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Division of Endocrinology and Metabolism, Department of Medicine at Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Barbara B. Kahn, M.D., Diabetes Unit, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215. E-mail: bkahn{at}bidmc.harvard.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Reduced GLUT4 expression in adipocytes is virtually a universal feature of insulin resistant states resulting from somewhat diverse etiologies, including not only obesity, impaired glucose tolerance, noninsulin-dependent diabetes mellitus, polycystic ovarian disease, some cases of gestational diabetes, and high fat feeding, but also insulinopenic diabetes and fasting (9). In contrast, in most of these states, there is no decrease in GLUT4 expression in muscle. In the few rodent models in which down-regulation of GLUT4 expression in muscle can be seen, it actually follows the onset of insulin resistance and thus is not the primary cause (10, 11). The contribution of down-regulation of GLUT4 expression in adipocytes to total body insulin resistance is unknown.
Recent transgenic studies demonstrate that overexpression of GLUT4 in muscle and adipose tissue together (12, 13, 14, 15, 16), in muscle alone (17, 18), or in adipocytes alone (19) enhances glucose tolerance and insulin-stimulated glucose uptake in vivo in normal mice and prevents insulin resistance (12) and ameliorates diabetes (13, 17) in mice with metabolic perturbations. Gibbs et al. (13) overexpressed GLUT4 driven by its own promoter in genetically obese, diabetic (db/db) mice and showed striking amelioration of the diabetic state. Similarly, GLUT4 overexpression simultaneously in muscle and adipose tissues in C57BL mice prevents impaired glucose tolerance that occurs in nontransgenic mice fed a high-fat diet (12). GLUT4 overexpression selectively in muscle, using an aldolase promoter, improves the glucose lowering effect of insulin in streptozotocin diabetic transgenic mice (17). Furthermore, Tsao et al. (18) overexpressed GLUT4 selectively in slow twitch muscle of transgenic mice using the myosin light chain promoter/enhancer and showed that glucose uptake in vivo is enhanced only in the muscles in which the transgene is expressed. This indicates that the effects of GLUT4 on glucose homeostasis are direct and are not, for the most part, the result of changes in circulating levels of hormones or substrates.
Because GLUT4 down-regulation in insulin-resistant states is most pronounced in adipocytes and there is no information as to whether the decreased glucose uptake into fat contributes to in vivo insulin resistance, we sought to prevent down-regulation of GLUT4 selectively in adipocytes and to study the impact in diabetic mice. Our specific questions were: 1) Can GLUT4 expression be maintained in adipocytes in a diabetic state in which it is usually down-regulated, if it is driven by a heterologous promoter that may not be subject to down-regulation in adipocytes, as the endogenous promoter is? 2) If GLUT4 expression can be maintained, or even increased above normal levels in adipocytes in the diabetic state, will insulin action in vivo improve? 3) Will overexpression of GLUT4 in adipose tissue ameliorate the catabolic/lipolytic state associated with insulinopenic diabetes? To answer these questions, we created diabetes in mice that overexpress GLUT4 driven by the aP2, fatty acid-binding protein, promoter/enhancer (19). We found that GLUT4 expression driven by this heterologous promoter can be maintained at high levels under conditions where the endogenous promoter normally down-regulates and that this sustains enhanced glucose transport in isolated adipocytes. Furthermore, overexpression of GLUT4 selectively in adipocytes improves whole-body insulin action, even with severe diabetes. These results are consistent with the interpretation that down-regulation of GLUT4 in adipocytes may contribute, either directly or indirectly, to in vivo insulin resistance in diabetes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood glucose and plasma insulin determinations
Blood glucose was measured with a One Touch II glucose meter
(Lifescan, Inc., Johnson & Johnson, Milpitas, CA). Plasma insulin was
measured with an RIA kit (Linco Research Inc., St. Louis, MO) using rat
insulin standards.
Glucose transport in isolated adipose cells
Adipose cells were isolated from gonadal fat pads of 1–5 mice
per experiment by collagenase digestion (1 mg/ml). Cells were incubated
at 37 C with constant shaking in a 4% suspension by volume (
40,000
cells/500 µl), in Krebs-Ringer-Phosphate buffer (pH 7.4) with HEPES
(20 mM), 2.5% BSA (fraction V), and 200 nM
adenosine. Cells were incubated in the absence (basal) or presence of
80 nM crystalline porcine insulin (insulin stimulated)
(gift of Eli Lilly, Indianapolis, IN) for 30 min. U-[14C]
glucose (ICN Biomedical, Costa Mesa, CA) (3 µM) was added
for 30 min, and the reaction was terminated by separating cells from
media by spinning the suspension through dinonyl phthalate oil (Kodak,
New Haven, CT) (23, 24).
At a glucose concentration of 3 µM under the assay conditions used, U-14C-glucose uptake has been shown to directly reflect glucose transport, and results parallel those with 3-O-methylglucose transport (23, 24). We validated this technique for adipocytes from nontransgenic and transgenic mice. At a glucose concentration of 3 µM, a cell concentration of 2–4% by vol and an incubation time of 30 min, this assay is linear for adipocytes from both nontransgenic and GLUT4 overexpressing mice. Furthermore, our initial comparisons of U-14C-glucose uptake and 3-O-methylglucose transport show similar effects of the transgene with both techniques.
Lipolysis in isolated adipose cells
A 10% suspension of isolated adipose cells from 1–2 mice per
group was prepared in KRPH buffer, 200 nM adenosine, 2.5%
BSA, and 2 mM glucose at pH 7.4. Cells [100 µl
(20,000 cells)] were incubated in a final vol of 500 µl with
adenosine deaminase (1 unit/ml, Sigma, St. Louis, MO) and
N6-[R-1-methyl-2-phenethyl]adenosine (10
µM, Sigma) (25, 26). Lipolysis was stimulated by
isoproterenol (10 nM, 100 nM, 1
µM, 10 µM, and 100 µM) for 15
min at 37 C with vigorous shaking. The effect of insulin in inhibiting
lipolysis was measured by adding insulin at 0.25 nM, 0.5
nM, 1 nM, 10 nM, and 100
nM for 15 min at 37 C and then stimulating lipolysis with
10 µM isoproterenol for 15 min at 37 C. The reactions
were terminated by spinning cells through dinonyl phthalate oil. The
glycerol released into the media was measured using a radiometric assay
(27). The assay was linear under the stated conditions.
Preparation of membranes and Western blotting for GLUT4
Total membranes were prepared from intact fat pads, separated by
SDS-PAGE, electrophoretically transferred to nitrocellulose, and
immunoblotted with an antiserum specific for the COOH terminal of GLUT4
(gift of H. Haspel), all as previously described (6, 28). Results were
quantitated by Phosphorimaging or densitometry of autoradiograms.
Adipose cell size and number
Isolated adipocytes were fixed with osmic acid and counted in a
Coulter counter (Coulter Electronics Ltd., Luton, Beds, UK) (29, 30),
and cell size (µg lipid/cell) was calculated as previously described
(30).
Insulin tolerance tests
After a 6-h fast, insulin (Humulin regular, Eli Lilly) was
injected ip at a dose of 0.9–1 mU/g BW for males and 0.7 mU/g BW for
females in unanesthetized and unrestrained mice. Different doses were
used because normal female mice were more sensitive to insulin than
normal male mice. An additional group of diabetic male mice was
injected with an insulin dose of 3.3 mU/g BW to determine the maximal
effect of insulin. Blood glucose was sampled from the tail vein before
injection and at 30, 45, and 60 min after injection.
Glucose transport in soleus muscle in vitro
3-O-methylglucose transport was performed in isolated soleus
muscles as previously described for rat epitrochlearis (31). Glucose
transport is expressed as µM 3-O-methylglucose
accumulated per ml of intracellular water per h.
Statistical analysis
Statistical analyses were carried out with ANOVA, Fisher’s
test, and t test using the Statview program (Abacus Concepts
Inc., Apple Computer Inc., Cupertino, CA). Differences were accepted as
significant at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows blood glucose and plasma insulin
levels in nondiabetic (control) and diabetic male and female mice of
both genotypes. On the day of injection, blood glucoses after a 6-h
fast were lower in transgenic male and female mice compared with
nontransgenic mice of the same sex (P < 0.05), as we
previously showed with an overnight fast (19). Fed glucoses on the day
the mice were killed were not different between genotypes for
nondiabetic mice. After streptozotocin injection, mice of both
genotypes and both sexes became diabetic, with blood glucoses more than
24.7 mM in males and more than 21.4 mM in
females of both genotypes on the day they were killed (12–14 days
after injection). Fed insulin levels in nondiabetic mice were
significantly lower in transgenic males compared with nontransgenic
males (P < 0.05) (19). Insulin levels also tended to
be lower in nondiabetic transgenic females (P < 0.06).
Insulin levels were reduced to the same degree in both nontransgenic
and transgenic mice after streptozotocin injection (0.71–0.73 ng/ml in
males of both genotypes and 1.00–1.06 ng/ml in females).
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shows the effect of the diabetic state on
body weight in nontransgenic and transgenic mice. Nondiabetic mice of
both genotypes and both sexes gained a small amount of weight, whereas
diabetic mice of both genotypes and both sexes lost weight. The amount
of weight gained or lost was not statistically different between
genotypes for either males or females. Thus, overexpression of the
transgene did not prevent weight loss. The relatively small weight gain
in nondiabetic mice over 12–14 days is in contrast to results in rats.
However, it is a consistent finding in our strain of mice that weight
gain is slow after the age of 12 weeks.
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). In
nondiabetic mice, gonadal fat pad weight was 44% (male) and 42%
(female) greater in transgenic than nontransgenic mice at the time of
death (P < 0.002). Diabetes resulted in a 72% (male)
and 42% (female) reduction in fat pad weight in nontransgenic mice and
a 77% (male) and 58% (female) reduction in transgenic mice. Figure 1C
shows that adipose cell size was similar in nondiabetic nontransgenic
and transgenic mice, confirming our previous reports (19). With
diabetes, adipose cell size in both genotypes and both sexes decreased:
56% in nontransgenic male, 75% in transgenic male, 44% in
nontransgenic female, and 52% in transgenic female mice. Thus,
overexpression of GLUT4 did not protect adipocyte size or adipose
mass.
Effects of diabetes on GLUT4 expression and glucose transport in
adipocytes
Figure 2 shows the effects of diabetes on the
regulation of GLUT4 protein levels in adipose tissue. Panel A shows a
representative Western blot, which indicates that GLUT4 expression
decreases in nontransgenic diabetic mice and that GLUT4 is markedly
overexpressed in both nondiabetic and diabetic transgenic mice. Panel B
shows the quantitation by phosphorimaging. In nontransgenic mice,
streptozotocin diabetes results in a 34% reduction in GLUT4 levels in
adipose tissue (P < 0.001). In nondiabetic transgenic
mice, GLUT4 is overexpressed 18-fold compared with nontransgenic
nondiabetic mice. With diabetes, GLUT4 levels in adipose tissue of
transgenic mice do not decrease significantly (P =
0.46) and remain 21-fold greater than in adipose tissue from diabetic
nontransgenic mice.
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shows the effects of diabetes and GLUT4
overexpression on glucose transport in adipocytes. In nontransgenic
mice, insulin stimulates glucose transport approximately 5-fold
(P < 0.0001). Diabetes results in no significant
change in basal glucose transport but a 46% decrease in insulin
stimulated glucose transport, compared with nontransgenic nondiabetic
mice (P < 0.02). Overexpression of the transgene in
nondiabetic mice results in a 17-fold increase in basal transport
(P < 0.0001) and a 7-fold increase in insulin
stimulated transport (P < 0.0001), as we previously
reported (19). Although the fold response to insulin
(insulin-stimulated divided by basal transport) is reduced in
adipocytes from transgenic mice because of the high basal transport,
the increment in attomoles of glucose transported per cell (insulin
stimulated minus basal) is four times greater in transgenic cells,
indicating that the GLUT4 overexpressing-cells are very responsive to
insulin. Even with diabetes, dramatic increases in glucose transport
are maintained in cells from transgenic mice. Although there is a
tendency for a slight reduction in insulin-stimulated glucose transport
in diabetic transgenic mice compared with nondiabetic transgenic mice,
this is not statistically significant. Most importantly, when comparing
values in diabetic mice directly, basal transport is increased 21-fold
(P < 0.0001) and insulin stimulated-transport, 10-fold
(P < 0.0001) in cells from transgenic diabetic mice,
compared with nontransgenic diabetic mice. The transport data shown are
for females. Overexpression of GLUT4 in adipocytes of male mice had a
similar effect, maintaining markedly increased glucose transport, even
in the setting of diabetes (not shown). In adipocytes from
nontransgenic male mice, streptozotocin diabetes was associated with a
60% decrease in insulin-stimulated glucose transport, compared with
nondiabetic mice. With GLUT4 overexpression, insulin-stimulated glucose
transport was 6.5-fold higher in male diabetic transgenic mice,
compared with male diabetic nontransgenic mice (P <
0.0025).
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shows dose response curves for
stimulation of lipolysis by the ß adrenergic agonist, isoproterenol.
Basal and maximal rates of lipolysis were similar in adipocytes from
nontransgenic and transgenic mice. The ED50 for stimulation
was reduced by 50% in transgenic adipocytes (P <
0.027), indicating slightly increased sensitivity to ß adrenergic
stimulation. The effect is too small to see on the log plot
and is shown in the bar graph inset.
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) encompassing the plasma insulin
concentrations in mice in this study (Table 1). Although there was a
tendency for a slightly diminished effect of insulin to inhibit
lipolysis at all insulin concentrations, this did not reach statistical
significance for any one concentration. Concentrations of 0.5–1.0
nM correspond to the plasma insulin concentrations in the
nondiabetic mice of both genotypes and 0.12–0.2 nM, to the
concentrations in diabetic mice.
Effects of GLUT4 overexpression in adipocytes of diabetic mice on
insulin responsiveness in vivo
Figure 5 shows the results of insulin tolerance
tests in awake, unrestrained diabetic mice of both genotypes. Initial
blood glucose, after a 6-h fast, was 21.9 ± 0.5 mmol/l in
nontransgenic and 22.7 ± 0.9 mmol/l in transgenic female mice.
When 0.7 mU insulin per gm BW was injected into nontransgenic diabetic
female mice, there was no significant change in blood glucose (Fig. 5).
In contrast, in transgenic diabetic female mice, blood glucose fell to
a level significantly lower than initial values and than nontransgenic
diabetic values at 30, 45, and 60 min after insulin injection
(P < 0.05). Studies also were carried out in male mice
using higher insulin doses (0.9–1.0 mU/g). Blood glucose fell in both
nontransgenic and transgenic males; however, the effect was greater in
transgenics. Blood glucose fell by 60 ± 7% at 60 min after
insulin injection in transgenic diabetic males, compared with 42
± 5% in nontransgenic diabetic males (P < 0.05,
n = 5–15 per group). When much higher doses of insulin were
injected (3.3 mU per gm BW), blood glucose fell rapidly in
nontransgenic diabetic mice also (25.4 ± 0.76 mM
before insulin and 7.79 ± 0.77 at 30 min after insulin; not
shown). Because the ameliorative effect of GLUT4 overexpression is
apparent at submaximal insulin concentrations and a high dose of
insulin rapidly lowers blood glucose also in nontransgenic diabetic
mice, it seems that adipose-specific GLUT4 overexpression increases
insulin sensitivity.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This may seem unexpected, considering that fat is thought to account for relatively little glucose use in vivo. However, in studies in which a comprehensive assessment of the pathways for adipose cell glucose metabolism was performed (including, importantly, glucose conversion to lactate), adipose tissue took up as much as 15% of an oral glucose load in normal lean humans and up to 30–50% in obese humans (32, 33). Additional evidence that glucose uptake into adipose tissue could play an important role in whole-body glucose homeostasis comes from studies in which overexpression of GLUT4 selectively in adipocytes of nondiabetic transgenic mice was shown to improve whole-body glucose tolerance and to lower plasma insulin levels, indicating increased insulin sensitivity (19). The current study demonstrates that in diabetic mice, overexpression of GLUT4 in adipocytes can improve insulin sensitivity. This improvement could be caused by direct effects in fat or possibly by indirect effects on other tissues. We found no significant difference in glucose transport in skeletal muscle from nontransgenic vs. transgenic mice. Preliminary results suggest no difference in the effect of submaximal insulin to suppress hepatic glucose output in nontransgenic and transgenic mice. However, this does not preclude possible differences in glucose uptake in muscle or glucose output by liver in the intact diabetic animal, caused by differential effects of circulating substrates or counterregulatory hormones in nontransgenic and transgenic mice.
The ameliorative effects of adipose-specific GLUT4 overexpression
occur, even though overexpression of GLUT4 does not reverse the
catabolic state of the diabetic mice. In fact, adipose cell integrity
is profoundly affected, as evidenced by a similar decrease in cell size
and fat pad mass in nontransgenic and transgenic diabetic mice. This is
probably caused, in large part, by accelerated lipolysis resulting from
the lack of insulin and the elevation in glucagon levels, which
accompany this uncontrolled diabetic state. In vitro
lipolysis studies show a slight increase in sensitivity to
isoproterenol in cells from GLUT4 overexpressing mice (Fig. 4A).
Furthermore, at insulin concentrations in the order of magnitude of the
levels in the mice in this study, there was no enhancement of the
antilipolytic effect of insulin (Fig. 4B). Thus, increased lipolysis,
driven by the uncontrolled diabetic state, most likely overrides the
modest increase in lipogenesis, resulting in decreased size of
adipocytes from transgenic mice, similar to that seen in nontransgenic
diabetic mice. The release of free fatty acids from lipolysis could
contribute to insulin resistance in other organs, such as skeletal
muscle and liver, in both nontransgenic and transgenic diabetic
mice.
This may, in part, explain the lack of improvement in ambient blood
glucose levels in diabetic transgenic mice, when plasma insulin levels
are very low, as in our study. Furthermore, although basal glucose
transport in isolated adipocytes from transgenic mice is increased
20-fold when measured at tracer glucose concentrations, the increase in
basal glucose uptake at physiological (5 mM) glucose
concentration is only 2- to 3-fold (22) and is probably lower at the
elevated glucose concentrations present in these diabetic mice. Hence,
in the setting of very low plasma insulin concentrations, the effect of
the transgene on glucose uptake in adipocytes may not be sufficient to
overcome the insulin resistance in skeletal muscle and liver induced by
the diabetic state. However, when insulin is administered, increased
sensitivity is evident in the transgenic mice (Fig. 5).
Leturque et al. (17) recently showed an improved effect of insulin injection on blood glucose in streptozotocin diabetic transgenic mice in which GLUT4 overexpression was driven by a muscle-specific promoter. Even though muscle is the major tissue responsible for insulin-stimulated glucose disposal (34) in vivo, only a very small improvement in ambient blood glucose levels was seen, compared with nontransgenic diabetic littermates (17). This occurred under experimental conditions in which both nontransgenic and transgenic mice had milder hyperglycemia and for a shorter duration of time than the mice in our study. Although the effect might be greater with higher levels of GLUT4 expression in muscle, these data underscore the fact that it is difficult to achieve a major improvement in blood glucose when insulin levels are very low. In contrast, when insulin is present, as in high-fat fed (12) or db/db (13) mice, even in the setting of marked insulin resistance, GLUT4 overexpression in muscle and fat simultaneously reduces insulin resistance (12) and results in much greater amelioration of the diabetic state (13). Although we did not see an improvement in glucose tolerance, in adipose-specific GLUT4 overexpressing mice fed a high-fat diet (35), glucose tolerance depends partly on the ability to secrete insulin, which can be impaired by high fat feeding. Thus, it is not as direct an assessment of insulin sensitivity as the insulin tolerance tests performed in the current study. In fact, in adipose-specific GLUT4 overexpressing mice fed a high fat diet, we did observe a consistent trend toward lower ambient insulin levels, compared with nontransgenic mice on the same diet (35), which is consistent with the notion that GLUT4 overexpression in fat reduces insulin resistance.
The improvement seen in this study in the setting of streptozotocin diabetes is somewhat surprising, considering that recent data indicate that insulin action is initiated by an elaborate cascade of signaling events (36). Streptozotocin diabetes has been shown to result in alterations that enhance multiple steps in insulin signaling, including insulin binding in adipocytes and muscle (37, 38, 39); tyrosine phosphorylation of the insulin receptor, as well as nonreceptor proteins including IRS-1 (40); PI3 kinase activity immunoprecipitated by IRS-1 (41); and the amount of the 85-kDa subunit of PI3 kinase that associates with IRS-1 in response to insulin (41). However, in spite of all these changes, insulin-stimulated glucose transport is depressed in adipocytes and muscle of streptozotocin diabetic rodents (10, 42). Only the overexpression of GLUT4 restores or increases insulin-stimulated glucose transport at the level of the tissue in which the transgene is expressed, and this improves whole body glucose uptake in response to insulin.
Our study demonstrates that using a heterologous promoter, GLUT4 expression can be maintained at very high levels, even in a tissue where its transcription is normally suppressed by diabetes (8). Furthermore, overexpression of GLUT4 in adipocytes improves insulin action in vivo in the setting of severe diabetes. This is consistent with the interpretation that glucose uptake into fat can play a significant role (either directly or indirectly) in the regulation of whole-body glucose homeostasis and that down-regulation of GLUT4 in adipocytes may contribute to the insulin resistance associated with diabetes. In comparison with several studies in which GLUT4 was overexpressed using its own promoter (12, 13, 14, 43) or muscle specific promoters (17, 18), driving GLUT4 with an adipocyte-specific promoter can achieve significantly higher levels of expression in both nondiabetic and diabetic mice. Although fat alone may not be the optimal target for GLUT4 overexpression, these data indicate that certain heterologous promoters may be very useful for high-level overexpression of GLUT4. Taken together with other recent studies (12, 13, 17), these data indicate that GLUT4 could be an important target for development of new therapies for treating or preventing diabetes, including (potentially) gene therapy.
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Acknowledgments |
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Footnotes |
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Present address for E. T. is Ergo Science Corp., 100 First Avenue, Charlestown, Massachusetts 02129.
Received November 27, 1996.
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M. V. Thai, S. Guruswamy, K. T. Cao, J. E. Pessin, and A. L. Olson Myocyte Enhancer Factor 2 (MEF2)-Binding Site Is Required for GLUT4 Gene Expression in Transgenic Mice. REGULATION OF MEF2 DNA BINDING ACTIVITY IN INSULIN-DEFICIENT DIABETES J. Biol. Chem., June 5, 1998; 273(23): 14285 - 14292. [Abstract] [Full Text] [PDF]
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K. M. Oshel, J. B. Knight, K. T. Cao, M. V. Thai, and A. L. Olson Identification of a 30-Base Pair Regulatory Element and Novel DNA Binding Protein That Regulates the Human GLUT4 Promoter in Transgenic Mice J. Biol. Chem., July 28, 2000; 275(31): 23666 - 23673. [Abstract] [Full Text] [PDF]
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) or
transgenic (•) mice. Dose response curves for
isoproterenol-stimulation of lipolysis (panel A) and insulin-inhibition
of lipolysis in the presence of 10 µM isoproterenol
(panel B) were measured as described in Materials and
Methods. The inset to panel A shows the
ED50 for isoproterenol stimulation of lipolysis in
adipocytes from nontransgenic (Ntg) and transgenic (Tg) mice. Results
are means ± SE for five to seven experiments. *,
Different from nontransgenic at P < 0.03.