630
Abnormalities of Carbohydrate and
Lipid Metabolism in Dahl Rats
Gerald M. Reaven, Jack Twersky, and Helen Chang
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Plasma glucose, insulin, and triglyceride concentration, blood pressure, and insulin action on
isolated adipocytes were determined in weight-matched Sprague-Dawley, Dahl salt-resistant, and
Dahl salt-sensitive rats. Blood pressure and plasma glucose concentrations were not significantly
different in the three groups. However, Dahl salt-sensitive rats had significantly higher plasma
insulin (39±2 microunits/ml) and triglyceride (213±11 mg/dl) concentrations than did SpragueDawley rats (27±2 microunits/ml and 101±6 mg/dl, respectively). Values for insulin (34±4
microunits/ml) and triglyceride (159 ±11 mg/dl) were intermediate in Dahl salt-resistant rats. In
contrast, maximal insulin-stimulated glucose transport was significantly lower in adipocytes
isolated from Dahl salt-sensitive as compared with Sprague-Dawley rats (400 ±16 versus 523 ±14
ft/cell/sec), with Dahl salt-resistant rats again having intermediate values. However, the ability of
insulin to maximally inhibit catecholamine-stimulated lipolysis was similar in all three groups,
averaging —20% of the activity present in the absence of insulin. All of these differences were seen
when the rats were eating conventional chow and did not change in Dahl rats after 2 weeks of an
8% NaCl diet On the other hand, the predicted rise in blood pressure took place in Dahl
salt-sensitive rats, increasing from 147±4 to 181 ±6 mm Hg. These data indicate that Dahl rats
have higher values for plasma triglyceride and insulin concentration than control Sprague-Dawley
rats, associated with a defect in insulin-stimulated glucose uptake by isolated adipocytes. These
metabolic changes are not dependent on Dahl rats eating a high salt diet and do not vary as a
function of salt intake. (Hypertension 1991;18:630-635)
I
t has recently become apparent that patients with
high blood pressure tend to be hyperinsulinemic,
hypertriglyceridemic, and resistant to insulinstimulated glucose uptake.1-5 Similar changes have also
been demonstrated in rats with spontaneous hypertension (SHR),6-8 as well as in normal Sprague-Dawley
(S-D) rats when the cornstarch in their diet is replaced
with fructose.9-12 Furthermore, it has been possible to
show that adipocytes isolated from SHR are resistant to
insulin-stimulated glucose uptake,7 and the magnitude
of this cellular defect is significantly related to the
associated increases in blood pressure and plasma
insulin and triglyceride concentrations.8 Because
plasma triglyceride concentrations also seem to be
increased in Dahl salt-sensitive (S) rats,13 the current
study was initiated to see if changes in insulin action
and concentration accompany the previously noted
From the Department of Medicine, Stanford University School
of Medicine and Geriatric Research, Education and Clinical
Center, Department of Veterans Affairs Medical Center, Palo
Alto, Calif.
Supported by Research Grants from the Department of Veterans Affairs and the Sandoz Research Institute.
Address for correspondence: G.M. Reaven, MD, GRECC (182B), VA Medical Center, 3801 Miranda Ave., Palo Alto, CA 94304.
Received July 23, 1990; accepted in revised form January 16,
1991.
abnormality in lipid metabolism in this genetic form of
rodent hypertension.
Methods
Male Dahl S and salt-resistant (R) Brookhavenderived rats were obtained from Harlan Sprague
Dawley, Inc., Indianapolis, Ind., as were male control
S-D rats. They were fed ad libitum with conventional
rat chow (Ralston Purina Co., St. Louis, Mo.) containing 0.6% NaCl, which in some experiments was
replaced with the same basic diet containing 8%
NaCl. Water was given ad libitum, and rats were
maintained on a 12-hr light/dark cycle (from 6:00 AM
to 6:00 PM). Plasma insulin14 and triglyceride15 concentration was measured on blood drawn from the
tail vein of unanesthetized rats at 2:00 PM, 6 hours
after removal of all food. Awake systolic blood pressure (IITC Co., Woodland Hills, Calif.) was measured at the same time in quietly restrained rats as
described previously.7-'1 In one series of experiments
all measurements were made before and at weekly
intervals for 2 weeks after increasing the dietary
content of the chow from 0.6% to 8% NaCl.
Isolated adipocytes were prepared from epididymal fat pads according to the method of Rodbell16
with minor modifications. The fat pads were minced
Reaven et al
Adipocyte Metabolism in Dahl Rats
631
TABLE 1. Weight, Blood Pressure, and Plasma Glucose, Insulin, and Triglyceride Concentrations in Dahl SaltSensitive, Dahl Salt-Resistant, and Sprague-Dawley Rats
Group
DahlS(n=20)
Dahl R (TI = 10)
S-D (TI=20)
Wt
(g)
258±6
253±4
252±7
Blood pressure
(mmHg)
Glucose
(mg/dl)
142±3
135±5
125±7
135 ±3
138±3
133±4
Insulin
(microunits/ml)
39+2
34±4
27±2
TG
(mg/dl)
213+10
158+11
102±6
Values are mean±SEM. Wt, weight; TG, triglyceride; Dahl S and Dahl R, Dahl salt-sensitive and salt-resistant rats;
S-D, Sprague-Dawley rats.
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with scissors and placed in plastic flasks in Krebs
bicarbonate buffer with 4% bovine serum albumin
(BSA), 3 mM glucose, and 1 mg/ml collagenase.
Collagenase digestion was carried out at 37°C in a
gyratory water bath shaker for 75 minutes. Cells were
washed three times in fresh Krebs buffer with 4%
albumin and 2.5 mM glucose and were allowed to
separate from the infranatant by flotation. A 100 jtl
aliquot of diluted cells was fixed in a solution of 2%
osmium tetraoxide in collidine buffer and counted in
a Coulter counter (Hialeah, Fla.) to determine cell
number. Lipocrit was also determined, and cell size
(/ng lipid/cell) was calculated from lipocrit and cell
number. Aliquots of cells were taken for measurement of glucose transport and catecholaminestimulated lipolysis.
Glucose transport by isolated adipocytes was determined by a recently validated method based on
the observation that glucose uptake is a measurement of glucose transport when studies are carried
out at trace glucose concentration.17-18 Briefly, isolated adipocytes (2% lipocrit) were incubated in 500
/il 3.5% albumin buffer in the absence and presence
of different concentrations of insulin (50-8,000 pM)
and tracer (300 nM) amounts of D-[U-14C]-glucose.
Cell suspension was incubated at 37°C for 1 hour with
continuous shaking at 40 rpm. The incubation was
terminated by centrifuging a 400 fil aliquot in a 500
fi\ microfuge tube, and the amount of activity associated with the adipocytes (and the total radioactivity
in the incubation medium) was determined by liquid
scintillation counting. Values for EQo (concentration
of insulin required for half-maximal effect) were
calculated from an insulin dose-response curve as
described previously.17-18 Earlier studies have demonstrated that values for glucose transport are similar
when either the conventional 3-O-methylglucose
method or the one in this study was used.17-18
The ability of insulin to inhibit catecholamineinduced lipolysis was estimated as follows. Adipocytes were diluted in Krebs buffer with 4% albumin
and 2.5 mM glucose buffer, pH 7.4; aliquots of
diluted cells placed in plastic vials (lxlO 5 cells/ml)
and incubated for 1 hour at 37°C in the presence of
adenosine deaminase (1 unit/ml) and isoproterenol
(10~7 M) in a 95% ( V 5 % CO2 atmosphere. At the
end of incubation, an aliquot (0.2 ml) of infranatant
was removed from each incubation mixture for measurement of grycerol concentration by an enzymatic
method.19 Measurements were made in the absence
and presence of increasing concentrations of insulin
in the incubation medium.
Results are expressed as mean±SEM. When
single measurements were made, statistical differences were assessed by one-way analysis of variance
(ANOVA), with the difference between any two
groups estimated by Bonferroni's multiple comparison test. When dose-response studies were performed, statistical comparisons were made by
three-way ANOVA, and the three factors were the
rat groups (S-D, Dahl S, or Dahl R), the dose of
insulin (basal and maximal), and each individual
rat. Each rat must be entered as an additional
factor because measurement of basal and maximal
responses to insulin were performed in preparations of adipocytes from individual rats, not from
two separate rats. The factor "rat" is then "nested"
under the factor "group," since there was no crossover of these two factors. The three-way ANOVA
was then followed by a post hoc Bonferroni multiple
comparison test to assess the pairwise differences
between any two variables.20
Results
Table 1 lists the weight, blood pressure, and
plasma glucose, insulin, and triglyceride concentrations of Dahl S, Dahl R, and S-D rats when they were
given conventional rat chow to eat. The weight of the
three groups was similar. Although mean blood pressure varied somewhat in the three groups, the differences were not statistically significant. Plasma glucose concentrations were also the same in all three
groups. However, the insulin (F=6.3, p<0.004) and
the triglyceride (F=40.0,/><0.001) concentrations of
the three groups were significantly different (one-way
ANOVA). Specifically, Dahl S rats had significantly
higher plasma insulin (p<0.01) and triglyceride
(p< 0.001) concentrations than did S-D rats. Plasma
insulin and triglyceride concentrations were also
higher, on average, in Dahl S as compared with Dahl
R rats, but only the difference in triglyceride level
was statistically significant (p<0.002). Dahl R rats
had higher average plasma insulin and triglyceride
concentration than did S-D rats, and the difference in
plasma triglyceride level was statistically significant
(/xO.OOl).
Glucose uptake by isolated adipocytes in the absence
of insulin (basal), in response to an insulin concentration of 8,000 pM (maximal), and the incremental increase in glucose uptake to insulin (maximal-basal) is
illustrated in Figure 1. When analyzed by three-way
632
600
Hypertension
r
Vol 18, No 5 November 1991
Dahl S
Dahl R
S-D
S 500 =
FIGURE 1. Bar graph shows glucose transport by adipocytes isolated from Sprague-Dawley (S-D, n=10), Dahl
salt-resistant (Dahl R, n~10), and Dahl salt-sensitive
(Dahl S, n=10) rats. Measurements were made in the
absence of insulin (Basal) and at a maximal insulin
concentration of 8,000 pM (Max). The incremental response in glucose uptake (k) due to insulin was calculated
by subtracting the basal from the maximal value.
400 -
o. 300 200
2
C3
100
Basal
Max
A
Basal
Max
Basal
A
Max
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ANOVA, it was clear that glucose transport was different among the three groups (F=5.0, /?<0.05). Since
there was statistically significant interaction between
"rat group" and "insulin dose" (F=16.1,p<0.001), the
differences among the three groups in terms of basal
glucose uptake were not the same as the differences in
maximal glucose uptake. Using Bonferroni's multiple
comparison approach, no differences were found in the
basal uptake of all three groups. However, using the
same approach, maximal insulin-stimulated glucose uptake was greatest in adipocytes from S-D rats, lowest in
adipocytes from Dahl S rats, and intermediate in adipocytes from DahJ R rats. All of these differences were
significant at thep<0.001 level. The incremental effect
of insulin on glucose transport in the three groups was
similar to the results of maximal transport.
The results shown in Figure 1 demonstrated that
maximal insulin-stimulated glucose transport by adipocytes isolated from Dahl S rats was lower than that
of S-D rats. To compare insulin sensitivity, complete
insulin dose-response curves were denned in Dahl S
and S-D rats. The results of these studies appear in
Figure 2 and indicate that insulin-stimulated glucose
transport by adipocytes isolated from Dahl S rats was
higher than that of S-D rats (F=10.1, p<0.005).
500
J
400
1
However, neither the EQo of adipocytes from Dahl S
and S-D rats (108+12 versus 110±10 pM) nor adipocyte cell size (0.232+0.004 versus 0.238+0.006 /xg
lipid/cell) were different in the two groups.
The effect of 2 weeks of a high salt diet on weight,
blood pressure, and plasma glucose, insulin, and
triglyceride concentrations of DahJ S and Dahl R rats
is shown in Table 2. It can be seen that the weight of
the two groups was the same at baseline and increased to a similar degree in response to 2 weeks of
a 8% NaCl diet. However, the blood pressure response of the two groups was significantly different
(F=23.7, p<0.001). In Dahl S rats, the blood pressure rose from 147±4 to 181±6 mm Hg (p<0.002),
whereas it did not change in Dahl R rats (133+5
versus 141+4 mmHg). There was no significant
change in plasma glucose, insulin, or triglyceride
TABLE 2. Weight, Blood Pressure, and Plasma Glucose, Insulin, and
Triglyceride Concentrations Before and 1 and 2 Weeks After an 8%
N a d Diet in Dahl Salt-Sensitive and Dahl Salt-Resistant Rats
DahlS(n = 10)
Dahl R (n = 10)
Before
260±15
One week
311±11
Two weeks
333±12
261±11
305 ±14
319±14
Variable
Weight (g)
Blood pressure (mm Hg)
Before
147±4
One week
170±2
Two weeks
181±6
133±5
137±3
141±4
Glucose (mg/dl)
Before
130±5
One week
132±3
Two weeks
129±2
140±4
136±3
132±9
Insulin (microunits/ml)
II
50
100
200
800
Insulin (pM)
II
8000
FIGURE 2. Line graph shows glucose transport by adipocytes
isolated from Sprague-Dawley (S-D, n=10) and Dahl saltsensitive (Dahl S, n=10) rats. Values depict glucose uptake in
the absence of insulin and in response to increasing doses of
insulin.
Before
40±4
One week
29±3
Two weeks
43±4
33±4
28±3
42±3
TG (mg/dl)
Before
191±34
One week
205±23
Two weeks
199 + 18
165+29
169+21
153±21
Values are rnean±SEM. DahJ S and Dahl R, Dahl salt-sensitive
and salt-resistant rats; TG, triglyceride.
Reaven et al
633
all three groups in the absence of insulin. In addition,
the response to the maximal inhibitory dose of insulin
was not different. The ability of insulin to inhibit
catecholamine-induced lipolysis was also evaluated
in adipocytes obtained from Dahl S and Dahl R rats
after 2 weeks of eating an 8% NaCl diet and indicated that lipolytic activity of isolated adipocytes was
also similar in the two groups of Dahl rats after the
high salt diet (data not shown).
500
400
§• 300
E 200
Discussion
The results of the current study have shown that
Dahl rats have higher plasma insulin and triglyceride
concentration than do S-D rats: the strain from which
Dahl rats were originally derived. Furthermore, although the differences between S-D and Dahl rats
were of greater magnitude in Dahl S rats, Dahl R rats
were always intermediate between S-D and Dahl R
rats. In addition to showing that Dahl rats had higher
plasma insulin and triglyceride concentrations than
S-D rats, a defect in the ability of insulin to stimulate
glucose uptake could also be demonstrated in adipocytes isolated from Dahl rats. As with the other
variables measured, glucose uptake by adipocytes
from Dahl R rats was intermediate between that of
S-D and Dahl S rats. It should be emphasized that
these changes were seen in both Dahl S and R rats
when they were eating a normal sodium intake. Thus,
the insulin resistance, hyperinsulinemia, and hypertriglyceridemia are not sodium dependent. Indeed,
very little if any of the measures, with the exception
of blood pressure in the Dahl S rats, changed with
the increase in dietary sodium intake.
The metabolic abnormalities observed in the Dahl
rats in this study resemble those previously described
in patients with high blood pressure,1"5 SHR,7-8 and
fructose-fed rats.9-12 The presence of insulin resistance, hyperinsulinemia, and hypertriglyceridemia in
multiple models of hypertension obviously focuses
attention on the relation between these metabolic
variables and the change in blood pressure. For
example, it could be speculated from the data in
Table 1 that Dahl S and Dahl R rats have higher
blood pressures than do S-D rats, along with their
somewhat higher values for plasma insulin concentration, implying a relation between these two vari-
= 100
o
100
200
800
Insulin (pM)
8000
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FIGURE 3. Line graph shows glucose transport by adipocytes
isolated from Dahl salt-resistant (Dahl R, n=10) and saltsensitive rats (Dahl S, n=10) 2 weeks after consuming an 8%
NaCl diet. Values depict glucose uptake in the absence of
insulin and in response to increasing doses of insulin.
concentrations in response to the high salt diet in
either Dahl S or DahJ R rats.
Figure 3 shows glucose uptake by isolated fat cells
from Dahl S and DahJ R rats after 2 weeks of an 8%
NaG diet. It is apparent that the values in the two
groups were quite similar. In addition, by comparing
Figures 2 and 3 it can be seen that glucose uptake by
adipocytes isolated from Dahl S rats was similar
when the rats were eating conventional rat chow or
an 8% NaCl diet.
The results in Figure 1 show that maximal insulinstimulated glucose uptake by adipocytes isolated
from Dahl S rats was lower than that of fat cells from
S-D rats. Insulin also acts on the fat cell to inhibit
lipolysis, and experiments were performed to evaluate this aspect of insulin action on adipocytes isolated
from Dahl S, Dahl R, and S-D rats. The data in
Figure 4 illustrate the ability of 10~7 isoproterenol to
stimulate lipolysis in adipocytes isolated from the
three groups of rats in the absence of insulin (basal)
and in response to a maximal dose of insulin (4,000
pM). These studies were performed while the rats
were eating conventional chow, and it can be seen
that catecholamine-induced lipolysis was the same in
400
Adipocyte Metabolism in Dahl Rats
r
Dahl S
FIGURE 4. Bar graph shows lipolytic activity (gfycerol
release) by adipocytes isolated from Sprague-Dawley
(S-D, n=10), Dahl salt-resistant (Dahl R, n=10), and
Dahl salt-sensitive (Dahl S, n=10) rats. Values depict
the lipolytic response to 10~7 isoproterenol in the absence of insulin (Basal) and at a maximal insulin dose
of 4,000pM (Max).
Basal
Max
Basal
Max
Basal
Max
634
Hypertension
Vol 18, No 5 November 1991
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ables. On the other hand, the obvious increase in
blood pressure after consumption of an 8% NaCl diet
in Dahl S rats was not associated with any change in
plasma insulin concentration (Table 2). Thus, at the
most, one might argue that insulin resistance and
hyperinsulinemia predispose an organism to develop
high blood pressure. There is evidence that acute
hyperinsulinemia21 can increase sodium and water
reabsorption. Perhaps Dahl R rats are less sensitive
to the anti-naturetic effects of hyperinsulinemia, and
they are, therefore, more resistant to salt-induced
hypertension. Thus, insulin resistance and hyperinsulinemia could be viewed as permissive, representing
changes that predispose an individual to high blood
pressure, but do not necessarily cause hypertension
by themselves. Such a view might also apply to
humans and help explain why the relation between
insulin levels and hypertension seems to vary as a
function of ethnic groups.22
Attention to this point has focused on the relation between insulin resistance, hyperinsulinemia,
and high blood pressure. It is apparent that Dahl
rats are also hypertriglyceridemic, as are rats with
fructose-induced hypertension,9"11 SHR,8 and patients with high blood pressure.3-4 Although the
relation between insulin resistance, hyperinsulinemia, and hypertension is obviously complex and
not well understood, that between insulin resistance, hyperinsulinemia, and hypertriglyceridemia
is more straightforward. Indeed, there is substantial
evidence in both humans23"25 and animals26"28 that
an increase in plasma triglyceride concentration is
the expected consequence of insulin resistance and
hyperinsulinemia. It is unlikely that the increase in
plasma triglyceride concentration associated with
insulin resistance and hyperinsulinemia in individuals with high blood pressure plays a role in the
regulation of blood pressure. On the other hand,
hypertriglyceridemia does increase risk of coronary
heart disease,29-31 and its presence in patients with
hypertension may contribute to morbidity and mortality from coronary heart disease in this clinical
syndrome.
In summary, Dahl S rats have higher plasma insulin
and triglyceride concentration than do control S-D rats.
In addition, isolated adipocytes from Dahl S rats are
insulin resistant as compared with those from S-D rats.
These changes are seen when Dahl S rats are given
conventional chow to eat, and only the blood pressure
goes up when they consume an 8% NaCl diet. Changes
similar to those described for the Dahl S rats are seen
in the Dahl R rat when eating chow but are intermediate in magnitude between the S-D and the Dahl S rat.
Although plasma insulin and triglyceride concentrations are similar in Dahl S and Dahl R rats when they
are given a high salt diet to eat, Dahl R rats do not have
an increase in blood pressure. These data show that
Dahl rats share the defect in insulin and triglyceride
metabolism previously noted in patients with high
blood pressure, in SHR, and in rats with fructoseinduced hypertension.148
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KEY WORDS
metabolism
carbohydrate metabolism
insulin • Dahl rats
lipid metabolism
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Abnormalities of carbohydrate and lipid metabolism in Dahl rats.
G M Reaven, J Twersky and H Chang
Hypertension. 1991;18:630-635
doi: 10.1161/01.HYP.18.5.630
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