Activation of liver G-6-Pase in response to insulin-induced
hypoglycemia or epinephrine infusion in the rat
Isabelle
Bady,
Carine
Zitoun,
Ludovic
Guignot, and
Gilles
Mithieux
Institut National de la Santé et de la Recherche
Médicale U. 449, Faculté de Médecine Laennec,
69372 Lyon, France
 |
ABSTRACT |
This study
was conducted to test the hypothesis of the activation of
glucose-6-phosphatase (G-6-Pase) in situations where the liver is
supposed to sustain high glucose supply, such as during the
counterregulatory response to hypoglycemia. Hypoglycemia was induced by
insulin infusion in anesthetized rats. Despite hyperinsulinemia,
endogenous glucose production (EGP), assessed by
[3-3H]glucose tracer dilution, was paradoxically not
suppressed in hypoglycemic rats. G-6-Pase activity, assayed in a
freeze-clamped liver lobe, was increased by 30% in hypoglycemia
(P < 0.01 vs. saline-infused controls). Infusion of
epinephrine (1 µg · kg
1 · min
1) in
normal rats induced a dramatic 80% increase in EGP and a 60% increase
in G-6-Pase activity. In contrast, infusion of dexamethasone had no
effect on these parameters. Similar insulin-induced hypoglycemia experiments performed in adrenalectomized rats did not induce any
stimulation of G-6-Pase. Infusion of epinephrine in adrenalectomized rats restored a stimulation of G-6-Pase similar to that triggered by
hypoglycemia in normal rats. These results strongly suggest that
specific activatory mechanisms of G-6-Pase take place and contribute to
EGP in situations where the latter is supposed to be sustained.
dexamethasone; endogenous glucose production
 |
INTRODUCTION |
LIVER
GLUCOSE-6-PHOSPHATASE (G-6-Pase) is a key enzyme in
systemic glucose homeostasis, because it catalyzes the last biochemical reaction of glucose synthesis, i.e., the hydrolysis of glucose 6-phosphate (G-6-P) in glucose and phosphate (26,
29). It thus confers on the liver, the major
gluconeogenic tissue, the capacity to release glucose into the blood to
meet the glucose requirements of the body. In addition to regulation
taking place at the level of gene expression, considerable evidence has
recently been provided that regulatory mechanisms of the activity of
G-6-Pase take place under conditions of inhibited endogenous glucose
production (EGP) (see Refs. 26 and 29 for recent
reviews). These particularly include suppressions of activity induced
by insulin and/or glucose (6, 11, 12, 21, 25, 27) or
nutrients that might be supplied upon refeeding (1, 5, 22,
23). On the other hand, in keeping with a crucial role of
G-6-Pase under conditions of increased glucose requirements, it has
been strongly suggested that G-6-Pase gene expression is rapidly
induced to compensate for the glucose deficiency resulting from partial
hepatectomy (13) or hemorrhage (17).
Moreover, we have recently shown that the G-6-P hydrolytic
flux is stimulated by glucagon infusion in vivo in the rat and in
isolated hepatocytes and that this activation may account by itself
for a concomitant increase in EGP (15). The mechanism in
the latter case seems to involve temperature-sensitive (e.g.,
membrane-dependent) events rather than intrinsic stimulations of enzyme
activity (15).
One crucial situation in which the liver is supposed to sustain a
high glucose supply is hypoglycemia. This also constitutes a major
problem that may be frequently encountered in the treatment of diabetic
patients. In this work, we have thus raised the question whether
G-6-Pase activity could be stimulated, contributing the production of
glucose by the liver in response to insulin-induced hypoglycemia in
rats. Additionally, we studied the involvement of counterregulatory
processes in this phenomenon by: 1) testing the effect of
infusion of dexamethasone (Dexa) or epinephrine (Epi) in normal rats;
2) performing the same experiments in adrenalectomized (ADX)
rats. Because glucokinase (GK) and glucose 6-phosphate
(G-6-P) are also crucial determinants of liver glucose
production (12, 25, 29), we measured these two parameters
in all experiments.
 |
MATERIALS AND METHODS |
Animals.
Seven-week-old male Sprague-Dawley rats (220-240 g, IFFA-Credo,
L'Arbresle, France) were housed for 1 wk of acclimatization in the
laboratory and given standard chow (50% carbohydrate, 23.5% protein,
12% water, 5% lipid, 4% cellulose, 5.5% mineral salt, on weight
basis) and water ad libitum. ADX rats (surgery performed at 4 wk of
age) were further given sodium chloride (0.9%) and sucrose (1%) added
in water. Experiments were performed in 8-wk-old animals in the
postabsorptive state, i.e., 5 h after food withdrawal, with free
access to drinking water.
Infusions.
Rats were anesthetized by intraperitoneal injection of pentobarbital
sodium (7 mg/100 g body wt). Polyethylene catheters were inserted into
the right jugular vein for infusions and into the left carotid artery
for blood sampling. [3-3H]glucose (Isotopchim, Ganagobie,
France) was infused at 8.88 kBq/min to assess the glucose disappearance
rate. A bolus (88.8 kBq/min) was infused for the first minute. Plasma
glucose specific activity was not clamped, but it did not vary for at
least the last 90 min of infusions (not shown). Insulin (Lilly France,
St Cloud, France) was infused at 480 pmol/h for both euglycemic and hypoglycemic clamps (infusions were primed at 4.80 nmol/h for 1 min). A
solution of glucose (1.67 mol/l) was infused to maintain either
euglycemia (euglycemic clamps) or hypoglycemia (hypoglycemic clamps)
above 3 mmol/l, as previously described (12, 23, 25). Dexa
or Epi (Sigma, La Verpillière, France) was infused in normal rats
at a rate of 0.7 and 1 µg · kg
1 · min
1,
respectively. Both infusions were primed at 10-fold this rate for 1 min. Control rats were infused with saline. Blood glucose was monitored
every 10-20 min using a Glucometer II (Bayer Diagnostics, Puteaux, France). Final blood glucose was accurately determined using an enzymatic assay as previously described
(22-25). Fifteen minutes before the final blood
sampling, a laparotomy was performed and protected by a wet gauze. A
liver lobe was freeze-clamped in situ at
196°C just after the final
blood sampling and stored at
80°C for further determinations. Our
protocols were approved by a local ethics committee for animal experimentation.
Enzyme assays and other determinations.
Enzyme activity determinations under conditions of increasing
concentration of G-6-P were performed in liver homogenates
at 30°C and pH 7.3, as previously described (12, 24).
The contribution of nonspecific phosphatase activity was estimated from
the hydrolysis of
-glycerophosphate and substracted in all
determinations (12, 24). GK activity was assayed at 30°C
and pH 7.3 in 12,000-g supernatants of liver homogenates as
described (12). Liver G-6-P and plasma glucose
were determined according to previously described enzymatic assay
procedures (12, 22-25). Plasma insulin and glucagon were determined using radioimmunoassays as described previously (12, 24). Plasma catecholamines were quantified by
high-performance liquid chromatography (32). The procedure
for the quantification of immunoreactive G-6-Pase protein has been
described in detail elsewhere (6, 12). EGP was calculated
at steady state from the specific activity of plasma glucose and the
rate of infusion of [3-3H]glucose, subtracting the rate
of infusion of unlabeled glucose when appropriate (12,
25). Statistical analyses were performed by ANOVA and by use of
the Student's t-test when significance was established.
 |
RESULTS |
Effect of hormone infusions in normal rats.
In agreement with previous results (11, 12, 25), the
infusion of insulin for 180 min in normal rats with maintenance of
euglycemia (see Figs. 1 and
2E) by glucose infusion (1.30 ± 0.03 mmol/h) resulted
in a dramatic suppression in EGP (Fig.
2A). This could likely be
accounted for by a strong decrease in the liver G-6-P
content (Fig. 2C), because there was no modification in the
liver G-6-Pase activity (Fig. 2B). In contrast, the infusion of insulin without glucose induced a rapid lowering in blood glucose (Fig. 1), resulting in a final plasma glucose concentration of 3.4 ± 0.3 vs. 8.6 ± 0.2 mmol/l in saline-infused rats (Fig.
2E). At variance with insulin-infused euglycemic rats, EGP
was not significantly lower in hypoglycemic rats (64 ± 6 µmol · kg
1 · min
1) than
in saline-infused rats (77 ± 10 µmol · kg
1 · min
1,
means ± SE, n = 5) (Fig. 2A), despite
plasma insulin levels being as markedly increased as those in
euglycemic rats (Fig. 2F). G-6-Pase activity in
hypoglycemic rats (11.2 ± 0.8 µmol · min
1 · g liver
1)
was higher by 40% (P < 0.01) compared with that in
saline-infused rats, i.e., 8.1 ± 1.2 µmol · min
1 · g
1 (Fig.
2B). However, there was no alteration in the G-6-Pase
Michaelis-Menten constant (Km) induced by
insulin either in euglycemia or in hypoglycemia (~2.5-3 mM).
G-6-P content was higher by ~40% in the liver of insulin-infused hypoglycemic rats than in saline-infused euglycemic rats: 245 ± 19 vs. 175 ± 9 nmol/g liver (P < 0.05), respectively (Fig. 2C). GK activity was higher in
insulin-infused hypoglycemic rats (2.0 ± 0.13 µmol · min
1 · g
1) than in
saline-infused rats (1.1 ± 0.02 µmol · min
1 · g
1),
whereas there was no change in GK activity induced by insulin infusion
in the presence of euglycemia (Fig. 2D). GK
Kms (~7-8 mM) were not different in both
insulin-infused groups and in saline-infused rats.

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Fig. 1.
Evolution of blood glucose concentrations during
infusions in normal (A) and ADX (B) rats.
Anesthetized rats were infused with saline or insulin at 480 pmol/h
with glucose when necessary to maintain euglycemia (eu) or hypoglycemia
above 3 mmol/l (hypo) (see RESULTS for the rates of glucose
infusion required) or dexamethasone (Dexa) at 0.7 µg · kg 1 · min 1 or
epinephrine (Epi) at 1 µg · kg 1 · min 1. Blood
glucose was monitored using a Glucometer II (Bayer). Results shown are
the means of 5-6 animals per group (A) and 4-5
animals per group (B). Error bars have been deleted for the
sake of clarity.
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Fig. 2.
Effect of hormone infusions on plasma and liver glucose
metabolic parameters in normal rats. Infusions in anesthetized rats
were as in Fig. 1. EGP, endogenous glucose production; GK, glucokinase;
G-6-Pase, glucose-6-phosphatase; G-6-P, glucose 6-phosphate.
At the end of infusions (180 min), a liver lobe was frozen in situ and
removed for enzyme and metabolite determinations, and blood was sampled
for plasma hormone and glucose determinations. EGP was calculated from
tracer data as described in MATERIALS AND
METHODS. Results are expressed as means ± SE.
*,**Different from saline, P < 0.05 and
P < 0.01, respectively.
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The infusion of Dexa (0.7 µg · kg
1 · min
1) for 180 min in normal rats had no significant effect on blood glucose (Fig. 1)
or on any of the parameters studied but one (Fig. 2). Indeed, a slight lowering in GK activity was evidenced in Dexa compared with
saline-infused rats: 0.8 ± 0.04 vs. 1.1 ± 0.02 µmol · min
1 · g
1,
respectively (P < 0.01, Fig. 2D). In
contrast, the infusion of Epi (1 µg · kg
1 · min
1) induced
a rapid and sustained increase in blood glucose (Fig. 1), a marked 80%
enhancement in EGP (138 ± 13 µmol · kg
1 · min
1,
mean ± SE, n = 6), a 60% activation in G-6-Pase
activity (12.9 ± 0.7 µmol · min
1 · g liver
1),
a 90% increase in the liver G-6-P content (329 ± 40 nmol/g liver), compared with saline-infused controls (Fig. 2, A,
B, and C). On the other hand, as in Dexa-infused rats,
there was a slight decrease in the liver GK activity (0.7 ± 0.08 µmol · min
1 · g
1) in
Epi-infused rats (Fig. 2D). There was no alteration in the G-6-Pase or GK Kms induced by either Dexa or Epi
(not shown). Despite the dramatically increased plasma glucose
concentration (Fig. 2E), there was no alteration of plasma
insulin level in Epi-infused rats compared with saline controls (Fig.
2F).
Minute levels of Epi were found in the plasma of saline- and
insulin-infused normal rats under conditions of euglycemia (compare with the levels in ADX rats in Table 1). There was a
marked increase in plasma Epi induced by hypoglycemia, roughly
equivalent to the levels reached during immobilization stress in the
rat. Noteworthy, the plasma Epi concentration induced by Epi infusion
was in the same order range (Table 1). In contrast, there was no
increase in plasma norepinephrine promoted by insulin-induced
hypoglycemia: 983 ± 45 vs. 781 ± 64 pg/ml in saline-infused
animals [not significant (NS)], in agreement with previous data
(34). In the same manner, there was no difference in the
plasma glucagon concentration in insulin-infused hypoglycemic rats
compared with saline-infused control rats (360 ± 55 vs. 306 ± 25 ng/l, respectively, NS). This was also in agreement with previous
data (7). Because cortisol and/or Dexa has no effect on
EGP (8, 10) or on the relevant liver metabolic parameters
(see above), we further focused on the effect of insulin-induced
hypoglycemia and of Epi in ADX rats.
Effect of hormone infusions in ADX rats.
Basal EGP (saline-infused rats) was about twice lower in ADX-rats than
in normal rats: 42 ± 8 vs. 77 ± 10 µmol · kg
1 · min
1
(P < 0.05), respectively (Fig.
3A). It had been necessary to infuse glucose in two of four rats to maintain euglycemia (0.15 ± 0.1 mmol/h as a mean). Insulin infusion in the presence of euglycemia (Fig. 1) induced a total suppression of EGP (Fig. 3A).
However, the amount of glucose infused to maintain euglycemia
was not different from that in normal rats (1.39 ± 0.1 vs.
1.30 ± 0.2 mmol/h, see above). Insulin infusion to achieve
hypoglycemia induced a rapid lowering of blood glucose (Fig. 1),
resulting in a final plasma glucose concentration of 3.2 ± 0.2 mmol/l vs. 6.4 ± 0.7 mmol/l in saline-infused rats
(P < 0.01, Fig. 3E). As in normal rats, there was no decrease in EGP in insulin-infused hypoglycemic ADX rats
with regard to their euglycemic counterparts (Fig. 3A).
However, it had been necessary to infuse glucose in three of four
animals to maintain blood glucose above 3 mmol/l (0.3 ± 0.1 mmol/h as a mean). G-6-Pase activities and G-6-P levels were
comparable in saline-infused ADX and normal rats (compare Fig. 2,
B and C vs. Fig. 3, B and
C). As in normal rats, insulin in euglycemia had no effect on
G-6-Pase (Fig. 3B) and had a marked decreasing effect on the
G-6-P content (Fig. 3C). In contrast with normal rats, there was no effect on G-6-Pase activity and G-6-P
content induced by hypoglycemia in ADX rats (Fig. 3, B
and C). GK activity was about two times lower in
euglycemic ADX rats (0.5 ± 0.05 µmol · min
1 · g
1)
compared with euglycemic controls (P < 0.01). There
was no stimulation of GK activity induced by hypoglycemia in ADX rats
(Fig. 3D).

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Fig. 3.
Effect of hormone infusions on plasma and liver glucose
metabolic parameters in adrenalectomized (ADX) rats. Infusions were as
in Fig. 1 and plasma and liver determinations as in Fig. 2. Data are
means ± SE; (significance as in Fig. 2).
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As expected, there was no increase in the plasma Epi concentration
induced by hypoglycemia in ADX rats (Table 1). The infusion of Epi
resulted in a marked increase in the plasma Epi level (Table 1).
Noteworthy, the latter restored the effects induced by hypoglycemia in
normal rats, e.g., rapid and sustained increase in blood and plasma
glucose (Figs. 1 and 3E), marked increases in EGP (Fig. 3A), G-6-Pase activity (Fig. 3B),
G-6-P content (Fig. 3C), and GK activity (Fig.
3D), and absence of increase in plasma insulin despite high
glycemia (Fig. 3F).
Finally, it should be specified that in none of the experiments
reported (relating to Figs. 2 or 3) might the increases in G-6-Pase
activity be accounted for by any significant increase in the amounts of
immunoreactive protein determined by Western blot (see, e.g., the
results relating to Epi infusion in normal rats in Fig.
4).

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Fig. 4.
Effect of Epi infusion on the amount of immunoreactive
G-6-Pase protein in normal rats. Twenty-five micrograms of
freeze-clamped liver protein were analyzed in each track. Densitometric
analysis did not reveal any significant difference between the two
groups.
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 |
DISCUSSION |
The question whether biochemical mechanisms of regulation of
G-6-Pase activity exist and participate in the modulation of EGP in
vivo has been a matter of controversy for many years (14, 28). To date, we have provided a body of evidence that G-6-Pase activity is inhibited under conditions of suppression of EGP (6, 12, 23, 24), confirming and extending previous findings from
other groups (11, 21). From those preceding studies, we
have demonstrated that reliable conditions to characterize G-6-Pase
activity biochemically under its "in situ" metabolically active
form were achieved by freeze-clamping a liver lobe at
196°C in
anesthetized rats (12, 24). It must be noted that the use of anesthetized animals is absolutely required in such a study as we
carried out. Indeed, it has been shown that very rapid (and transient)
increases in EGP (lasting
10 min) and glycemia (lasting
30-40
min) occur at the time of anesthesia in rats (4, 30). Thus
the anesthesia of animals a long time before samplings seems the only
way to reliably correlate EGP with metabolic parameters obtained from
freeze-clamped livers. The observation that basal EGP in normal rats in
this study (~75
µmol · kg
1 · min
1) was
slightly higher than that determined in some recent studies using
conscious rats [e.g., ~11
mg · kg
1 · min
1, i.e., 61 µmol · kg
1 · min
1
(18, 31)] might suggest that anesthetized animals could
be somewhat stressed. However, this is unlikely, because anesthesia decreases plasma catecholamines and circulating glucagon levels (30). Moreover, anesthetized rats studied herein exhibited
very low (trace) circulating epinephrine levels (Table 1). It should be
mentioned that anesthesia has been shown to induce insulin resistance
of EGP to some extent (4). This could have attenuated some
of the effects of insulin in this study. However, this cannot impede
the interpretation of the data, because all rats studied herein were
anesthetized. In addition, insulin markedly suppressed EGP in
euglycemia in both normal and ADX rats (Figs. 2 and 3).
In this work, we have tested the hypothesis of the activation of
G-6-Pase under conditions in which the liver is supposed to sustain
active glucose supply to the body. The first experimental model studied
has been insulin-induced hypoglycemia in normal rats. Noteworthy,
despite a dramatic increase in plasma insulin concentration, EGP was
paradoxically not suppressed in hypoglycemic rats (results of
Fig. 2). This is in agreement with recent work performed in dogs and
humans (3, 7). The combination of two opposite effects may
explain this absence of alteration of EGP. On the one hand, G-6-Pase
activity and G-6-P concentration were both markedly
increased, contributing to glucose synthesis and output from the liver.
On the other hand, GK activity was increased, enhancing glucose
recycling and utilization by the liver. The latter increase may likely
reflect the rapid induction of the GK gene as the result of the 3-h
period of hyperinsulinemia (9, 24). It has been strongly
suggested that translocation mechanisms of GK from the nucleus to the
cytoplasm, depending on regulatable association with a GK-regulatory
protein, may also greatly influence the GK-dependent liver glucose
phosphorylation (2, 33). It is unfortunately impossible to
assess the contribution of these translocation processes under the
conditions that are crucially required to obtain reliable estimations
of G-6-Pase activity and G-6-P concentration, e.g.,
homogenates from freeze-clamped livers. We have not further addressed
this question in the present work. It is important to note that the
latter effects are the result of the hypoglycemic fact and not of
hyperinsulinemia. In the presence of euglycemia, indeed, insulin
induced markedly different effects, i.e., dramatic suppression in EGP,
no effect on G-6-Pase or GK activities, and strong decrease in liver
G-6-P content (see Fig. 2), in agreement with our previous
data (12). In this latter work, it was suggested that
hyperinsulinemia and a high glucose-phosphorylating flux were both
required to induce the inhibition of G-6-Pase activity in the liver of
rats infused with glucose. Noteworthy, despite concomitant elevated
plasma insulin concentration and enhanced glucose phosphorylation,
G-6-Pase was activated in hypoglycemic rats. This suggested that
another factor, independent of both the former factors and triggered by
hypoglycemia (presumably counterregulatory hormones), might be dominant
over the effect of insulin and glucose phosphorylation, resulting in
the activation of the enzyme.
Because glucagon and norepinephrine were not significantly increased in
the plasma of hypoglycemic rats, in agreement with previous data
(7, 34), and Dexa infusion had no effect on EGP and the
relevant hepatic parameters (see RESULTS), the likely candidate hormone was Epi. In strong agreement with this hypothesis, plasma Epi was strongly increased in response to hypoglycemia. Furthermore, Epi infusion to establish plasma Epi levels very similar
to those in hypoglycemic rats had very comparable effects, e.g., on the
activation of G-6-P activity and increase in
G-6-P content. Noteworthy, at slight variance with
insulin-induced hypoglycemia, EGP and plasma glucose were additionally
markedly increased in Epi-infused rats (see Fig. 2). This might likely
be accounted for by the nonoccurrence of an increased liver
glucose-recycling flux (no increase, even a decrease in GK activity).
The latter could be explained by the absence of hyperinsulinemia as a
result of the insulinostatic effect of Epi (16). This
absence of hyperinsulinemia and increased glucose-recycling flux and/or
the presence of high plasma Epi levels might also explain why
hyperglycemia is not able to inhibit EGP, at variance with previous
data (12, 31). The experiments performed in ADX rats are
in strong agreement with a crucial role of Epi in the G-6-Pase
activation. It is beyond the scope of the present study to discuss the
numerous metabolic alterations taking place in ADX rats. The key
observation in these experiments has been that, despite very similar
conditions of plasma insulin and glucose concentrations with regard to
normal rats, no activation of G-6-Pase took place in insulin-induced hypoglycemic ADX rats (results of Fig. 3). It was noteworthy that Epi
infusion not only induced a dramatic increase in EGP in ADX rats but
also restored several events triggered by hypoglycemia in normal rats,
e.g., a stimulation to a similar extent of G-6-Pase activity and the
increase in G-6-P concentration, both contributing to the
increased glucose production. It must be mentioned that Epi infusion
likely altered blood parameters like pressure and heart rate. However,
this could not alter the quantification of EGP, because only tracer and
glucose infusion rates and glucose specific activity are required for
the calculations in the one-pool model at steady state that we used
(see MATERIALS AND METHODS).
In conclusion, several types of intracellular mechanisms may be
crucially involved in the processes of control of EGP in response to
insulin-induced hypoglycemia, such as those that promote the increase
in the liver G-6-P concentration, for example. Our
results also strongly suggest a major role of Epi in these processes, in keeping with previous results (19, 20). However, the
present work constitutes the first evidence that one of these
mechanisms is the biochemical activation of the G-6-Pase enzyme. This
definitively indicates that G-6-Pase and the molecular mechanisms of
regulation of its activity constitute crucial factors involved in the
control of EGP, not only in the situations in which it is suppressed
but also in those in which it has to be sustained.
 |
ACKNOWLEDGEMENTS |
We thank Drs. R. Cohen and J. M. Cottet-Emard for precious help in
the insulin, glucagon, and catecholamine determinations.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: G. Mithieux, INSERM U. 449, Faculté de Médecine R.T.H.
Laennec, rue Guillaume Paradin, 69372 Lyon Cédex 08, France (E-mail:
mithieux{at}laennec.univ-lyon1.fr).
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.
10.1152/ajpendo.00098.2001
Received 6 March 2001; accepted in final form 19 November 2001.
 |
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