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).
|
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.
![]() |
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. ![]() |
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]) inSevere 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.
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).
![]() |
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.
![]() |
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 (
3t
c) 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 (
3c
t) 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 (
3t
c) 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 (
3t
c) (34, 43, 59) and
(
3c
t) (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 (
3t
c) genotype likely reflects a
linkage disequilibrium with diabetogenic variant(s) located within the SUR1 gene or in flanking genes.
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.
![]() |
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.
![]() |
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.
![]() |
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
![]() |
REFERENCES |
---|
1.
Adams, TE,
Alpert S,
and
Hanahan D.
Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells.
Nature
325:
223-228,
1987[ISI][Medline].
2.
Aguilar-Bryan, L,
Nichols CG,
Wechsler SW,
Clement JP, IV,
Boyd AE, III,
Gonzalez G,
Herrera-Sosa H,
Nguy K,
Bryan J,
and
Nelson DA.
Cloning of the beta high-affinity sulfonylurea receptor: a regulator of insulin secretion.
Science
268:
423-426,
1995[ISI][Medline].
3.
Aizawa, T,
Komatsu M,
Asanuma N,
Sato Y,
and
Sharp GW.
Glucose action "beyond ionic events" in the pancreatic beta cell.
Trends Pharmacol Sci
19:
496-499,
1998[ISI][Medline].
4.
Allison, J,
Campbell IL,
Morahan G,
Mandel TE,
Harrison LC,
and
Miller JF.
Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic beta cells.
Nature
333:
529-533,
1988[ISI][Medline].
5.
Allison, J,
Malcolm L,
Culvenor J,
Bartholomeusz RK,
Holmberg K,
and
Miller JF.
Overexpression of beta 2-microglobulin in transgenic mouse islet beta cells results in defective insulin secretion.
Proc Natl Acad Sci USA
88:
2070-2074,
1991[Abstract].
6.
Ashcroft, FM,
and
Rorsman P.
ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion.
Biochem Soc Trans
18:
109-111,
1990[ISI][Medline].
7.
Babenko, AP,
Aguilar-Bryan L,
and
Bryan J.
A view of sur/KIR6.X, KATP channels.
Annu Rev Physiol
60:
667-687,
1998[ISI][Medline].
8.
Bienengraeber, M,
Alekseev AE,
Abraham MR,
Carrasco AJ,
Moreau C,
Vivaudou M,
Dzeja PP,
and
Terzic A.
ATPase activity of the sulfonylurea receptor: a catalytic function for the KATP channel complex.
FASEB J
14:
1943-1952,
2000
9.
Campbell, IL,
Hobbs MV,
Dockter J,
Oldstone MB,
and
Allison J.
Islet inflammation and hyperplasia induced by the pancreatic islet-specific overexpression of interleukin-6 in transgenic mice.
Am J Pathol
145:
157-166,
1994[Abstract].
10.
Cook, DL,
Satin LS,
Ashford ML,
and
Hales CN.
ATP-sensitive K+ channels in pancreatic beta-cells. Spare-channel hypothesis.
Diabetes
37:
495-498,
1988[Abstract].
11.
D'Alessio, DA,
Verchere CB,
Kahn SE,
Hoagland V,
Baskin DG,
Palmiter RD,
and
Ensinck JW.
Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse.
Diabetes
43:
1457-1461,
1994[Abstract].
12.
Devedjian, JC,
George M,
Casellas A,
Pujol A,
Visa J,
Pelegrin M,
Gros L,
and
Bosch F.
Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes.
J Clin Invest
105:
731-740,
2000
13.
Devedjian, JC,
Pujol A,
Cayla C,
George M,
Casellas A,
Paris H,
and
Bosch F.
Transgenic mice overexpressing alpha2A-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasis.
Diabetologia
43:
899-906,
2000[ISI][Medline].
14.
Drain, P,
Li L,
and
Wang J.
KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit.
Proc Natl Acad Sci USA
95:
13953-13958,
1998
15.
Efrat, S,
Fleischer N,
and
Hanahan D.
Diabetes induced in male transgenic mice by expression of human H-ras oncoprotein in pancreatic beta cells.
Mol Cell Biol
10:
1779-1783,
1990[ISI][Medline].
16.
Ellard, S,
Beards F,
Allen LI,
Shepherd M,
Ballantyne E,
Harvey R,
and
Hattersley AT.
A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria.
Diabetologia
43:
250-253,
2000[ISI][Medline].
17.
Elliott, EA,
and
Flavell RA.
Transgenic mice expressing constitutive levels of IL-2 in islet beta cells develop diabetes.
Int Immunol
6:
1629-1637,
1994[Abstract].
18.
Enkvetchakul, D,
Loussouarn G,
Makhina E,
Shyng SL,
and
Nichols CG.
The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding.
Biophys J
78:
2334-2348,
2000
19.
Epstein, PN,
Boschero AC,
Atwater I,
Cai X,
and
Overbeek PA.
Expression of yeast hexokinase in pancreatic beta cells of transgenic mice reduces blood glucose, enhances insulin secretion, and decreases diabetes.
Proc Natl Acad Sci USA
89:
12038-12042,
1992[Abstract].
20.
Epstein, PN,
Overbeek PA,
and
Means AR.
Calmodulin-induced early-onset diabetes in transgenic mice.
Cell
58:
1067-1073,
1989[ISI][Medline].
21.
Epstein, PN,
Ribar TJ,
Decker GL,
Yaney G,
and
Means AR.
Elevated beta-cell calmodulin produces a unique insulin secretory defect in transgenic mice.
Endocrinology
130:
1387-1393,
1992[Abstract].
22.
Froguel, P,
Vaxillaire M,
Sun F,
Velho G,
Zouali H,
Butel MO,
Lesage S,
Vionnet N,
Clement K,
and
Fougerousse F.
Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.
Nature
356:
162-164,
1992[ISI][Medline].
23.
Glaser, B,
Kesavan P,
Heyman M,
Davis E,
Cuesta A,
Buchs A,
Stanley CA,
Thornton PS,
Permutt MA,
Matschinsky FM,
and
Herold KC.
Familial hyperinsulinism caused by an activating glucokinase mutation.
N Engl J Med
338:
226-230,
1998
24.
Gloyn, AL,
Hashim Y,
Ashcroft SJ,
Ashfield R,
Wiltshire S,
and
Turner RC.
Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with type 2 diabetes mellitus (UKPDS 53).
Diabet Med
18:
206-212,
2001[ISI][Medline].
25.
Gribble, FM,
Tucker SJ,
and
Ashcroft FM.
The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide.
EMBO J
16:
1145-1152,
1997
26.
Grimberg, A,
Ferry RJ, Jr,
Kelly A,
Koo-McCoy S,
Polonsky K,
Glaser B,
Permutt MA,
Aguilar-Bryan L,
Stafford D,
Thornton PS,
Baker L,
and
Stanley CA.
Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations.
Diabetes
50:
322-328,
2001
27.
Grupe, A,
Hultgren B,
Ryan A,
Ma YH,
Bauer M,
and
Stewart TA.
Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis.
Cell
83:
69-78,
1995[ISI][Medline].
28.
Gu, D,
Arnush M,
Sawyer SP,
and
Sarvetnick N.
Transgenic mice expressing IFN- in pancreatic
-cells are resistant to streptozotocin-induced diabetes.
Am J Physiol Endocrinol Metab
269:
E1089-E1094,
1995
29.
Guazzini, B,
Gaffi D,
Mainieri D,
Multari G,
Cordera R,
Bertolini S,
Pozza G,
Meschi F,
and
Barbetti F.
Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online.
Hum Mutat
12:
136,
1998.
30.
Guillam, MT,
Dupraz P,
and
Thorens B.
Glucose uptake, utilization, and signaling in GLUT2-null islets.
Diabetes
49:
1485-1491,
2000[Abstract].
31.
Guillam, MT,
Hummler E,
Schaerer E,
Yeh JI,
Birnbaum MJ,
Beermann F,
Schmidt A,
Deriaz N,
Thorens B,
and
Wu JY.
Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2.
Nat Genet
17:
327-330,
1997[ISI][Medline].
32.
Hanahan, D.
Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes.
Nature
315:
115-122,
1985[ISI][Medline].
33.
Hani, EH,
Boutin P,
Durand E,
Inoue H,
Permutt MA,
Velho G,
and
Froguel P.
Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians.
Diabetologia
41:
1511-1515,
1998[ISI][Medline].
34.
Hani, EH,
Clement K,
Velho G,
Vionnet N,
Hager J,
Philippi A,
Dina C,
Inoue H,
Permutt MA,
Basdevant A,
North M,
Demenais F,
Guy-Grand B,
and
Froguel P.
Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians.
Diabetes
46:
688-694,
1997[Abstract].
35.
Hansen, L,
Echwald SM,
Hansen T,
Urhammer SA,
Clausen JO,
and
Pedersen O.
Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM.
Diabetes
46:
508-512,
1997[Abstract].
36.
Hansen, T,
Echwald SM,
Hansen L,
Moller AM,
Almind K,
Clausen JO,
Urhammer SA,
Inoue H,
Ferrer J,
Bryan J,
Aguilar-Bryan L,
Permutt MA,
and
Pedersen O.
Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene.
Diabetes
47:
598-605,
1998[Abstract].
37.
Harrigan, RA,
Nathan MS,
and
Beattie P.
Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment.
Ann Emerg Med
38:
68-78,
2001[ISI][Medline].
38.
Hart, LM,
de Knijff P,
Dekker JM,
Stolk RP,
Nijpels G,
van der Does FE,
Ruige JB,
Grobbee DE,
Heine RJ,
and
Maassen JA.
Variants in the sulphonylurea receptor gene: association of the exon 16-3t variant with type II diabetes mellitus in Dutch Caucasians.
Diabetologia
42:
617-620,
1999[ISI][Medline].
39.
Higgins, CF.
The ABC of channel regulation.
Cell
82:
693-696,
1995[ISI][Medline].
40.
Huopio, H,
Reimann F,
Ashfield R,
Komulainen J,
Lenko HL,
Rahier J,
Vauhkonen I,
Kere J,
Laakso M,
Ashcroft F,
and
Otonkoski T.
Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1.
J Clin Invest
106:
897-906,
2000
41.
Huopio, H,
Shyng SL,
Otonkoski T,
and
Nichols CG.
KATP channels and insulin secretion disorders.
Am J Physiol Endocrinol Metab
283:
E207-E216,
2002
42.
Inoue, H,
Ferrer J,
Warren-Perry M,
Zhang Y,
Millns H,
Turner RC,
Elbein SC,
Hampe CL,
Suarez BK,
Inagaki N,
Seino S,
and
Permutt MA.
Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM.
Diabetes
46:
502-507,
1997[Abstract].
43.
Inoue, H,
Ferrer J,
Welling CM,
Elbein SC,
Hoffman M,
Mayorga R,
Warren-Perry M,
Zhang Y,
Millns H,
Turner R,
Province M,
Bryan J,
Permutt MA,
and
Aguilar-Bryan L.
Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians.
Diabetes
45:
825-831,
1996[Abstract].
44.
Ishihara, H,
Tashiro F,
Ikuta K,
Asano T,
Katagiri H,
Inukai K,
Kikuchi M,
Yazaki Y,
Oka Y,
and
Miyazaki J.
Inhibition of pancreatic beta-cell glucokinase by antisense RNA expression in transgenic mice: mouse strain-dependent alteration of glucose tolerance.
FEBS Lett
371:
329-332,
1995[ISI][Medline].
45.
Iwasaki, N,
Kawamura M,
Yamagata K,
Cox NJ,
Karibe S,
Ohgawara H,
Inagaki N,
Seino S,
Bell GI,
and
Omori Y.
Identification of microsatellite markers near the human genes encoding the beta-cell ATP-sensitive K+ channel and linkage studies with NIDDM in Japanese.
Diabetes
45:
267-269,
1996[Abstract].
46.
Janson, J,
Soeller WC,
Roche PC,
Nelson RT,
Torchia AJ,
Kreutter DK,
and
Butler PC.
Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.
Proc Natl Acad Sci USA
93:
7283-7288,
1996
47.
Kane, C,
Shepherd RM,
Squires PE,
Johnson PR,
James RF,
Milla PJ,
Aynsley-Green A,
Lindley KJ,
and
Dunne MJ.
Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy.
Nat Med
2:
1344-1347,
1996[ISI][Medline].
48.
Kato, I,
Suzuki Y,
Akabane A,
Yonekura H,
Tanaka O,
Kondo H,
Takasawa S,
Yoshimoto T,
and
Okamoto H.
Transgenic mice overexpressing human vasoactive intestinal peptide (VIP) gene in pancreatic beta cells. Evidence for improved glucose tolerance and enhanced insulin secretion by VIP and PHM-27 in vivo.
J Biol Chem
269:
21223-21228,
1994
49.
Khachatryan, A,
Guerder S,
Palluault F,
Cote G,
Solimena M,
Valentijn K,
Millet I,
Flavell RA,
and
Vignery A.
Targeted expression of the neuropeptide calcitonin gene-related peptide to beta cells prevents diabetes in NOD mice.
J Immunol
158:
1409-1416,
1997[Abstract].
50.
Kinard, TA,
de Vries G,
Sherman A,
and
Satin LS.
Modulation of the bursting properties of single mouse pancreatic beta-cells by artificial conductances.
Biophys J
76:
1423-1435,
1999
51.
Knobler, H,
Weiss Y,
Peled M,
and
Groner Y.
Impaired glucose-induced insulin response in transgenic mice overexpressing the L-phosphofructokinase gene.
Diabetes
46:
1414-1418,
1997[Abstract].
52.
Koster, JC,
Marshall BA,
Ensor N,
Corbett JA,
and
Nichols CG.
Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes.
Cell
100:
645-654,
2000[ISI][Medline].
53.
Koster, JC,
Marshall BA,
Ensor N,
Corbett JA,
and
Nichols CG.
Diet-induced glucose intolerance in mice expressing ATP-insensitive KATP channels in pancreatic beta cells (Abstract).
Diabetes
51, Suppl 2:
A370,
2002.
54.
Krakowski, ML,
Kritzik MR,
Jones EM,
Krahl T,
Lee J,
Arnush M,
Gu D,
Mroczkowski B,
and
Sarvetnick N.
Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes.
J Endocrinol
162:
167-175,
1999
55.
Kubisch, HM,
Wang J,
Bray TM,
and
Phillips JP.
Targeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress.
Diabetes
46:
1563-1566,
1997[Abstract].
56.
Leibowitz, G,
Glaser B,
Higazi AA,
Salameh M,
Cerasi E,
and
Landau H.
Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up.
J Clin Endocrinol Metab
80:
386-392,
1995[Abstract].
57.
Li, L,
Wang J,
and
Drain P.
The I182 region of k(ir)6.2 is closely associated with ligand binding in K(ATP) channel inhibition by ATP.
Biophys J
79:
841-852,
2000
58.
Martin, L,
Keller GA,
Liggitt D,
Oakley H,
Pitts-Meek SL,
Siegel MW,
Terrell T,
and
Stewart TA.
Male-specific beta-cell dysfunction and diabetes resulting from increased expression of a syngeneic MHC class I protein in the pancreata of transgenic mice.
New Biol
2:
1101-1110,
1990[Medline].
59.
Meirhaeghe, A,
Helbecque N,
Cottel D,
Arveiler D,
Ruidavets JB,
Haas B,
Ferrieres J,
Tauber JP,
Bingham A,
and
Amouyel P.
Impact of sulfonylurea receptor 1 genetic variability on non-insulin-dependent diabetes mellitus prevalence and treatment: a population study.
Am J Med Genet
101:
4-8,
2001[ISI][Medline].
60.
Miki, T,
Nagashima K,
Tashiro F,
Kotake K,
Yoshitomi H,
Tamamoto A,
Gonoi T,
Iwanaga T,
Miyazaki J,
and
Seino S.
Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice.
Proc Natl Acad Sci USA
95:
10402-10406,
1998
61.
Miki, T,
Tashiro F,
Iwanaga T,
Nagashima K,
Yoshitomi H,
Aihara H,
Nitta Y,
Gonoi T,
Inagaki N,
Miyazaki J,
and
Seino S.
Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel.
Proc Natl Acad Sci USA
94:
11969-11973,
1997
62.
Misler, S,
Barnett DW,
Gillis KD,
and
Pressel DM.
Electrophysiology of stimulus-secretion coupling in human beta-cells.
Diabetes
41:
1221-1228,
1992[Abstract].
63.
Mueller, R,
Krahl T,
and
Sarvetnick N.
Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice.
J Exp Med
184:
1093-1099,
1996[Abstract].
64.
Nadal, A,
Quesada I,
and
Soria B.
Homologous and heterologous asynchronicity between identified alpha-, beta- and delta-cells within intact islets of Langerhans in the mouse.
J Physiol
517:
85-93,
1999
65.
Nestorowicz, A,
Glaser B,
Wilson BA,
Shyng SL,
Nichols CG,
Stanley CA,
Thornton PS,
and
Permutt MA.
Genetic heterogeneity in familial hyperinsulinism.
Hum Mol Genet
7:
1119-1128,
1998
66.
Nichols, CG,
Shyng SL,
Nestorowicz A,
Glaser B,
Clement JP,
Gonzalez G,
Aguilarbryan L,
Permutt MA,
and
Bryan J.
Adenosine diphosphate as an intracellular regulator of insulin secretion.
Science
272:
1785-1787,
1996[Abstract].
67.
Ohta, Y,
Tanizawa Y,
Inoue H,
Hosaka T,
Ueda K,
Matsutani A,
Repunte VP,
Yamada M,
Kurachi Y,
Bryan J,
Aguilar-Bryan L,
Permutt MA,
and
Oka Y.
Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM.
Diabetes
47:
476-481,
1998[Abstract].
68.
Page, R,
Hattersley A,
and
Turner R.
Beta-cell secretory defect caused by mutations in glucokinase gene.
Lancet
340:
1162-1163,
1992[Medline].
69.
Philipson, LH,
Rosenberg MP,
Kuznetsov A,
Lancaster ME,
Worley JF, III,
Roe MW,
and
Dukes ID.
Delayed rectifier K+ channel overexpression in transgenic islets and beta-cells associated with impaired glucose responsiveness.
J Biol Chem
269:
27787-27790,
1994
70.
Picarella, DE,
Kratz A,
Li CB,
Ruddle NH,
and
Flavell RA.
Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas.
Proc Natl Acad Sci USA
89:
10036-10040,
1992[Abstract].
71.
Picarella, DE,
Kratz A,
Li CB,
Ruddle NH,
and
Flavell RA.
Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice.
J Immunol
150:
4136-4150,
1993
72.
Porter, SE,
Sorenson RL,
Dann P,
Garcia-Ocana A,
Stewart AF,
and
Vasavada RC.
Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse.
Endocrinology
139:
3743-3751,
1998
73.
Postic C and Magnuson MA. Role of glucokinase (GK) in the
maintenance of glucose homeostasis. Specific disruption of the gene by
the Cre-loxP technique. J Annu Diabetol Hotel Dieu: 115-124, 1999.
74.
Ribar, TJ,
Epstein PN,
Overbeek PA,
and
Means AR.
Targeted overexpression of an inactive calmodulin that binds Ca2+ to the mouse pancreatic beta-cell results in impaired secretion and chronic hyperglycemia.
Endocrinology
136:
106-115,
1995[Abstract].
75.
Ribar, TJ,
Jan CR,
Augustine GJ,
and
Means AR.
Defective glycolysis and calcium signaling underlie impaired insulin secretion in a transgenic mouse.
J Biol Chem
270:
28688-28695,
1995
76.
Rissanen, J,
Markkanen A,
Karkkainen P,
Pihlajamaki J,
Kekalainen P,
Mykkanen L,
Kuusisto J,
Karhapaa P,
Niskanen L,
and
Laakso M.
Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin.
Diabetes Care
23:
70-73,
2000[Abstract].
77.
Sakura, H,
Ashcroft SJ,
Terauchi Y,
Kadowaki T,
and
Ashcroft FM.
Glucose modulation of ATP-sensitive K-currents in wild-type, homozygous and heterozygous glucokinase knock-out mice.
Diabetologia
41:
654-659,
1998[ISI][Medline].
78.
Sakura, H,
Eto K,
Kadowaki H,
Simokawa K,
Ueno H,
Koda N,
Fukushima Y,
Akanuma Y,
Yazaki Y,
and
Kadowaki T.
Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus.
J Clin Endocrinol Metab
75:
1571-1573,
1992[Abstract].
79.
Sakura, H,
Wat N,
Horton V,
Millns H,
Turner RC,
and
Ashcroft FM.
Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in white Caucasian subjects or evidence of abnormal function when expressed in vitro.
Diabetologia
39:
1233-1236,
1996[ISI][Medline].
80.
Sarvetnick, N,
Liggitt D,
Pitts SL,
Hansen SE,
and
Stewart TA.
Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma.
Cell
52:
773-782,
1988[ISI][Medline].
81.
Sarvetnick, N,
Shizuru J,
Liggitt D,
Martin L,
McIntyre B,
Gregory A,
Parslow T,
and
Stewart T.
Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma.
Nature
346:
844-847,
1990[ISI][Medline].
82.
Schwanstecher, C,
Meyer U,
and
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
83.
Seghers, V,
Nakazaki M,
DeMayo F,
Aguilar-Bryan L,
and
Bryan J.
Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion.
J Biol Chem
275:
9270-9277,
2000
84.
Sharma, N,
Crane A,
Gonzalez G,
Bryan J,
and
Aguilar-Bryan L.
Familial hyperinsulinism and pancreatic beta-cell ATP-sensitive potassium channels.
Kidney Int
57:
803-808,
2000[ISI][Medline].
85.
Shyng, S,
Ferrigni T,
and
Nichols CG.
Control of rectification and gating of cloned KATP channels by the Kir6.2 subunit.
J Gen Physiol
110:
141-153,
1997
86.
Shyng, S,
Ferrigni T,
and
Nichols CG.
Regulation of KATP channel activity by diazoxide and MgADP. Distinct functions of the two nucleotide binding folds of the sulfonylurea receptor.
J Gen Physiol
110:
643-654,
1997
87.
Shyng, SL,
Cukras CA,
Harwood J,
and
Nichols CG.
Structural determinants of PIP(2) regulation of inward rectifier K(ATP) channels.
J Gen Physiol
116:
599-608,
2000
88.
Stewart, TA,
Hultgren B,
Huang X,
Pitts-Meek S,
Hully J,
and
MacLachlan NJ.
Induction of type I diabetes by interferon-alpha in transgenic mice.
Science
260:
1942-1946,
1993[ISI][Medline].
89.
Stirling, B,
Cox NJ,
Bell GI,
Hanis CL,
Spielman RS,
and
Concannon P.
Identification of microsatellite markers near the human ob gene and linkage studies in NIDDM-affected sib pairs.
Diabetes
44:
999-1001,
1995[Abstract].
90.
Takamura, T,
Kato I,
Kimura N,
Nakazawa T,
Yonekura H,
Takasawa S,
and
Okamoto H.
Transgenic mice overexpressing type 2 nitric-oxide synthase in pancreatic beta cells develop insulin-dependent diabetes without insulitis.
J Biol Chem
273:
2493-2496,
1998
91.
Terauchi, Y,
Sakura H,
Yasuda K,
Iwamoto K,
Takahashi N,
Ito K,
Kasai H,
Suzuki H,
Ueda O,
and
Kamada N.
Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose.
J Biol Chem
270:
30253-30256,
1995
92.
Thomas, PM,
Cote GJ,
Wohllk N,
Haddad B,
Mathew PM,
Rabl W,
Aguilar-Bryan L,
Gagel RF,
and
Bryan J.
Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.
Science
268:
426-429,
1995[ISI][Medline].
93.
Thorens, B,
Guillam MT,
Beermann F,
Burcelin R,
and
Jaquet M.
Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion.
J Biol Chem
275:
23751-23758,
2000
94.
Trapp, S,
Tucker SJ,
and
Ashcroft FM.
Activation and inhibition of K-ATP currents by guanine nucleotides is mediated by different channel subunits.
Proc Natl Acad Sci USA
94:
8872-8877,
1997
95.
Tucker, SJ,
Gribble FM,
Proks P,
Trapp S,
Ryder TJ,
Haug T,
Reimann F,
and
Ashcroft FM.
Molecular determinants of KATP channel inhibition by ATP.
EMBO J
17:
3290-3296,
1998
96.
Tucker, SJ,
Gribble FM,
Zhao C,
Trapp S,
and
Ashcroft FM.
Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor.
Nature
387:
179-183,
1997[ISI][Medline].
97.
Ueda, K,
Komine J,
Matsuo M,
Seino S,
and
Amachi T.
Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide.
Proc Natl Acad Sci USA
96:
1268-1272,
1999
98.
Valera, A,
Solanes G,
Fernandez-Alvarez J,
Pujol A,
Ferrer J,
Asins G,
Gomis R,
and
Bosch F.
Expression of GLUT-2 antisense RNA in beta cells of transgenic mice leads to diabetes.
J Biol Chem
269:
28543-28546,
1994
99.
Vasavada, RC,
Garcia-Ocana A,
Zawalich WS,
Sorenson RL,
Dann P,
Syed M,
Ogren L,
Talamantes F,
and
Stewart AF.
Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia.
J Biol Chem
275:
15399-15406,
2000
100.
Velho, G,
Froguel P,
Clement K,
Pueyo ME,
Rakotoambinina B,
Zouali H,
Passa P,
Cohen D,
and
Robert JJ.
Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young.
Lancet
340:
444-448,
1992[ISI][Medline].
101.
Vionnet, N,
Stoffel M,
Takeda J,
Yasuda K,
Bell GI,
Zouali H,
Lesage S,
Velho G,
Iris F,
and
Passa P.
Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus.
Nature
356:
721-722,
1992[ISI][Medline].
102.
Wogensen, L,
Ma YH,
Grodsky GM,
Robertson RP,
Burton F,
Sutcliffe JG,
and
Sarvetnick N.
Functional effects of transgenic expression of cholera toxin in pancreatic beta-cells.
Mol Cell Endocrinol
98:
33-42,
1993[ISI][Medline].
103.
Zhang, Y,
Warren-Perry M,
Sakura H,
Adelman J,
Stoffel M,
Bell GI,
Ashcroft FM,
and
Turner RC.
No evidence for mutations in a putative beta-cell ATP-sensitive K+ channel subunit in MODY, NIDDM, or GDM.
Diabetes
44:
597-600,
1995[Abstract].