1 Department of Cellular and Molecular Medicine, Graduate School of Medicine, 3 Research Center for Pathogenic Fungi and Microbial Toxicoses, and 5 Gene Research Center, Chiba University, Chiba 260-8670; 4 Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0295, Japan; and 2 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
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ABSTRACT |
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ATP-sensitive potassium
(KATP) channels are known to be critical in the control of
both insulin and glucagon secretion, the major hormones in the
maintenance of glucose homeostasis. The involvement of KATP
channels in glucose uptake in the target tissues of insulin, however,
is not known. We show here that Kir6.2(/
) mice lacking Kir6.2, the
pore-forming subunit of these channels, have no KATP
channel activity in their skeletal muscles. A
2-deoxy-[3H]glucose uptake experiment in vivo showed that
the basal and insulin-stimulated glucose uptake in skeletal muscles and
adipose tissues of Kir6.2(
/
) mice is enhanced compared with that in wild-type (WT) mice. In addition, in vitro measurement of glucose uptake indicates that disruption of the channel increases the basal
glucose uptake in Kir6.2(
/
) extensor digitorum longus and the
insulin-stimulated glucose uptake in Kir6.2(
/
) soleus muscle. In
contrast, glucose uptake in adipose tissue, measured in vitro, was
similar in Kir6.2(
/
) and WT mice, suggesting that the increase in
glucose uptake in Kir6.2(
/
) adipocytes is mediated by altered
extracellular hormonal or neuronal signals altered by disruption of the
KATP channels.
Kir6.2; SUR2; sulfonylurea; insulin; knockout mice
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INTRODUCTION |
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KATP
channels are found in many tissues, including heart, pancreatic
-cell, pituitary, skeletal and smooth muscle, and brain, where they
couple the metabolic state of the cell to the membrane potential
(1, 3, 35). The channel is a heterooctameric complex of
two subunits. A Kir6.1 or Kir6.2 subunit, belonging to the inwardly
rectifying potassium channel subfamily Kir6.x, forms the
potassium-conducting pore. A SUR1 or SUR2 subunit, belonging to the
ATP-binding cassette (ABC) protein superfamily, confers various drug
sensitivities (1, 3, 35). Several splice variants of SUR2,
such as SUR2A and SUR2B, have been identified (6, 17, 18).
Different combinations of the Kir6.x subunit (Kir6.1 or Kir6.2) and the
SUR subunit (SUR1 or SUR2) comprise KATP channels with
distinct nucleotide and pharmacological properties in native tissues
(1, 3, 35). Kir6.2 and SUR1 constitute the
KATP channel in pancreatic
-cells, substantia nigra
(21, 40), and the ventromedial hypothalamus (VMH)
(24). Co-expression of Kir6.2 plus SUR2A (17)
and Kir6.2 plus SUR2B (18) elicits KATP
channel currents resembling those in cardiac muscle and smooth muscle,
respectively. Kir6.1 and SUR2B also comprise the KATP channels in vascular smooth muscle, which are activated by nucleoside diphosphates and are sensitive to sulfonylureas (41).
Recently, disruption of Kir6.1 in mice has been shown to cause coronary vasospasm that mimics Prinzmetal angina in humans (26).
The KATP channel in skeletal muscles was first
identified by Spruce et al. (37), and its pharmacological
and electrophysiological properties have been examined in native
skeletal muscles isolated from several vertebrates (2,
10). The electrophysiological properties of the KATP
channels recorded in native skeletal muscles vary to some extent in
sensitivities to ATP, glibenclamide, and K+ channel openers
(2, 5, 10). These differences could be due to differences
in experimental conditions, species, or even splice variants of SUR2
(6). One postulated role for the KATP channel
is to control electrical activity of the cell membrane in response to
alterations in the metabolic state of the muscle fibers. The channels
become activated during metabolic inhibition, and opening of the
channels inhibits massive depolarization of the cell membrane and
shortens the duration of action potential (13). The
channels are also activated during fatigue development (20). Activation of the KATP channels with
pinacidil induces a faster decrease in tetanic force and reduces the
development of resting tension during fatigue, whereas it improves
force recovery after fatigue (23). These actions probably
function to conserve energy (i.e., ATP) during fatigue or metabolic
inhibition (13, 23). We generated Kir6.2-deficient
[Kir6.2(/
)] mice (25) and confirmed that the
KATP channels in skeletal muscle are involved in
determining resting tension during fatigue development
(11).
In addition to the role in contractile activity of skeletal muscle,
KATP channels also may be involved in glucose uptake in skeletal muscles. Sulfonylureas have been shown to improve glycemic control in patients with type 2 diabetes mellitus by acting on extrapancreatic tissues to reduce insulin resistance (22).
However, no direct evidence has been reported of the involvement of
skeletal muscle KATP channels in the extrapancreatic
effects of sulfonylureas. Using Kir6.2(/
) mice, we found that the
glucose-lowering effect of insulin is enhanced in Kir6.2(
/
) mice
(25). The involvement of KATP channels in
glucose uptake was also indicated by SUR2-deficient [SUR2(
/
)]
mice (7).
In the present study, we confirmed that there is no KATP
channel activity on the plasma membrane of skeletal muscles of
Kir6.2(/
) mice. We found both in vivo and in vitro
insulin-stimulated glucose uptake to be significantly increased in
specific skeletal muscles of Kir6.2(
/
) mice compared with WT mice.
We also found that insulin-stimulated glucose uptake of adipose tissues
in Kir6.2(
/
) mice is enhanced significantly in vivo but not in
vitro. These data indicate that Kir6.2-containing KATP
channels are involved in glucose uptake in both skeletal muscles and
adipocytes and that they are involved in the regulation of glucose
uptake in skeletal muscles directly and in adipose tissues indirectly.
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MATERIALS AND METHODS |
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Animals.
Kir6.2(/
) mice were generated as described previously
(25). Animals were cared for according to guidelines
established by the Animal Care Committees of Chiba and Ottawa Universities.
Insulin Tolerance Test
Various doses (0.05, 0.1, 0.2, 0.5, and 0.75 U/kg) of human insulin (Humulin R, Eli Lilly, Indianapolis, IN) were injected intraperitoneally in awake male mice (18-22 wk) after a 16-h fast. Blood samples were taken from the orbital sinus to determine blood glucose levels. Blood glucose levels were measured in whole blood with Antosense Glucose II (Sankyo, Tokyo, Japan) as previously described (25).Northern Blotting of Phosphoenolpyruvate Carboxykinase mRNA
After food deprivation for 0, 6, 12, 18, or 24 h, 16-wk-old male mice were killed, and total RNA was extracted from the liver. Sixteen-week-old male mice were injected orally with 10 cal/kg of mixed meal (Twinline, Otsuka Pharmaceuticals, Tokushima, Japan), and total RNA of the liver was extracted 1 h after the meal. Ten micrograms of total RNA samples were fractionated by electrophoresis and subjected to Northern blot analysis. The [32P]dCTP-labeled partial fragment (nt +121~+947) of mouse phosphoenolpyruvate carboxykinase (PEPCK) cDNA was used as the probe. The consistency of the relative amounts of RNA loaded into each lane was evaluated by estimating the 28S and 18S ribosomal RNA (not shown) and also by probing the blots with [32P]dCTP-labeled human glyceraldehyde-3-phosphate dehydrogenase (GAPDH).Measurement of the Glycogen Content
The glycogen content in liver was measured as follows. The liver was lysed in 0.6 ml of 1 N NaOH and heated for 45 min at 65°C. Twenty microliters of the solution were incubated for 30 min at 25°C in a buffer containing 1.14 mg/ml of amyloglucosidase. The glucose produced was measured by F-kit glucose (Roche Diagnostics, Basel, Switzerland). The protein was measured by Bradford's method.Glucose Uptake in Vivo
The experiment was started at 10:00 AM. To establish the rate constant of basal glucose uptake, male mice aged 20-24 wk were fasted for 16 h and injected via the caudal vein with 12.5 µCi of 2-deoxy-D-[3H]glucose (2-[3H]DG; Amersham Pharmacia Biotech, Buckinghamshire, UK) and 2.5 µCi of [14C]sucrose (Amersham Pharmacia Biotech) dissolved in 0.05 ml of saline. Blood was taken before and 0, 2, 5, and 10 min after injection of radioactive tracers. The mice were killed by cervical dislocation 20 min after injection, and skeletal muscles [extensor digitorum longus (EDL), soleus, and red and white part of gastrocnemius] and epididymal white adipose tissues (WAT) were rapidly dissected and weighed. The rate constant of the 2-[3H]DG uptake was calculated as previously described (38). For measurement of insulin-stimulated glucose uptake, the fed mice were injected with 0.5 U/kg of human insulin intraperitoneally. Fifteen minutes after insulin injection, the injection of the radioactive tracers, dissection of the tissues, and calculation of the rate constant of 2-[3H]DG uptake were done as in the basal glucose uptake measurement.Electrophysiological Recordings of Skeletal Muscles
Muscle fibers were isolated from flexor digitorum brevis of 2-wk-old wild-type (WT) and Kir6.2(Glucose Uptake by Skeletal Muscles in Vitro
Glucose uptake capacity by skeletal muscles in vitro was measured using 2-[3H]DG, a nonmetabolized glucose marker as described by Hansen et al. (14) with a few modifications. Briefly, mice were fasted for 16 h before the uptake measurements. After excision, EDL and soleus muscles were incubated for 1 h in 1.8 ml of physiological saline solutions containing (in mM) 118.5 NaCl, 4.7 KCl, 2.4 CaCl2, 3.1 MgCl2, 25 Na2HCO3, and 2 NaH2PO4, supplemented with 8 mM glucose or 2-DG, 32 mM mannitol, and 0.1% albumin (Sigma-Aldrich, St. Louis, MO). Solutions were continuously exposed to 95% O2-5% CO2 to maintain pH at 7.4. 2-[3H]DG uptakes were then measured by exposing muscles for 10 or 20 min to 2.0 µCi/ml of 2-[3H]DG (Amersham Pharmacia Biotech) and various concentrations of unlabeled glucose or 2-DG. Muscles were also exposed to 0.3 µCi/ml [14C]mannitol (Amersham Pharmacia Biotech) to determine the extracellular volume. To maintain osmolarity, the total concentration of unlabeled 2-DG and mannitol was kept at 40 mM. After the incubation, muscles were homogenized in 2 ml of 6% perchloric acid (PCA). Homogenates were centrifuged for 15 min at 1,200 g. 2-[3H]DG and [14C]mannitol were then counted from 1 ml of supernatant using a WinSpectral liquid scintillation counter (model 1414, Perkin-Elmer Life Sciences, Boston, MA). Quenching was corrected by counting 1 µCi of 2-[3H]DG and [14C]mannitol in 1 ml of physiological solution and another 1 µCi of 2-[3H]DG and [14C]mannitol in 1 ml of 6% PCA.Insulin-Induced Glucose Uptake in Skeletal Muscles in Vitro
The uptake of 2-[3H]DG by skeletal muscles in the presence of various insulin doses was measured in vitro as described above, except that muscles were exposed to 1, 100, or 10,000 µU/ml of insulin (Humulin R) and 8 mM 2-DG during the 1-h incubation and during the uptake measurement.Glucose Uptake in Isolated Adipocytes in Vitro
Twenty- to twenty-eight-week-old male mice were killed after a 16-h fast, and their epididymal fat tissues were promptly removed. Adipocytes were isolated by a protocol modified from Rodbell (30). Briefly, the fat was minced and incubated with 2 mg/ml of collagenase (Collagenase D, Roche Applied Science, Basel, Switzerland) in Krebs-Ringer phosphate HEPES (HKRB) buffer with 4% BSA at 37°C for 40 min with occasional shaking. After digestion, the cell suspension was passed through a 900-µm filter, and the cells were washed three times with fresh HKRB plus 1% BSA. After a final wash, the cells were diluted to a 20% suspension and divided into reaction vials. After preincubation at 37°C for 20 min, the cells were treated with 0.1, 0.3, 1, 3, 10, 30, 100, or 300 µU/ml of Humulin R for 15 min before addition of D-[U-14C]glucose. Glucose uptake was stopped by adding 13.3 µM cytochalasin B and 0.2 mM phloretin. After cell separation by spinning the suspension with oil, glucose uptake into the cells was measured by counting cell pellets solubilized in ACS II liquid scintillation analysis cocktail (Amersham Pharmacia Biotech). ![]() |
RESULTS |
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Response of Kir6.2(/
) Mice
to Blood Glucose-Lowering Stress
Dose-response relationship of insulin-induced hypoglycemia.
As we reported previously (25), the glucose-lowering
effect of intraperitoneal insulin injection is significantly enhanced in Kir6.2(/
) mice (Fig.
1A). The decrease in blood
glucose levels was significantly larger in Kir6.2(
/
) than in WT
mice, when 0.1, 0.2, or 0.5 U/kg of insulin was injected. Thus the
differences between Kir6.2(
/
) and WT mice were apparent when the
mice were injected with relatively low doses (0.1 or 0.2 U/kg) of
insulin.
|
Effects of fasting on blood glucose and serum insulin levels.
We then examined changes in blood glucose levels during food
deprivation to determine whether a massive fall in blood glucose occurs
during prolonged fasting in Kir6.2(/
) mice. The blood glucose
levels of Kir6.2(
/
) mice were significantly lower than those of WT
mice at 6, 12, 18, and 24 h. In particular, Kir6.2(
/
) mice
exhibited a rapid and severe fall in blood glucose levels between 6 and
12 h after food deprivation (Fig. 1B): blood glucose levels fell by 3.93 ± 0.52 mM in Kir6.2 (
/
) mice
(n = 8), whereas only a slight decrease was observed in
WT mice (0.97 ± 0.51 mM, n = 8). After 9 h
of fasting, the percent decrease in serum insulin levels was similar in
Kir6.2(
/
) and WT mice, as the insulin levels decreased to 46.4 and
56.3% of those in the fed state, respectively [Kir6.2(
/
), fed
state, 1,052 ± 104 ng/ml; 9-h fast, 487 ± 71 ng/ml,
n = 8; WT, fed state, 1,997 ± 181 ng/ml; 9-h
fast, 1,118 ± 190 ng/ml, n = 8].
Gluconeogenesis and Glycogenolysis in the Liver During Fasting
The liver is the major source of glucose during fasting, the glucose being produced from gluconeogenesis or glycogenolysis. We examined PEPCK (a key gluconeogenic enzyme) mRNA expression and glycogen content during fasting as markers of gluconeogenesis and glycogenolysis, respectively.PEPCK mRNA expression.
In WT mice, PEPCK mRNA expression in liver was markedly suppressed
1 h after the mice had ingested 10 cal/kg of mixed meal, whereas
its expression gradually increased during food deprivation (Fig.
2). The increase in PEPCK mRNA expression
levels during fasting was less in the fed state and after 6 h of
fasting in Kir6.2(/
) mice than in WT mice, whereas after extended
fasting (longer than 12 h) , the increase was comparable to that
in WT mice. These results suggest that delayed increased PEPCK mRNA might have contributed to the early, abrupt drop in blood glucose levels after food deprivation in Kir6.2(
/
) mice.
|
Liver glycogen content.
Because glycogenolysis is promoted during fasting, the glycogen content
of the liver was measured before and after 24 h of food
deprivation. The liver glycogen content of Kir6.2(/
) mice fed ad
libitum was similar to that of WT mice [Kir6.2(
/
), 246 ± 49 µg/mg protein; WT, 299 ± 77 µg/mg protein,
n = 4] and decreased to almost the same extent as in
controls during fasting [Kir6.2(
/
), 69 ± 14 µg/mg protein;
WT, 56 ± 12 µg/mg protein, n = 4].
Absence of the Sarcolemmal KATP Channel in Skeletal
Muscles of Kir6.2(/
) Mice
|
Glucose Uptake in Skeletal Muscle and Adipose Tissues
Glucose uptake by skeletal muscles and adipose tissues in vivo.
Glucose uptake in skeletal muscles and WAT was examined in vivo. Uptake
was measured both in the basal state (after a 16-h fast and without
exogenous insulin) and after intraperitoneal insulin injection (Fig.
4A). The basal uptake by EDL
muscle and white and red gastrocnemius muscles in Kir6.2(/
) was
significantly greater than that in WT mice. The uptake by soleus muscle
was, on the other hand, similar in WT and Kir6.2(
/
) mice. Insulin, at 0.5 U/kg body weight, significantly increased glucose uptake in all
muscles. The insulin effect was significantly greater in Kir6.2(
/
)
muscles than in WT muscles, especially in soleus and red gastrocnemius.
Similarly, both the basal and insulin-stimulated glucose uptake in WAT
of Kir6.2(
/
) mice was significantly greater than that in the WT
tissues (Fig. 4B).
|
Glucose uptake by skeletal muscles in vitro.
In vivo glucose uptake in skeletal muscle is affected not only by
insulin but also by exogenous factors and muscle activity (15). To better understand the difference in basal and
insulin-stimulated glucose uptake measured in vivo, we also measured
glucose uptake in vitro. Basal glucose uptake was also determined with
8, 15, and 32 mM unlabeled 2-DG over a 20-min period. Basal glucose
uptake of 2-DG was significantly greater in Kir6.2(/
) than in WT
EDL muscle only at high 2-DG concentration (32 mM) (Fig.
5A). Basal glucose uptake in
soleus muscle of Kir6.2(
/
) mice tended to be greater than that of
WT mice (Fig. 5B), but the difference was not significant.
|
Insulin-induced glucose uptake of skeletal muscles in vitro.
We determined whether the increased insulin-induced glucose uptake by
skeletal muscle also occurs in vitro. Insulin at 100 and 10,000 µU/ml
increased 2-DG uptake in EDL and soleus muscle (Fig.
6, A and B). In
soleus muscle, 100 µU/ml of insulin increased 2-DG uptake in
Kir6.2(/
) more than in WT mice, whereas there was no difference in
the insulin effect between Kir6.2(
/
) and WT mice at 10,000 µU/ml
(Fig. 6B). Contrary to the in vivo observations (Fig.
4A), the insulin effect in vitro was not different in
Kir6.2(
/
) EDL than in WT muscle (Fig. 6A).
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Glucose uptake of adipose tissues in vitro.
Glucose uptake in adipocytes isolated from epididymal fat also was
compared. Glucose uptake in the adipocytes of Kir6.2(/
) and WT mice
was similar in the presence of insulin at all concentrations from 1 to
300 µU/ml (Fig. 7).
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DISCUSSION |
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KATP channels are expressed in many cells and tissues,
and they regulate various cellular functions by linking the metabolic state of the cell to membrane potential (1, 3, 35). We previously showed that the channel is critical in glucose-induced insulin secretion in pancreatic -cells by use of transgenic mice expressing dominant-negative Kir6.2 specifically in pancreatic
-cells (27). The finding was further confirmed in
Kir6.2-deficient [Kir6.2(
/
)] mice, in which the Kir6.2 gene,
which encodes for the pore subunit of the
-cell KATP
channel, is disrupted, resulting in complete lack of KATP
channel activity (25). Studies using Kir6.2(
/
) mice
demonstrate not only the importance of the KATP channel in
glucose-induced insulin secretion but also that the glucose-lowering
effect of insulin is significantly enhanced in mice lacking these
channels (25). In the present study, we found that a
relatively low dose (0.1 and 0.2 U/kg) of insulin lowered blood glucose
levels in Kir6.2(
/
) mice significantly more than in WT mice (Fig.
1A). This study also shows that fasting leads to enhanced
hypoglycemia in Kir6.2(
/
) mice compared with WT mice (Fig.
1B). Furthermore, analysis of glucose-responsive neurons in
the VMH shows that Kir6.2(
/
) mice have a defect in glucose sensing
during hypoglycemia, which leads to impaired glucagon secretion from
the pancreatic
-cells under those conditions (24). Therefore, the enhanced effects of insulin and fasting on blood glucose
levels may be due to 1) low capacity of the liver to produce glucose because of the lack of glucagon stimulation or 2)
enhanced glucose uptake in peripheral tissues. Both possibilities were investigated.
Glucose Production During Hypoglycemia
Glucagon is known to increase glucose release from the liver by activating gluconeogenesis. The rate-limiting step of gluconeogenesis is the conversion of oxaloacetate to phosphoenolpyruvate, which is catalyzed by PEPCK (31). The activity of PEPCK is known to be controlled at the transcriptional level, and glucagon induces PEPCK mRNA expression (33). Indeed, despite food deprivation causing a larger fall in the blood glucose levels in Kir6.2(Glucose Uptake in Skeletal Muscle and Adipose Tissues
Blood glucose levels during fasting are determined not only by glucose supply from the liver but also by glucose utilization in the peripheral tissues, including skeletal muscles and adipose tissues. Although KATP channels are known to be present in skeletal muscles (37), there is no report of functional expression in adipose tissues (29). Electrophysiological recording clearly shows that Kir6.2-containing KATP channels are present in skeletal muscles. The channel in skeletal muscles opens when the intracellular ATP concentration is decreased by metabolic inhibition (13) or muscle fatigue (20). Sulfonylureas such as glibenclamide and glimepiride (4, 9) have been used to investigate the role of the KATP channels in glucose uptake in skeletal muscles, but whether or not the extrapancreatic effects of sulfonylureas also are mediated by closure of KATP channels is controversial (8, 28).The gene-targeting technique is the most straightforward strategy to
clarify the involvement of molecules in cellular functions. Using
Kir6.2-deficient mice, we found that basal glucose uptake in the
skeletal muscles in vivo after a 16-h fast was significantly enhanced
in Kir6.2(/
) gastrocnemius and EDL muscles compared with those of
WT mice but that it was not in soleus muscle (Fig. 4A).
Similarly, in vitro basal glucose uptake was greater in Kir6.2(
/
) EDL muscle than in WT EDL muscle, but no difference was observed in the
soleus muscles (Fig. 5). The effect of insulin on glucose uptake also
was greater in Kir6.2(
/
) muscles than in WT muscles, except for the
EDL muscle in vitro (Figs. 4 and 5). These results thus provide direct
evidence for the involvement of the KATP channel in glucose
uptake in skeletal muscle, in agreement with previous findings in
SUR2-deficient mice (7). This study, however, clearly shows that the effects of disruption of the KATP channels
on glucose uptake differ in muscles composed of different types of
fibers. Although not observed in vivo, the EDL but not the soleus
muscles of Kir6.2(
/
) mice showed enhanced capacity for basal
glucose uptake compared with WT muscles. The enhanced insulin effect on glucose uptake in Kir6.2(
/
) mice was much greater in soleus than in
EDL muscle both in vivo and in vitro, whereas in vivo, it was greater
in red gastrocnemius than in white gastrocnemius.
Both soleus and red gastrocnemius muscles of both Kir6.2(/
) and WT
mice are composed primarily of type I and IIA fibers, which are
slow-twitch oxidative fibers (36, 39, and M. Thabet and J.-M. Renaud,
unpublished results), whereas white gastrocnemius and EDL
muscles are composed primarily of type IIX and IIB fibers, which are
fast-twitch glycolytic fibers (32, 36, and M. Thabet and J.-M. Renaud,
unpublished results). Thus it appears that lack of KATP
channel activity affects insulin-sensitive glucose uptake to a greater
extent in type I and IIA fibers than in type IIX and IIB fibers,
although the basal glucose uptake capacity is increased more in the
latter. It is interesting to note that the stimulatory effect of
insulin on glucose transport is also greater in soleus than in EDL
muscle (19).
We found that glucose uptake in Kir6.2(/
) adipose tissues also is
enhanced in vivo but not in vitro. Because KATP channels have not been detected in adipocytes (29), the effect of
increased glucose uptake in Kir6.2(
/
) adipocytes is most likely indirect.
Four mouse models lacking KATP channels have been
generated: Kir6.2(/
) (25), SUR1(
/
)
(35), SUR2(
/
) (7), and
Kir6.1(
/
) (26). Although the glucose-lowering effect
of a low dose of insulin is not increased in SUR1(
/
)
(34), insulin sensitivity is enhanced in both SUR2(
/
)
(7) and Kir6.2(
/
) (25) mice. When we
consider these observations together with the findings of the present
study, we can conclude that the Kir6.2/SUR2 channel apparently
participates in glucose uptake in skeletal muscles directly and that
the Kir6.2-containing channel is involved in glucose uptake in adipose
tissues indirectly.
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ACKNOWLEDGEMENTS |
---|
This work was supported by a Grant-in-Aid for Creative Scientific Research (10NP0201) and for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by a Scientific Research Grant from the Ministry of Health, Labour, and Welfare, Japan; and by grants from Novo Nordisk Pharma, Takeda Chemical Industries, the Yamanouchi Foundation for Research on Metabolic Disorders, and the National Science and Engineering Research Council of Canada.
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FOOTNOTES |
---|
Present address of Y. Minokoshi: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215.
Address for reprint requests and other correspondence: S. Seino, Dept. of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba Univ. 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan (E-mail: seino{at}med.m.chiba-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
August 13, 2002;10.1152/ajpendo.00313.2002
Received 15 July 2002; accepted in final form 3 August 2002.
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