Insulin Resistance in the Conscious Spontaneously Hypertensive Rat:

Euglycemic Hyperinsulinemic Clamp Study

Sonia Hulman, Bonita Falkner, and Nancy Freyvogel
To determine whether spontaneously hypertensive rats (SHR) are insulin resistant when compared with their genetic control,
Wistar-Kyoto rats (WKY), insulin-stimulated glucose utilization was studied in both strains with the euglycemic hyperinsuline-
mic clamp technique. This methodology can determine if insulin resistance is present and whether it is due to ineffective
stimulation of peripheral glucose utilization, or to incomplete suppression of (hepatic) endogenous glucose production (EGP)
by insulin, or both. Twelve WKY and 15 SHR (all male) had long-term catheters surgically placed. After surgical recovery, fasting
metabolic parameters were measured in the conscious, unstressed state. Clamp studies were then performed on nine WKY and
eight SHR. EGP was measured before and during euglycemic hyperinsulinemia with the tracer-dilution technique (6-3H-
glucose). Indices of fasting metabolism (plasma glucose, insulin, and hepatic EGP) were not different between WKY and SHR.
During the clamp studies, the glucose infusion rate (GIR) required to maintain euglycemia was significantly lower in SHR (SHR,
0.055 2 0.003 Y WKY, 0.106 + 0.001 mmol/kg . min-l; P c .OOl). EGP was completely suppressed during euglycemic hyperinsu-
linemia in all WKY and in six of eight SHR. We conclude that conscious, nonstressed SHR are insulin resistant when compared
with WKY. Attenuated insulin-stimulated peripheral glucose utilization implicates skeletal muscle, and not liver, as the primary
site of insulin resistance in SHR.
Copyright 0 1993 by W.B. Saunders Company
I
NSULIN RESISTANCE, or suboptimal biological re-
sponse to insulin, is associated with human essential
hypertension, even in the absence of obesity.1,2 Preliminary
experimental studies in spontaneously hypertensive rats
(SHR), a non-obese genetic animal model for hyperten-
sion, have provided some evidence of insulin resistance.
Comparison of insulin-stimulated glucose metabolism be-
tween the two strains in the conscious, unrestrained state
will determine whether SHR represents an animal model of
insulin-resistant hypertension. This study was undertaken
to compare insulin-stimulated glucose metabolism in Wistar-
Kyoto rats (WKY) and SHR in vivo, and to provide an
answer to the question: Is the SHR a non-obese, nondia-
betic animal model of hypertension and insulin resistance?
MATERIALS AND METHODS
Animals and Surgery
Animals were purchased from Taconic Farms in Germantown,
NY, at age 8 weeks. Data on male WKY and SHR from four
different litters of each strain are reported. The protocol was
approved by the Animal Welfare Committee of Hahnemann
University, Philadelphia, PA. The animals were maintained on
standard laboratory rat chow (Rodent Laboratory Chow 5001,
Purina, Richmond, VA). They were housed in a room with 12-hour
light-dark cycling. After a l-week acclimation period, both strains
began training for indirect tail-cuff blood pressure measurement
(IITC, Life Sciences Institute, Woodland Hills, CA). Blood pres-
sure measurements with this instrument were validated by direct
intraarterial measurements. A 2-week training period resulted in
stable blood pressure measurements. Thereafter, weight and blood
pressure were measured biweekly on the same day; the final weight
obtained (less than 72 hours before study) is reported here.
From the Department of Pediatrics, Medical College of Pennsylva-
nia, Philadelphia, PA.
Submitted April 20, 1991; accepted April 30, 1992.
Address reprint requests to Sonia Hulman, MD, Department of
Pediatrics, Medical College of Pennsylvania, 3300 Henry Ave, Philadel-
phia, PA 19129.
Copyright 0 1993 by W.B. Saunders Company
00260495/93/4201-0003$03.0010
14
When the animals were approximately 12 to 13 weeks old, they
underwent surgery for implantation of long-term catheters. After
intraperitoneal anesthesia with acepromazine, ketamine, and xyla-
zine, one small (0.5-cm) midline incision was made, which permit-
ted catheterization of the internal jugular vein (Silastic medical
grade, Becton Dickinson, Parsippany, NJ) and the contralateral
carotid artery (PE 10, Becton Dickinson). The catheters were
exteriorized to the ventral surface of the neck and sealed with a
viscous solution of polyvinylpyrrolidone (PVP-10, Sigma. St Louis,
MO), which was later (at the time of the clamp study) slowly
flushed through the catheters to establish patent access to the
vessels; the catheters required no further care before surgery. The
animals recovered from surgery in a neonatal incubator. which
prevented postoperative hypothermia.
During the clamp study in both WKY and SHR, infusion was
performed through the artery and sample withdrawal was obtained
through the vein because of difficulty withdrawing blood through
the arterial catheter. Smith et al3 have shown that the possible mass
effect of arterial hyperglycemia on peripheral insulin-stimulated
glucose utilization is 10%. The use of arterial infusion in the clamp
study could result in a glucose infusion rate (GIR) that is 10%
greater than if venous infusion were used.
Measurement of Hepatic Endogenous Glucose Production
and I nsulin-Stimulated Glucose Metabolism
Each animal was studied after it had regained preoperative
weight, which was usually after 72 hours. Animals were fasted for at
least 12 hours before study and were fully conscious, unrestrained,
and quiet for the duration of the study. Measurement of fasting
(hepatic) endogenous glucose production (EGP) was made with
the tracer-dilution method before initiation of euglycemic hyperin-
sulinemia. A primed constant infusion of tritiated glucose (prime, 1
&i; infusion, 0.1 @?i/min D-6-3H-glucose; NEN, Boston, MA)
was delivered through the arterial catheter and continued for 60
minutes. Both Smith et al3 and Clark et al4 have shown that a steady
state of tritium-labeled glucose is reached in the rat after 60
minutes of infusion. During the final 10 minutes, three samples
were withdrawn and plasma was isolated by centrifugation. Por-
tions of the three plasma samples were analyzed immediately with
the glucose oxidase method for glucose concentration (Glucostat,
Model 27, YSI. Yellow Springs, OH). Glucose concentration of
each plasma sample was determined three times. Another portion
of the plasma sample was used for the measurement of glucose
Metabolism, Vol42, No 1 (January), 1993: pp 14-18
INSULIN RESISTANCE IN CONSCIOUS SHR 15
specific activity (GSA), and the remainder was immediately frozen
at -80C for subsequent radioimmunoassay of plasma insulin
concentration (see below). Euglycemic hyperinsulinemia was then
instituted with a simultaneous infusion of insulin (regular human
insulin, Eli Lilly, Indianapolis, IN) at 4.0 mu/kg min- and
glucose (20% dextrose). Infusion of tritiated glucose was continued
during euglycemic hyperinsulinemia to determine the effect of
hyperinsulinemia on EGP. During the insulin infusion (clamp
period). a small (0.050-mL) blood sample was withdrawn every 10
minutes for immediate measurement of plasma glucose concentra-
tion. GIR was adjusted up or down to maintain (or clamp) plasma
glucose level at fasting concentration. All infusions were delivered
by a Harvard syringe pump (Model 22, Harvard Apparatus, South
Natick. MA), which can be calibrated to deliver infusions in
microliters per minute. Euglycemic hyperinsulinemia was main-
tained for 90 minutes; during the final 10 minutes, three samples
were withdrawn for measurement of plasma GSA, insulin concen-
tration, and plasma glucose concentration.
Assays
Glucose. Plasma glucose concentration was measured with the
glucose oxidase method, as noted above. Glucose concentration in
diluted infusate was measured, and this concentration was used to
calculate GIR in millimoles per kilogram per minute.
Insulin. Plasma insulin was measured by radioimmunoassay
(DPC Coat-A-Count, Los Angeles, CA) using a human standard.
Rat insulin and human insulin differ by only three amino acid
residues. so cross-reactivity of the human antibody and rat antigen
should be present. To ensure that cross-reactivity was occurring,
radioimmunoassay of serial dilutions of fasting WKY and SHR
plasma was performed with human antibody and compared with a
human insulin-standard curve. There was parallel displacement of
the rat plasma curve, indicating cross-reactivity of the two species.
Consequently, human standard can be used for both fasting rat
plasma and clamped rat plasma. Plasma insulin concentration is
expressed as picomoles per liter.
GSA. GSA was determined with the Somogyi meth0d.s Briefly,
rat plasma samples (0.05-mL) were deproteinized with 0.100 mL
each of O.lN ZnS04 and O.lN Ba(OH)Z. After a 30-minute
room-temperature incubation. 0.05 mL supernatant was dried
overnight (toevaporate tritiated water). The samples were reconsti-
tuted with 0.05 mL distilled water. After addition of 10 mL
Ecolume (ICN, Irvine. CA), a water-soluble, biodegradable scintil-
lation cocktail, counts were determined in a liquid scintillation
counter (Beckman Instruments, Fullerton, CA). After correction
for quenching, counts per minute per milliliter were determined
for each sample. GSA in the fasting state was calculated by
determining the quotient of corrected counts per milliliter and
glucose concentration from the three samples withdrawn at the end
of the first 90 minutes. Mean coefficient ofvariation of GSA in both
strains was lOS%, which is similar to that reported by Smith et al.J
The calculation of glucose turnover (or rate of appearance [R,]) in
the fasting state was performed with Steeles equation6
(R:, = infusion rate of tracer/specific activity of tracer) and was
based on the assumption of achievement of a steady state. R, is
expressed in millimoles per kilogram per minute. It is recognized
that the Steele equation6 underestimates the rate of glucose
turnover in the fasting state. Because tritiated lactate, which is
produced specifically when 6->H-glucose is used to label the
glucose pool. was not chromatographically removed. the estimation
of GSA may be high, resulting in an underestimation of R,.K
Despite the use of 6-3H-glucose in this study, the results presented
here for glucose turnover in the fasting state (see the Results and
Table 3) are comparable to those obtained by Smith et al, who
used 3-3H-glucose to label the glucose pool (which does not result
in formation of tritiated lactate).
During euglycemic hyperinsulinemia, GSA was determined from
the three samples withdrawn at the end of the clamp using the
methods previously described. Hepatic EGP during euglycemic
hyperinsulinemia was calculated as the difference between the rate
of disappearance of glucose ([Rd] = infusion rate of tracer/specific
activity of tracer) and the GIR required to maintain euglycemia.
However, according to Dunn et a&s 19% of tritium counts can be
lost from glucose to lactate when 6-3H-glucose is used. As discussed
above, GSA may be overestimated due to contamination of the
sample with counts from tritiated lactate, which will lead to a
systematic overestimation of R+9
As in the fasting state, the determination of EGP with the
tracer-dilution method is dependent on the achievement of a
steady state. The mean coefficient of variation of GSA in both
strains during euglycemic hyperinsulinemia was 9.2%. Although
this does not prove that a steady state exists, it indicates that the
labeling of the glucose pool during euglycemic hyperinsulinemia is
relatively stable.
Calculations
Glucose production from nonhepatic sources is negligible in the
fasting state, so the rate of glucose production determined from
this equation is interpreted as hepatic EGP R,,3.4 as follows: R, =
F/GSA. where F is the tracer infusion rate. Fasting glucose
production expressed for each rat is the mean of three samples.
During euglycemic hyperinsulinemia, glucose R, is equal to
glucose Rd. because euglycemia is maintained with the GIR.
Therefore, any remaining EGP is the difference between glucose
Rd and GIR. ie. EGP = Rd - GIR. Total insulin-stimulated
glucose metabolism (RJ is the sum of GIR and any persistent EGP
during clamped hyperinsulinemia. Rd, or total glucose metabolism.
may be underestimated when using the tracer-dilution technique.
Because of the mass effect of arterial infusion of glucose on glucose
metabolism, the GIR component of total glucose metabolism may
be overestimated. These two potential errors in the methodology
oppose each other and are unlikely to confound differences in total
glucose metabolism between the two strains.
Statistical Methods
Blood pressure, weight, and fasting metabolic variables were
compared with Students t test. Metabolic variables during euglyce-
mic hyperinsulinemia were analyzed with two-way ANOVA, fol-
lowed by Scheffes test for pairwise comparisons.
RESULTS
Fasting
Male rats from four different litters of both WKY and
SHR were studied over an 18-month period. Fasting-state
data are presented for 12 WKY and 15 SHR (Table 1).
Because WKY gain weight faster than SHR,tO catheter
surgery and metabolic studies were performed at a slightly
younger age in WKY to control for weight. This resulted in
a cohort of SHR that was slightly older than WKY (mean
a&?eWKY7
92.1 ? 11.7 d; mean agesHn, 110.2 ? 8.7 d;
P < .OOl). Despite attempts to control for weight, weight in
SHR was lower than in WKY and had a narrower range
(weightwKy: 266 to 378 g; mean, 312.0 + 43.9 g; weightsuR:
244 to 310 g; mean, 272.1 k 19.0 g; P < .OOl). Blood
pressure in SHR is higher than in WKY, despite lower body
weight (WKY. 119.5 2 15.5; SHR, 186.1 ? 7.0 mm Hg;
HULMAN, FALKNER, AND FREYVOGEL 16
Table 1. Fasting-State Data in WKY and SHR
Age (d)
Weight (g)*
BP (mm Hg)*
Fasting metabolic parameters
Glucose (mmol/L)
Insulin (pmol/L)
Molar ratio of insulin/glucose
(x106)
R, (mmolikg min-I)
WKY
(n = 12)
92.1 + 11.7
312.0 2 43.9
119.5 * 15.5
6.4 2 1.0
148 t 54
23.3 2 8.7 28.1 + 9.6
0.035 2 0.004 0.036 2 0.014
SHR
(n = 15)
110.2 ? 8.7
272.1 + 19.0
186.1 2 7.0
5.9 + 0.9
170 & 65
NOTE. Results are means + SD. The following equations may be
used to convert from Systeme International to standard units: [glucose]
in mmol/L x 18 = [glucose] in mg/dL; [insulin] in pmol/L x 0.139 =
[insulin] in pU/mL; and R,, Rd, and GIR in mmol/kg min~l x 180 = R,,
R,,, and GIR in mg/kg . min~l
P < ,001.
P < .OOl). Although the differences in age and weight are
statistically significant, they predict opposite effects on
insulin-stimulated glucose metabolism in SHR (greater age
predicts reduced insulin sensitivity, lower weight predicts
greater insulin sensitivity). Fasting plasma glucose concen-
tration is the same in WKY and SHR (WKY, 6.4 ? 1.0;
SHR, 5.9 + 0.9 mmol/L), as is fasting plasma insulin
concentration (WKY, 148 * 54; SHR, 170 ? 65 pmol/L).
The molar ratio (~10~) of insulin to glucose, which is an
index of relative insulin response to fasting glycemia, is the
same in both strains (WKY, 23.3 + 8.7; SHR, 28.1 2 9.6).
The R, of glucose in the fasting state is the same in both
strains (WKY, 0.035 ? 0,004; SHR, 0.036 ? 0.014 mmol/
kg. min-I). The fasting metabolic parameters reported
here are consistent with those reported in conscious,
chronically catheterized Sprague-Dawley rats, and also
indicate that the animals have not experienced a stress
response.
Euglycemic Hyperinsulinemia
Clamp studies were performed on eight WKY and nine
SHR (Table 2). Clamp studies were attempted in all 27
WKY and SHR that were studied in the fasting state, but
there were 10 technical failures due to catheter obstruction.
Weight, blood pressure, age, and fasting metabolic parame-
Table 2. Euglycemic-Clamp Data in WKY and SHR
WKY SHR
(n = 9) (n = 8)
Glucose (mmol/L] 5.7 2 0.6 5.7 + 0.7
Insulin (pmol/L) 504 2 265 743 + 616
GIR (mmol/kg min-I)* 0.106 2 0.001 0.055 + 0.003
EGP (mmol/kg min-) 0 0.0004 2 0.008
Rd (mmol/kg . mini)* 0.106 ? 0.001 0.055 + 0.022
NOTE. Results are means + SD. Mean age, weight, and blood
pressure were the same in these WKY and SHR as those in Table 1. SHR
require significantly less glucose to maintain euglycemia than WKY,
and have significantly lower total glucose metabolism than WKY (P <
,001).
*P < .OOl.
ters were not different in the subset of rats that completed
the clamp compared with the total population, which is
described above (data not shown). Clamped plasma glucose
concentrations were the same in WKY and SHR, and were
the same as fasting plasma glucose concentrations in both
strains. There was a broad range of clamped plasma insulin
concentrations (WKY, 504 ? 265; SHR, 743 2 616 pmol/
L), despite the use of similar insulin infusion rates in all
animals. GIR was greater than Rd in all WKY, which is
typically interpreted to indicate that EGP is completely
suppressed. GIR was equal to Rd in six SHR; however, it
was less than Rd in two SHR. Total insulin-stimulated
glucose utilization is significantly lower in SHR than in
WKY (WKY, 0.106 +- 0.001 v SHR, 0.055 ? 0.003 mmol/
kg. min-I; P < .OOl, Table 2). Despite overestimation of
GSA, these data indicate that insulin resistance in SHR
most likely does not arise from inability of insulin to
suppress hepatic EGP, but from reduced peripheral insulin-
stimulated glucose utilization.
DISCUSSION
The data obtained from the euglycemic hyperinsulinemic
clamp in this study verify the presence of insulin resistance
in conscious, unstressed SHR. To our knowledge, this is the
first report describing reduced insulin-stimulated glucose
metabolism in SHR, without the confounding effect of
anesthesia.
An early histological study found that SHR, compared
with WKY, had reduced numbers of pancreatic islets.
These investigators also found that SHR secreted less
insulin during an oral glucose challenge, resulting in glu-
cose intolerance. Other investigators found greater hyper-
glycemia in SHR than in WKY in response to oral glucose,
although insulin response was not reported.12 These two
early reports suggested that glucose metabolism in SHR
was similar to that of insulinopenic diabetes. The more
recent work of Tsutsu et al found different results; they
studied older (22 weeks), conscious, chronically catheter-
ized WKY and SHR with an intravenous glucose tolerance
test. Their data demonstrated lower plasma glucose and
insulin concentrations in response to an intravenous glu-
cose challenge in SHR than in WKY. Although only the
first 30 minutes after intravenous glucose bolus were
investigated, they concluded that WKY are insulin resis-
tant, but not SHR. Gaboury et alI4 studied anesthetized
17-week-old WKY and SHR with both oral and intravenous
glucose tolerance tests. In their study, measurements of
plasma insulin and glucose concentrations were obtained
for up to 6 hours following a glucose challenge. These
investigators also found that plasma concentrations of
glucose and insulin are higher in WKY than in SHR in
response to either oral or intravenous glucose. This differ-
ence between WKY and SHR persisted for the duration of
each tolerance study, and was reflected in greater inte-
grated areas under the glucose and insulin curves in WKY
compared with SHR for both tests. On the other hand,
results from a study in younger anesthetized rats (8 weeks)
are contrary to the findings of Tsutsu et alI3 and Gaboury et
INSULIN RESISTANCE IN CONSCIOUS SHR 17
a1.14 Using an oral glucose tolerance test, Mondon and
Reaven found greater plasma glucose and insulin concen-
trations in SHR than in WKY. With the data from these
three studies,J~J4 which were conducted in animals of
varying age, weight, and state of consciousness, conclusions
about insulin resistance in WKY and SHR based on data
from the insulin secretory response to an oral or intrave-
nous glucose challenge cannot be drawn.
Two in vitro studies have resulted in a more consistent
picture of glucose metabolism in WKY and SHR. Reaven et
alIs found that adipocytes isolated from SHR had impaired
insulin-stimulated glucose utilization compared with adipo-
cytes from WKY. In their perfusion study, they also
reported that the degradation of insulin was less efficient in
skeletal muscle and kidneys from SHR, as compared with
WKY. These differences were not present in liver.lh These
in vitro studies suggest that in SHR there is insulin
resistance in peripheral tissue.
of fasting glucose metabolism. However, fasting glucose R,
showed more variability in SHR than in WKY and, with the
imposition of euglycemic hyperinsulinemia, R, was not
uniformly suppressed (two of eight had persistent glucose
production at low levels of clamped insulinemia). Increased
sympathetic nervous system activity can induce insulin
resistance at the level of the liver by interfering with
suppression of hepatic EGP by insulin. In a clinical study in
normal volunteers, Diebert and DeFronzo infused epineph-
rine during the fasting state, which replicated stress
plasma levels of hormone. I9 They found that epinephrine
infusion stimulated fasting EGP, which could not be sup-
pressed by the subjects endogenous insulin secretion. The
variability of R;, in SHR may reflect the impact of increased
sympathetic nervous system activity on the liver in these
animals.?
In vivo studies of insulin-stimulated glucose metabolism,
unlike in vivo studies of insulin response to a glucose
challenge, also suggest the presence of insulin resistance in
SHR. Mondon and Reavenl) demonstrated insulin resis-
tance in very young anesthetized SHR (8 weeks) with the
insulin suppression test. These investigators found that
SHR had higher steady-state plasma glucose concentra-
tions than WKY, which is indicative of insulin resistance in
SHR. Their findings are consistent with a report from our
laboratory, in which we demonstrated impaired insulin-
stimulated glucose utilization using the euglycemic hyperin-
sulinemic clamp technique in anesthetized SHR.17 Both
reports are confounded by the use of pentobarbital anesthe-
sia, which is known to affect glucose metabolism.4.1x The
conclusion that SHR are insulin resistant based on the
earlier study from this laboratory was offered with the
caveat that glucose kinetics could have been affected by
pentobarbital anesthesia and postoperative stress. Clark et
al4 have shown that pentobarbital anesthesia results in
reduced peripheral glucose utilization in Wistar rats. These
results4 are consistent with our finding of a lower GIR
(index of peripheral glucose utilization) in both strains of
anesthetized animals (GIRwKu, 3.2 mgikg . min- [0.0178
mmol/kg min-1; GIRSHR, 2.3 mg/kg . min-I [0.0128 mmoli
kg. minm])17 when compared with conscious WKY and
SHR in the current study.
This study suggests that there was suppression of EGP by
insulin in both conscious WKY and SHR during euglycemic
hyperinsulinemia. Therefore, our findings indicate that
under conditions of euglycemic hyperinsulinemia, insulin
resistance in SHR cannot be explained by nonsuppressed
hepatic glucose production. Resistance to insulin stimula-
tion in SHR emanates from reduced glucose utilization in
skeletal muscle. Increased sympathetic nervous system
activity in the fed state could also contribute to insulin
resistance at the level of peripheral insulin-sensitive tissues,
primarily skeletal muscle. In the clinical study cited above,
Diebert and DeFronzo found that in addition to its effects
on fasting hepatic EGP, epinephrine infusion during eugly-
cemic hyperinsulinemia reduced glucose utilization at the
level of peripheral muscle. It is possible that increased
sympathetic nervous system activity in SHR could explain
both the variability of fasting EGP and the reduced ability
of insulin to stimulate peripheral glucose utilization, result-
ing in insulin resistance in SHR. Alternatively, it is possible
that SHR have a primary metabolic defect in insulin action.
Subsequent excesses in prevailing insulinemia may enhance
sympathetic nervous system activity, which in turn imposes
its effect on EGP. Further study will bc necessary to resolve
these issues.
In the present report, WKY and SHR had similar indices
ACKNOWLEDGMENT
The authors acknowledge the invaluable assistance of Gloria
Rosado.
REFERENCES
1. Fuh M, Shieh SM, Wu DA. et al: Abnormalities of carbohy-
drate and lipid metabolism in patients with hypertension. Arch
Intern Med 147:1035-1038, 1987
2. Ferrannini E. Buzzigoli G, Bonadonna R, et al: Insulin
resistance in essential hypertension. N Engl J Med 317:350-357.
1987
3. Smith D. Rossetti L, Ferrannini E, et al: In vivo glucose
metabolism in the awake rat: Tracer and insulin clamp studies.
Metabolism 36:1167-1174, 1987
4. Clark PW, Jenkins AB, Kraegen EW: Pentobarbital reduces
basal live glucose output and its insulin suppression in rats. Am J
Physiol258:E701-E707, 1990
5. Somogyi MJ: Determination of blood sugar. J Biol Chem
160:69-73, 1945
6. Steele R: Influence of glucose loading and of injected insulin
on hepatic output. Ann NY Acad Sci 82:420-430. 1959
7. Cobelli C, Mari A. Ferrannini E: The non-steady state
problem: Error analysis of Steeles model and new developments
for glucose kinetics. Am J Physiol 252:E679-E689. 1987
8. Dunn A, Katz J, Golden S, et al: Estimation of glucose
turnover and recycling in rabbits using various [?H, Cl glucose
labels. Am J Physiol230:1159-1162. 1976
9. Ferrannini E, Groop LC: Hepatic glucose production in
insulin resistant states. Diabetes Metab Rev 5:7l l-725. 1989
18 HULMAN, FALKNER, AND FREYVOGEL
10. Mondon C, Reaven GM: Evidence of abnormalities of
insulin resistance in rats with spontaneous hypertension. Metabo-
lism 37:303-305,1988
11. Postnov YV, Gorkova SI, Solovyova LP: Reduction of the
B-cell component of pancreatic islets in spontaneously hyperten-
sive rats. Virchows Arch [A] 371:79-87, 1976
12. Yamori Y, Ohta K, Ohtaka M, et al: Glucose metabolism in
spontaneously hypertensive rats. Jpn Heart J 559-560,1978
13. Tsutsu N, Taketa Y, Nunor K, et al: Glucose tolerance and
insulin secretion in conscious unrestrained normotensive and
spontaneously hypertensive rats. Metabolism 38:63-66, 1989
14. Gaboury CL, Karanja N, Holcomb S, et al: Patterns of
insulin secretion and responsiveness in Wistar-Kyoto and spontane-
ously hypertensive rats. Am J Hypertens 4:661-666, 1991
15. Reaven GM, Hollenbeele SB, Chen Y-D: Relationship
between glucose tolerance, insulin secretion, and insulin action in
non-obese individuals with varying degrees of glucose tolerance.
Diabetologia 32:52-55,1989
16. Mondon CE, Reaven GM, Azhar S, et al: Abnormal insulin
metabolism by specific organs from rats with spontaneous hyperten-
sion. Am J Physiol257:E491-E498,1989
17. Hulman S, Falkner B, Chen YQ: Insulin resistance in the
spontaneously hypertensive rat. Metabolism 40:359-361, 1991
18. Lang CH, Bagby GJ, Hargrove DM, et al: Alterations in
glucose kinetics induced by pentobarbital anesthesia. Am J Physiol
253:E647-E663. 1987
19. Diebert DC, DeFronzo RA: Epinephrine induced insulin
resistance in man. J Clin Invest 65:717-721. 1980
20. Frohlich ED: Is the spontaneously hypertensive rat a model
for human hypertension? J Hypertens 4:515-519, 1986 (suppl3)