in insulin secretion, highlighted by the critical causative role of mutations of the channel subunits in the HI disease. Recombinant expression experiments have demonstrated the underlying molecular defects, and as patients are genotyped, the correlation of clinical phenotype with underlying defect is being pursued. It is important to note that the multimeric nature of the KATP channel will generate multiple channel phenotypes and consequences in a heterozygous condition, and this complexity will be compounded by the influences of other genes on both channel expression and the cellular metabolism and electrical substrates. Future phenotypic studies of KATP channel dysfunction in HI patients and in animal models should have implications both for understanding the pathophysiological mechanisms and potential treatments of the HI disease and also for mechanisms of impaired insulin secretion in the far more common type II diabetes.
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ACKNOWLEDGEMENTS |
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We are grateful to the numerous collaborators who have been involved with our own studies.
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FOOTNOTES |
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Our own experimental work has been supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-55282 to C. G. Nichols and DK-57699 to S. L. Shyng), the Juvenile Diabetes Foundation (Grant 196087 to T. Otonkoski), and the Foundation for Pediatric Research (to H. Huopio).
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.00047.2002
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