Effects of
-adrenergic blockade on hepatic and renal
glucose production during hypoglycemia in conscious dogs
Eugenio
Cersosimo,
Irina N.
Zaitseva, and
Mohamed
Ajmal
Department of Medicine, State University of New York at Stony
Brook, Stony Brook, New York 11794-8154
 |
ABSTRACT |
To investigate the role of
-adrenergic
mechanisms in the counterregulatory response of the liver and kidney to
hypoglycemia, we studied 10 dogs before and after a 2-h
constant infusion of insulin (4 mU · kg
1 · min
1)
either without (n = 4) or with (8 µg/min, n = 6) propranolol and
variable dextrose to maintain hypoglycemia, 7 days after surgical placement of sampling catheters in left renal and hepatic veins and
femoral artery. Systemic glucose appearance
(Ra) and endogenous (EGP),
hepatic (HGP), and renal (RGP) glucose production were measured by a
combination of arteriovenous difference and peripheral infusion of
[6-3H]glucose, renal
blood flow with a flow probe, and hepatic plasma flow by indocyanine
green clearance. Without
-adrenergic blockade, arterial glucose
decreased from 5.12 ± 0.02 to 2.53 ± 0.07 mmol/l, glucose Ra increased from 17.8 ± 0.7 to 30.5 ± 2.5 (P < 0.01) when EGP was 22.2 ± 0.5, HGP from 13.5 ± 1.1 to
19.3 ± 1.3, and RGP from 2.4 ± 1.0 to 8.6 ± 0.9 µmol · kg
1 · min
1
(all P < 0.05). When propranolol was
infused, glucose decreased from 5.97 ± 0.02 to 2.71 ± 0.03 mmol/l, glucose Ra increased from 16.3 ± 1.0 to 25.1 ± 1.6 when EGP was 9.9 ± 0.4, HGP
decreased from 14.4 ± 0.7 to 10.4 ± 0.6, and RGP decreased from
3.8 ± 1.3 to 1.1 ± 0.8 µmol · kg
1 · min
1
(all P < 0.05). Our data indicate
that
-adrenergic blockade impairs glucose recovery during sustained
hypoglycemia, in part, by preventing the simultaneous compensatory
increase in HGP and RGP.
propranolol; liver; kidney; carbohydrate; counterregulation
 |
INTRODUCTION |
EPINEPHRINE is a potent stimulus for glucose
production, and its release plays an important role in glucose recovery
during insulin-induced hypoglycemia (11, 16). Evidence suggests that the plasma glucose-raising effect of epinephrine is mediated via both
- and
-adrenergic mechanisms and involves direct and indirect actions, which include stimulation of glucose production and limitation of glucose utilization (8, 22, 23). Epinephrine action to increase
hepatic glucose production is largely mediated through
2-adrenergic receptors and is
well documented in dogs (18, 26). The potential contribution of the
kidney and the effects of epinephrine on renal glucose production
during hypoglycemia, however, are not known. Recent findings indicating
that epinephrine infusion increases renal glucose production in
postabsorptive healthy subjects (27) and that renal contribution to
glucose production in hypoglycemic dogs is enhanced and dependent on
elevation of circulating counterregulatory hormones (4) suggest that adrenergic stimulation of glucose production by the kidney may represent an important additional mechanism in the body's defense against insulin-induced hypoglycemia. The present studies were therefore undertaken to investigate the contribution of the liver and
kidney to glucose production during sustained hypoglycemia with
simultaneous
-adrenergic blockade in conscious dogs.
 |
METHODS |
Animals and surgery. All studies were
approved by the Institutional Animal Care and Use Committee at the
State University of New York at Stony Brook and followed National
Institutes of Health guidelines for animal experimentation. Seven days
before the experiment, a laparotomy was performed in 20- to 25-kg male mongrel dogs (n = 10) under halothane
anesthesia, and Silastic sampling catheters were placed in the left
renal and hepatic veins and in the aorta, and a flow probe was placed
around the left renal artery, as previously described (2).
Experimental protocol. On the morning
of the experiment, after an 18-h overnight fast, the catheters and the
flow probe were exteriorized under local anesthesia, and an infusion
catheter was inserted into the precava via a lateral saphenous vein.
The Doppler flow probe was connected to a transducer, and unilateral renal blood flow was monitored continuously throughout the experiment. At 0800 (time =
120 min), after obtaining blood for assay
blanks, a primed constant systemic infusion of
[6-3H]glucose (10 µCi, 0.20 µCi/min) together with a constant indocyanine green (ICG)
infusion (0.08 mg/min) were started and continued to the end of the
study. Baseline femoral artery and renal and hepatic vein blood samples
were obtained every 10 min from
30 to 0 min for the measurement
of microhematocrit, hepatic plasma flow, plasma insulin, glucagon,
catecholamines, glucose concentration, and specific activity (SA).
After completion of baseline collections, animals were randomized to
receive a 2-h constant systemic infusion of either insulin (4 mU · kg
1 · min
1)
alone (n = 4) or in combination with
propranolol (8 µg/min, n = 6)
together with a variable infusion of dextrose to maintain hypoglycemia
at ~2.2 mmol/l. Blood samples were obtained again at 10-min intervals
between 90 and 120 min, and, at the end of the experiment, the dog was
euthanized with an intravenous infusion of a solution of pentothal and
concentrated potassium chloride, and the position of the catheters was
verified at necropsy.
Analytic techniques. Plasma glucose
concentrations were measured by a glucose oxidase method using a
Beckman Glucose Analyzer II (Beckman, Fullerton, CA). Plasma
[3H]glucose SA was
determined in deproteinized plasma (25) after deionization with ion
exchange resins, as previously described (3). Plasma ICG concentration
was determined by a colorimetric assay (17); insulin (15) and glucagon
(1) by radioimmunoassays; and catecholamines by HPLC (19).
Calculations. Hepatic plasma flow
(HPF) was calculated by ICG clearance using the following equation
|
(1)
|
where
INFICG is ICG infusion rate
(mg/min), [ICG] is plasma ICG concentration (mg/ml), the
subscript a indicates artery, and the subscript hv indicates hepatic
vein. Left renal plasma flow (RPF) was calculated by multiplying renal
blood flow by the 1
hematocrit factor. Systemic glucose rates
of appearance (glucose Ra) were
calculated using the steady-state formula
|
(2)
|
where
INFGlc is the
[6-3H]glucose infusion
rate (dpm/min), and Glc is glucose. Left renal fractional
extraction of glucose and splanchnic fractional extraction of glucose
(FEGlc) were calculated using
the following formula
|
(3)
|
where
[Glc] is plasma glucose concentration, SA refers to
tritiated glucose specific activity, and the subscript v indicates renal or hepatic vein. The numerator in this formula represents [3H]glucose
radioactivity extracted by the kidney or splanchnic tissues, and the
denominator represents arterial
[3H]glucose
radioactivity. Left renal glucose utilization and splanchnic glucose
utilization (utilization) were calculated using the formula
|
(4)
|
where
R(H)PF equals either unilateral renal plasma flow or hepatic plasma
flow. Net left renal glucose balance and splanchnic glucose balance
(balance) were calculated using the following formula
|
(5)
|
Positive
values represent net output and negative values net uptake of glucose.
Left renal glucose production and hepatic glucose production
(production) were calculated as the algebraic difference between
glucose utilization (Eq. 4) and
balance (Eq. 5). Because glucose is
extracted into whole blood and there is rapid equilibration between red
blood cell and plasma glucose concentration, Eqs.
3-5 will underestimate hepatic and renal glucose production and utilization.
Statistics. All values are expressed
as means ± SE. Data obtained at baseline in each group were
compared with those from the study period using a paired
t-test; data between groups during the
study periods were compared using a nonpaired
t-test. All P values below 0.05 were considered
statistically significant.
 |
RESULTS |
Unilateral renal plasma flow was 7.45 ± 1.20 and 6.18 ± 1.00 ml · kg
1 · min
1
in the baseline period and did not change significantly
[P = not significant (NS)]
during hypoglycemia with (7.08 ± 0.70 ml · kg
1 · min
1)
or without (7.83 ± 0.70 ml · kg
1 · min
1)
simultaneous propranolol infusion (P = NS). Hepatic plasma flow increased from 28.20 ± 2.20 to 38.10 ± 2.00 ml · kg
1 · min
1
(P < 0.05) during hypoglycemia, but
it did not change (20.46 ± 2.10 vs. 22.97 ± 1.90 ml · kg
1 · min
1,
P = NS) when propranolol was
infused. Arterial plasma insulin levels increased from 50 ± 4 to
981 ± 67 and from 40 ± 4 to 1,075 ± 75 pmol/l (all
P < 0.01) in the hypoglycemia and
-blockade groups, respectively. Table 1
summarizes data on arterial, renal, and hepatic vein plasma glucose
concentration and SA in the baseline and during the last 30 min of the
hypoglycemic study period with or without
-adrenergic blockade. Net
left renal glucose balance switched from
0.74 ± 0.51 to a
net output of 1.72 ± 0.40 µmol · kg
1 · min
1
(P < 0.05), and net splanchnic
glucose output increased from 12.97 ± 1.27 to 17.91 ± 1.50 µmol · kg
1 · min
1
(P < 0.05) during hypoglycemia. When
propranolol was infused, net left renal glucose uptake increased from
1.42 ± 0.61 to
2.69 ± 0.42 µmol · kg
1 · min
1
(P < 0.05 vs. baseline and
hypoglycemia without propranolol), and net splanchnic glucose output
decreased from 11.46 ± 1.45 to 7.81 ± 0.80 µmol · kg
1 · min
1
(P < 0.05 vs. baseline and
hypoglycemia without propranolol). Figure 1
depicts net splanchnic and total renal glucose balance in the baseline
and during the last 30 min of the hypoglycemic study period with or
without
-adrenergic blockade. Arterial
[3H]glucose SA was
constant during the baseline period and in the last 30 min of the
hypoglycemic study period in both groups, indicating steady state had
been achieved. Mean plasma
[3H]glucose SA was
consistently lower in the renal and hepatic vein than in the artery in
all animals, except that when propranolol was infused in the
hypoglycemic period, mean plasma
[3H]glucose specific
activities in the artery and in the renal vein (2,846 ± 231 vs.
2,749 ± 146, P = NS) were not
different from each other (Table 1).
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Table 1.
Arterial, renal, and hepatic vein plasma Glc concentration and SA in
postabsorptive conscious dogs during the baseline period and in the
last 30 min of a 120-min hypoglycemic hyperinsulinemic clamp with and
without -adrenergic blockade
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Fig. 1.
Net splanchnic and renal glucose balance in
µmol · kg 1 · min 1
in postabsorptive conscious dogs in the baseline and during the last 30 min of a 120-min hypoglycemic clamp with and without -adrenergic
blockade. Total net renal glucose balance was estimated by multiplying
unilateral renal glucose balance by a factor of 2, assuming each kidney
contributes equally to glucose balance during the baseline and in the
hypoglycemic periods in both groups. Baseline values represent the
means ± SE of all 10 studies. Positive net glucose balance
indicates net output, and negative values indicate net uptake.
* P < 0.05 vs. baseline and
between groups.
|
|
Systemic glucose Ra increased from
17.8 ± 0.7 to 30.5 ± 1.5 during hypoglycemia, when
endogenous glucose production was 22.2 ± 1.5 µmol · kg
1 · min
1
(P < 0.05 vs. baseline),
and from 16.3 ± 1.0 to 25.1 ± 1.6 during hypoglycemia with
-blockade, when endogenous glucose production was 9.9 ± 0.4 µmol · kg
1 · min
1
(P < 0.05 vs. baseline and
hypoglycemia without propranolol). During hypoglycemia without
-blockade, renal fractional extraction of glucose increased from 6.2 ± 0.8 to 13.1 ± 0.3% (P < 0.05), renal glucose utilization did not change (1.95 ± 0.48 vs.
2.59 ± 0.37 µmol · kg
1 · min
1,
P = NS), and renal glucose production
increased threefold from 1.21 ± 0.50 to 4.31 ± 0.43 µmol · kg
1 · min
1
(P < 0.05). When propranolol was
infused during hypoglycemia, renal fractional extraction of glucose
increased from 7.4 ± 0.6 to 17.0 ± 0.9%
(P < 0.05), renal glucose
utilization did not change (3.30 ± 0.70 vs. 3.25 ± 0.35 µmol · kg
1 · min
1,
P = NS), and renal glucose production
decreased from 1.88 ± 0.63 to 0.56 ± 0.42 µmol · kg
1 · min
1
(P < 0.05 vs. baseline and
hypoglycemia without propranolol). During hypoglycemia without
-blockade, splanchnic fractional extraction of glucose increased
from 0.4 ± 0.2 to 1.5 ± 0.4%
(P < 0.05), splanchnic glucose
utilization did not change (0.52 ± 0.30 vs. 1.42 ± 0.57 µmol · kg
1 · min
1,
P = NS), and hepatic glucose
production increased from 13.49 ± 1.09 to 19.34 ± 1.30 µmol · kg
1 · min
1
(P < 0.05). When propranolol was
infused during hypoglycemia, splanchnic fractional extraction of
glucose increased from 2.4 ± 0.4 to 4.1 ± 0.7%
(P < 0.05), splanchnic glucose
utilization did not change (2.96 ± 0.60 vs. 2.55 ± 0.56 µmol · kg
1 · min
1,
P = NS), and hepatic glucose
production decreased from 14.42 ± 0.72 to 10.36 ± 0.63 µmol · kg
1 · min
1
(P < 0.05 vs. baseline and
hypoglycemia without propranolol).
Figure 2 depicts the contribution of the
liver and kidney to glucose production in the baseline and during the
last 30 min of the hypoglycemic study period with or without
-adrenergic blockade. The sum of hepatic (14.05 ± 0.87) and
renal (3.22 ± 1.16) glucose production (17.27 ± 1.86 µmol · kg
1 · min
1)
is equivalent to endogenous glucose production (glucose
Ra = 16.90 ± 1.70 µmol · kg
1 · min
1)
in postabsorptive dogs (n = 10). In
contrast, during hypoglycemia the sum of hepatic (19.34 ± 1.30) and
renal (8.62 ± 0.86) glucose production (27.96 ± 2.16 µmol · kg
1 · min
1)
exceeds endogenous glucose production (22.23 ± 0.48 µmol · kg
1 · min
1), as calculated by
the difference between systemic glucose
Ra (30.48 ± 1.52 µmol · kg
1 · min
1)
and mean exogenous infusion rates (8.25 ± 0.48 µmol · kg
1 · min
1). Similarly, but to
a lesser degree, when propranolol is infused, the sum of hepatic (10.36 ± 0.63) and renal (1.12 ± 0.84) glucose production (11.48 ± 1.47 µmol · kg
1 · min
1)
is slightly higher than endogenous glucose production (9.92 ± 0.48 µmol · kg
1 · min
1),
as calculated by the difference between systemic glucose
Ra (25.12 ± 1.62 µmol · kg
1 · min
1)
and mean exogenous infusion rates (15.20 ± 0.40 µmol · kg
1 · min
1).
In response to hypoglycemia, arterial plasma glucagon and epinephrine levels increased comparably in both groups by 3- and 12-fold, respectively. Arterial plasma norepinephrine levels, however, were
higher (P < 0.05) in the presence
than in the absence of
-blockade during hypoglycemia (Table
2).

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Fig. 2.
Hepatic and total renal glucose production in
µmol · kg 1 · min 1
in postabsorptive conscious dogs in the baseline and during the last 30 min of a 120-min hypoglycemic hyperinsulinemic clamp with and without
-adrenergic blockade. Total renal glucose production was estimated
by multiplying unilateral renal glucose production by a factor of 2, assuming each kidney contributes equally to glucose production during
the baseline and in the hypoglycemic periods in both groups.
* P < 0.05 vs. baseline and
between groups.
|
|
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Table 2.
Arterial plasma glucagon and catecholamine concentrations in
postabsorptive conscious dogs during the baseline period and in the
last 30 min of a 120-min hypoglycemic hyperinsulinemic clamp with and
without -adrenergic blockade
|
|
 |
DISCUSSION |
The present studies confirm previous findings in dogs (3,
4) indicating that renal glucose production, which represents ~15-25% in the postabsorptive state, makes a substantial
contribution (up to ~40%) to tracer-determined glucose production
during hypoglycemia and further demonstrate that the compensatory
elevation in glucose production by the liver and kidney, which occurs
in these hypoglycemic conditions, is prevented by
-adrenergic
blockade. Sustained insulin-induced hypoglycemia is associated with a
reversal in renal glucose balance to net output, a threefold increase
in renal glucose production, and a simultaneous 40% increase in
hepatic glucose production. The infusion of propranolol, a nonspecific
-adrenergic blockade, during a comparable degree of hypoglycemia
decreases renal glucose production by ~70% and hepatic glucose
production by ~30% to values below postabsorptive rates.
As a result, as shown in Fig. 1,
-adrenergic blockade reduces net
splanchnic glucose output from 17.91 to 7.81 µmol · kg
1 · min
1
and induces a switch from net renal glucose output of 3.44 to net
uptake of 5.38 µmol · kg
1 · min
1
during hypoglycemia. These observations complement earlier data (4, 9,
13) in support of the view that stimulation of gluconeogenesis, in both
the liver and kidney, is critical in sustaining glucose production
during hypoglycemia caused by continuous insulin infusion.
Moreover, our findings are consistent with recent reports indicating
that hepatic and renal glucose production are enhanced by epinephrine
infusion in animals (6, 26) and in humans (27). Although the mechanisms
for this increase in gluconeogenesis during insulin-induced
hypoglycemia are not entirely clear, in accordance with data published
by Frizzell et al. (13) and by Davis et al. (9), our studies provide
evidence that the increase in hepatic glucose production during
hypoglycemia is largely dependent on an elevation in hepatic plasma
flow (from ~28 to ~38
ml · kg
1 · min
1
in our series). The fact that this elevation in hepatic plasma flow is
entirely avoided by the concomitant infusion of propranolol suggests
that
-adrenergic blockade prevents the increment in hepatic glucose
production associated with hypoglycemia, in part, by altering blood
flow to the liver. The additional possibility that
-adrenergic
blockade may reduce hepatic gluconeogenesis during sustained
hypoglycemia by decreasing peripheral release and hepatic utilization
of gluconeogenic precursors is suggested by the observation that,
although hepatic blood flow is maintained, propranolol reduces hepatic
glucose production below postabsorptive rates. The latter is further
supported by a previous report indicating that peripheral lactate
release and hepatic glucose production increase simultaneously during
epinephrine infusion (26).
Considering that renal plasma flow is unaffected by hypoglycemia in
either the presence or absence of
-adrenergic blockade, our findings
imply that adrenergic stimulation of renal glucose production in
hypoglycemia must involve changes in peripheral release and renal
utilization of gluconeogenic precursors. Although these were not
evaluated in the current studies, recent data obtained in our
laboratory demonstrating that increased renal glucose production in
hypoglycemic dogs is accompanied by enhanced peripheral release and
renal utilization of lactate and glycerol (5) and the fact that
propranolol is capable of blocking epinephrine's inhibition of
peripheral glucose utilization and stimulation of adipose tissue lipolysis after insulin-induced hypoglycemia in humans (16) are
entirely consistent with the notion that
-adrenergic mechanisms mediate renal gluconeogenesis primarily by an indirect effect on
peripheral tissues. Whether
-adrenergic mechanisms alter
gluconeogenic efficiency directly in the kidney, as it has been shown
in the liver (26), is not known.
The combination of arteriovenous balance and isotope dilution can
effectively partition glucose utilization and production in a tissue
bed and has been previously applied to investigate splanchnic (12) and
renal (3) glucose metabolism. Unlike previous experiments, however, in
the present studies glucose production and utilization by the
splanchnic tissues and kidney were determined simultaneously. Although
estimated rates of glucose Ra and
the individual rates of hepatic and renal glucose production in our
studies are in close agreement with previously published data in
conscious dogs by other investigators (13, 14, 28), the fact that
simultaneous measurements across the liver and kidney yield values for
endogenous glucose production rates in hypoglycemia that are higher
than those determined by conventional steady-state isotope dilution
raises interest and concern.
The use of monocompartmental equations can be associated with as much
as 20% underestimation of the Ra
of glucose under conditions in which there are large and rapid changes
in plasma SA, such as during hyperinsulinemia (7,10). Thus, even though
isotopic steady state was approximated during the last 30 min of the
hypoglycemic periods when statistical comparisons were made in our
studies, underestimation of overall glucose
Ra may have been partly
responsible for these discrepancies. Nonetheless, the possibility that
both hepatic and renal glucose production may have been overestimated in these conditions cannot be discarded. The use of arteriovenous difference combined with tracer dilution across a tissue or organ overestimates the rate of release of a tracee into the venous efflux to
the extent that the bidirectional movement of a tracer between the two
compartments reflects the relative intracellular abundance of a tracee,
particularly if isotope equilibrium has not been reached. In addition,
it does not take into account possible tracer dilution that might occur
in an intermediary compartment, i.e., "ideal precursor pool"
(29). These discrepancies underscore the need to interpret data
obtained with arteriovenous difference and isotope dilution techniques
with caution and suggest that our calculated rates of hepatic and renal
glucose production might represent near-quantitative assessment of true
rates. On the other hand, analyzing each individual rate separately,
our results demonstrate that, while the contribution of the liver to
endogenous glucose production in hypoglycemia increases by ~40%,
that of the kidney increases by approximately threefold. Propranolol
infusion induces an ~30% reduction in hepatic glucose production and
almost completely suppresses renal glucose production, despite
sustained hypoglycemia.
The observation that the
-adrenergic blocking agent propranolol
impairs the recovery of plasma glucose after insulin-induced hypoglycemia by reducing hepatic and renal glucose production is of
potential clinical significance. Varying degrees of blunted epinephrine
response and inappropriate rebound in endogenous glucose production
have been documented in hypoglycemic healthy subjects (16) and in
patients with diabetes (20, 21, 24). Our animal data provide evidence
that glucose production by the kidney, in addition to the liver, is
blocked by propranolol and could be partly responsible for the delay in
glucose recovery during insulin-induced hypoglycemia. This is
particularly important, especially in view of the fact that epinephrine
appears to play a greater role in glucose counterregulation during
prolonged, as opposed to brief, hypoglycemia (11), a condition more
likely to occur in insulin-treated diabetes patients. Therefore, it is
conceivable that patients using
-blocking agents are prone to
hypoglycemia because of defective counterregulation attributed to
simultaneous inhibition of hepatic and renal glucose production.
Further studies are required to determine whether propranolol is
capable of reducing glucose production by the human kidney and whether
renal glucose production plays any role in plasma glucose recovery in
patients with diabetes under comparable hypoglycemic conditions.
In summary, we have confirmed that glucose production by the liver and
kidney increases concomitantly during insulin-induced hypoglycemia in
conscious dogs. Propranolol significantly reduces both hepatic and
renal glucose production, which may impair the glucose
counterregulatory response to prolonged hypoglycemia. Although the
mechanisms are not entirely clear, our data indicate that the
compensatory increase in glucose production by the liver is largely
dependent on a rise in hepatic plasma flow, which is entirely blunted
by
-blockade. In contrast, renal plasma flow is unaffected, thus
suggesting that propranolol may also decrease peripheral release and
renal utilization of gluconeogenic precursors. We conclude that
-adrenergic blockade impairs glucose recovery during sustained
hypoglycemia, in part, by preventing the simultaneous compensatory
increase in hepatic and renal glucose production.
 |
ACKNOWLEDGEMENTS |
We thank Drs. N. N. Abumrad and P. E. Molina for the catecholamine
assay, E. Hayes for excellent technical help, and L. Cersosimo for
editorial assistance.
 |
FOOTNOTES |
This work was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grant DK-49861 and by the American Diabetes Association.
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. §1734 solely to indicate this fact.
Address for reprint requests: E. Cersosimo, Div. of Endocrinology,
Dept. of Medicine, Health Science Center T15-060, SUNY at Stony
Brook, Stony Brook, NY 11794-8154.
Received 29 April 1998; accepted in final form 15 July 1998.
 |
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