(Hypertension. 1996;27:354-359.)
© 1996 American Heart Association, Inc.
Articles |
Metabolic and Hemodynamic Effects of a Graded Intracoronary Insulin Infusion in Normal and Fat Anesthetized Dogs
A Preliminary Study
From the Divisions of Pediatric Cardiology and Adult Cardiology, Departments of Pediatrics and Internal Medicine, University of Minnesota, Minneapolis.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Abstract This study evaluated both cardiac hemodynamic and metabolic effects of a graded intracoronary artery infusion of insulin in four normal and five obese anesthetized dogs. Dogs were anesthetized with isoflurane, a catheter was advanced under fluoroscopic guidance into the coronary sinus and great cardiac vein, and a 20-MHz 3F coronary Doppler catheter was advanced into either the mid left anterior descending or circumflex coronary artery. A graded intracoronary insulin infusion was administered (starting at 0.3 mU/min and doubling every 40 minutes until a maximum dose of 2.4 mU/min was achieved). Coronary glucose extraction, coronary blood flow velocity, and coronary artery size were measured at each infusion rate. An intracoronary artery infusion of insulin stimulated myocardial glucose uptake in normal dogs. However, in high-fat–fed dogs, weight gain was associated with a reduction in the ability of insulin to promote glucose uptake by cardiac muscle and a rightward shift in the dose-response curve. In normal dogs, an intracoronary insulin infusion resulted in an increase in coronary blood flow and coronary vasodilation (with insulin coronary vascular resistance index decreases to 0.72±0.06, P<.01), whereas with weight gain the vasodilator response to insulin was lost. The loss of coronary artery vasodilation to local hyperinsulinemia in fat-fed dogs is consistent with other reports in obese or hypertensive humans that document an impairment in the action of insulin to increase skeletal muscle blood flow.
Key Words: obesity • insulin resistance • coronary blood flow • myocardial metabolism
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
As with skeletal muscle, cardiac muscle uses free fatty acids as the principal oxidative fuel; however, a number of in vivo studies in both animals and humans have demonstrated that the heart can derive energy from the oxidation of carbohydrates.1 2 3 4 5 In vitro studies have demonstrated that insulin stimulates glucose transport into cardiac myocytes6 7 8 9 and enhances glycolysis and glycogen synthesis.10 There have been limited in vivo studies of the ability of insulin to regulate cardiac glucose uptake. Barrett et al,4 using a single dose euglycemic clamp technique in conjunction with great cardiac vein catheterization, demonstrated that in the dog, insulin at physiological concentrations stimulates cardiac glucose uptake and does not alter coronary blood flow. Rogers et al11 demonstrated in humans that a glucose/insulin/potassium infusion increases great cardiac vein flow and glucose uptake. Ferrannini et al1 demonstrated in six middle-aged healthy humans that a single insulin dose euglycemic clamp resulted in enhanced myocardial glucose, lactate, and pyruvate uptake; decreased cardiac lipolysis; and no change in cardiac hemodynamics.
Natali et al12 demonstrated in essential hypertensive humans that during graded intra-arterial hyperinsulinemia, glucose uptake by the forearm tissues is significantly reduced. Recently, Baron, Laakso, and coworkers13 14 15 16 and others17 18 19 20 observed that the reduced rate of insulin-mediated glucose uptake that occurs in obesity and hypertension may be in large part due to an impairment in the action of insulin to increase skeletal muscle blood flow. No studies have evaluated whether obesity results in either a reduction in cardiac glucose uptake or impairment in the action of insulin to increase cardiac muscle blood flow.
In the present study, we measured the cardiac hemodynamic and metabolic (glucose uptake) effects of a graded, local (intracoronary artery) infusion of insulin in normal and obese anesthetized dogs.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Animal Model
Five adult mongrel dogs were surgically instrumented with an ascending aortic catheter and two right atrial catheters. After surgery, the dogs were allowed to recover for 3 weeks before baseline measurements were made. All dogs received a regular diet of one can of dog food (Ken-L-Ration) for 2 weeks followed by 6 weeks of a high-fat diet consisting of 2 lb cooked beef fat in addition to their regular diet of one can per day of dog food.21 In addition, all dogs received vitamin supplements and antibiotics throughout the study. All dogs were housed in air-conditioned cages and were fed between 1 and 3 PM each day. Blood pressure, heart rate, and body weight were measured daily. Cardiac output, plasma glucose, and insulin were measured twice a week during the study. All measurements were made between 8 and 11 AM and before the daily feeding (the dogs having not been fed since 5 PM the previous day).
Study Protocol
To study the cardiac hemodynamic and
metabolic (glucose uptake) effects of a graded, local
(intracoronary artery) infusion of insulin, we
anesthetized the five fat-fed dogs and an additional four
conditioned mongrel dogs with a mixture of isoflurane (2.5%) in oxygen
and fentanyl citrate/droperidol (Innovar). The internal jugular vein
was entered percutaneously, and a 5F NIH catheter
(USCI) was advanced under fluoroscopic guidance into the
coronary sinus and great cardiac vein. The right femoral artery
was cannulated percutaneously, and an 8F guiding
catheter was advanced into the left main coronary artery. A
20-MHz 3F coronary Doppler catheter (NuMed Inc) was then
advanced through the 8F guiding catheter and positioned with
fluoroscopic guidance into either the mid left anterior descending or
circumflex coronary artery.22 23 24 The
catheter
position and range control were adjusted to obtain an audio signal of
phasic coronary blood flow velocity. An acceptable phasic
signal had the following qualities: the systolic signal was
less than 25% of the diastolic signal, the
coronary blood flow velocity in early systole approximated
zero, and the audio signal did not contain phasic low-frequency
sounds caused by reflection of the ultrasonic pulse from the vessel
wall. In all experiments, the range control was adjusted to obtain the
maximal frequency shift (Fig 1
). Coronary artery
size was estimated by performing coronary angiography with
nonionic contrast (iohexal [Omnipaque], Sanofi Winthrop
Pharmaceutical). The coronary arteries were measured with
automated edge detection (Reiber-Coronary Angiography
Analysis System II, PIE Medical) (Fig 2).25 A
cineframe from each view was
digitized directly from the film to a matrix of approximately
1000x1500 pixels. The outline of the angiographic catheter was
determined with a semiautomated edge-detection algorithm, with
correction for pincushion distortion. The arterial contour
was similarly detected by an automated algorithm with a
user-identified and computer-smoothed centerline. The mean
diameter of the vessel was then determined. The cross-sectional
area of the vessel was calculated by the following formula:
Area=(
)(Diameter2/4).
|
|
Intracoronary
Infusion Studies
Basal glucose, insulin, and blood gases were
determined by
averaging three sets of arterial and great cardiac vein
blood samples obtained over 30 minutes. Coronary blood flow
velocity and coronary artery size were measured as described
above. After basal blood samples and flows were obtained, an
intracoronary insulin infusion was started at a dose of 0.3
mU/min. This infusion rate was maintained for 40 minutes and then
doubled every 40 minutes until 160 minutes (maximum dose rate of 2.4
mU/min), thereby creating four steps of regional
hyperinsulinemia. Arterial and great
cardiac vein blood was sampled after 30 minutes of each dose, and
coronary artery blood flow velocity and coronary artery
size were measured at the end of each 40-minute infusion period. A
final set of measurements was made after the insulin infusion had been
off for 40 minutes.
All the procedures in this study were in accordance with the University of Minnesota guidelines on animal experimentation.
Laboratory Measurements
Arterial pressure was measured with
P23Db pressure
transducers (Statham) and recorded on an AR6 optical recorder
(PPG Biomedical Systems). Blood for serum glucose determination was
drawn, put in untreated polypropylene tubes, and centrifuged
with an Eppendorf microcentrifuge (Brinkmann Instruments).
The glucose concentration of the supernatant was then measured in
duplicate by the glucose oxidase method with a glucose analyzer
(model A23, Yellow Springs Instruments). Serum insulin was measured by
a double-antibody radioimmunoassay (ICN Biomedicals, Inc). Blood
gas analyses (oxygen, carbon dioxide, and pH) were carried out
with an Instrumentation Laboratory System 1302.
Data Analysis
The change in coronary blood flow velocity during each
insulin infusion rate was calculated as the quotient of the mean
coronary blood flow velocity (kilohertz shift) after 40 minutes
of the infusion (when a steady state had been achieved) and the basal
coronary blood flow velocity.22 23 Change in
coronary blood flow was calculated by multiplying the
fractional change in cross-sectional coronary area
(cross-sectional area intervention/cross-sectional area basal)
by the change in coronary blood flow velocity. An index of
coronary resistance was calculated for each insulin infusion as
the quotient of (mean aortic pressure at that infusion flow/peak
coronary blood flow velocity) and (basal aortic pressure/basal
coronary blood flow velocity).22 23 Cardiac
glucose uptake was estimated by multiplying the cardiac arteriovenous
glucose difference (arterial minus great cardiac vein
glucose concentrations) by the change in coronary blood
flow.
Statistical Analysis
All values are mean±SE. Within
each group, a repeated measures
ANOVA was performed for each variable to determine whether a
significant change in the variable occurred as a result of the
intracoronary insulin infusion. A two-factor ANOVA for
repeated measures was then performed for each variable to assess
differences between the dogs fed the high-fat diet and the control
dogs.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Hemodynamic, Hormonal, and Metabolic Data
Over the 6 weeks of the high-fat diet, the five dogs significantly increased their body weights from 22.7±0.8 to 25.9±0.7 kg (P<.001). The gain in weight was associated with a significant increase in arterial pressure (P<.001), heart rate (P<.001), and cardiac output (P<.01) (Table 1
). Plasma glucose
concentration did not increase significantly with weight gain; however,
serum insulin concentration did increase significantly (91±17 to
238±32 pmol/L, P<.001). At the time of the acute study to
measure the cardiac hemodynamic and
metabolic (glucose uptake) effects of a graded, local
(intracoronary artery) infusion of insulin, the
high-fat–fed dogs were significantly heavier
(P<.001), had significantly higher arterial
pressure (P<.001), and had significantly higher fasting
insulin concentration (P<.001) (Table 1) compared
with the
control dogs.
|
Cardiac Hemodynamic and Metabolic
Effects of a Graded Intracoronary Insulin
Infusion
Arterial and great cardiac vein oxygen, carbon
dioxide, and pH were stable throughout the study and were not different
between the two groups of dogs. In the basal state, the great cardiac
vein insulin concentration was not significantly different from the
arterial insulin concentration. Before and during the
graded intracoronary infusion of insulin, the
high-fat–fed dogs had significantly higher insulin values
(Table 2). The graded intracoronary insulin
infusion resulted in no significant increase in arterial
insulin concentration; however, at the highest insulin infusion rate
(2.4 mU/min), arterial insulin concentration tended to
increase in both groups of dogs.
|
In the basal state, mean arterial
pressure was
significantly higher in the fat-fed dogs (113±3 versus 107±4
mm Hg, P<.001). During the intracoronary
insulin infusion, arterial pressure tended to decrease in
both groups of dogs, but the decrease was significant only in the
control group (P<.05). In the control group of dogs,
insulin resulted in a dose-dependent, significant increase in both
coronary blood flow velocity (P<.05) (Fig 3A) and
coronary blood flow (P<.05),
a decrease in coronary resistance (P<.01), and no
change in coronary artery diameter. In the fat group of dogs,
insulin resulted in no significant change in coronary blood
flow velocity (Fig 3A), coronary blood flow, coronary
artery diameter, or coronary resistance. Cross-sectional
coronary area did not change significantly during insulin
infusion in either group; however, in the control group, insulin tended
to cause a slight increase in area, whereas in the fat group no such
trend was observed.
|
CBFV) after graded intracoronary insulin infusion. The
great cardiac vein (GCV) insulin concentration was used as an estimate
of the plateau plasma insulin level reached after a 40-minute infusion
of each insulin dose (0.3, 0.6, 1.2, and 2.4 mU/mL). A significant
increase in CBFV was achieved in only the control group
(P<.05). B, Effect of a graded intracoronary
insulin infusion on glucose extraction across the coronary bed.
Arteriovenous glucose difference (A-V Glucose) was calculated by
subtracting the aortic plasma glucose concentration from the GCV
glucose concentration. A significant increase in coronary
glucose extraction was achieved in both the control (P<.01)
and fat (P<.05) groups. Compared with the control group,
the amount of glucose extracted in the fat group was significantly less
at all insulin infusion rates (P<.05), and the
dose-response curve was shifted to the right. C, Effect of a graded
intracoronary insulin infusion on glucose uptake across the
coronary bed. Estimated (Est) cardiac glucose uptake was
calculated by multiplying the cardiac arteriovenous glucose difference
by the change in coronary blood flow that occurred at each
insulin infusion rate. A significant increase in estimated cardiac
glucose uptake occurred in both the control (P<.01) and fat
(P<.05) groups. Compared with the control group, the amount
of estimated cardiac glucose uptake in the fat group was significantly
less at all insulin infusion rates (P<.05), and the
dose-response curve was shifted to the right. In all panels,
Control indicates control dogs (n=4); Fat, dogs fed a high-fat diet
for 6 weeks (n=5).
In both groups of dogs, intracoronary insulin
infusion was
associated with a gradual decrease in the arterial
concentration of glucose. In the control group of dogs, basal cardiac
arteriovenous glucose concentration averaged 0.08±0.02 mmol/L, and
insulin-stimulated glucose extraction increased in a
dose-dependent fashion up to a maximal mean cardiac arteriovenous
glucose concentration of 0.52±0.04 mmol/L (P<.01) (Fig
3B
). Similarly, the intracoronary insulin infusion in
control dogs was associated with an increase in estimated cardiac
glucose uptake (Fig 3C), estimated by multiplying the change in
coronary blood flow by the arteriovenous glucose concentration
at each insulin infusion rate (P<.01). In the fat-fed
dogs, both cardiac glucose extraction (0.09±0.03 to 0.36±0.14
mmol/L,
P<.05) and estimated cardiac glucose uptake increased less
than in the control group of dogs (P<.05), such that the
dose-response curve shifted to the right (Fig 3C).
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The present study demonstrates that an intracoronary artery insulin infusion within the physiological range stimulates myocardial glucose uptake in normal dogs. These findings are in agreement with other reports in both dogs and humans which suggest that physiological hyperinsulinemia results in enhanced myocardial glucose uptake.1 2 3 4 5 6 7 8 9 10 11 One of the unique aspects of the current study is that for the first time it has been demonstrated that weight gain in the dog is associated with a reduction in the ability of insulin to promote glucose uptake by cardiac muscle (Fig 3B
and 3C). Since weight
gain resulted in a
rightward shift in the dose-response curve, we believe this
represents a reduced sensitivity of insulin to cause cardiac
muscle to promote glucose uptake.26 The current study
cannot say anything about the responsiveness to insulin, because only
the physiological range of plasma insulin levels
was explored, thereby precluding the determination of the maximal
cardiac response to insulin. Since at an infusion rate of 2.4 mU/min we
were beginning to observe some spillover of insulin into the
systemic circulation (ie, an increase in arterial insulin
concentration and a decrease in arterial glucose
concentration), it is unlikely that the current design of
intracoronary insulin infusion can be used to evaluate the
maximal insulin responsiveness. The current study also demonstrated that in normal dogs, a graded intracoronary insulin infusion results in an increase in coronary blood flow and coronary vasodilation (with insulin infusion, the coronary vascular resistance index decreases to 0.72±0.09xbasal resistance, P<.01). Our findings are consistent with the reports of Liang et al27 and Rogers et al11 but conflict with the reports of Ferrannini et al1 and Barrett and coworkers (Barrett et al4 and Young et al5 ), who failed to demonstrate any change in coronary blood flow with euglycemic hyperinsulinemia. A possible explanation for the differences in results may relate to the method used to measure coronary blood flow. Both Ferrannini et al and Barrett and coworkers used a multithermistor thermodilution catheter that was introduced into the great cardiac vein to measure coronary blood flow, whereas Liang et al used radiolabeled microspheres and in the current study we used a coronary Doppler catheter to estimate coronary blood flow. Both of these latter techniques are more sensitive in measuring small changes in coronary blood flow than the thermodilution technique.28 Specifically, we (R.F.W.) validated the accuracy of the coronary Doppler catheter in both calves and dogs.22 In this study the Doppler catheter was validated against both an epicardial Doppler flow probe (r=.95; range in individual animals, .90 to .99) and volumetrically measured coronary sinus blood flow (r=.97). One of the disadvantages of the Doppler method used in the current study is that velocity is measured rather than volumetric flow. We tried to circumvent this problem by using quantitative coronary arteriography to measure the size of the coronary artery at the point of flow velocity measurement. Previous investigators have shown that when quantitative arteriography is used to measure the size of the artery at the point of flow velocity measurement, an accurate estimation of coronary blood flow can be obtained.29 We used the change in coronary vascular resistance as our index of the ability of insulin to induce coronary vasodilation, because this measurement, a ratio of coronary flow velocity and mean arterial pressure, does not rely on an accurate determination of coronary artery cross-sectional area. Similar results were obtained when the change in coronary vascular resistance was calculated using the ratio of coronary blood flow rather than coronary flow velocity.
In addition to demonstrating that insulin causes an increase in coronary blood flow and coronary vasodilation, the current study also demonstrated for the first time that with weight gain the vasodilator response to insulin was lost. The loss of coronary artery vasodilation to local hyperinsulinemia is consistent with the reports of Baron, Laakso, and coworkers13 14 15 16 and others,17 18 19 20 who observed that an impairment in the action of insulin to increase skeletal muscle blood flow occurs in humans with non–insulin-dependent diabetes mellitus, obesity, or hypertension. In the current study, we documented in normal dogs that an intracoronary infusion of insulin resulted in an approximate 30% increase in coronary blood flow. This increase in insulin-induced coronary flow is similar to the approximate 33% increase in forearm flow reported in healthy men by Jamerson et al20 but less than the almost 60% increase in leg blood flow reported by Laasko et al.16 However, Laasko et al reported maximal insulin-mediated leg blood flow during a high dose (supraphysiological), whole-body insulin clamp, whereas in both the current study and the study of Jamerson et al, an intra-arterial insulin infusion (in a physiological dose) was used.
It is important to remember that since the current study was done in anesthetized animals, since it did not measure volumetric coronary blood flow, and since it did not evaluate the full insulin dose-response curve, it provides only preliminary evidence to suggest that the heart, like skeletal muscle, develops insulin resistance in association with weight gain. Longitudinal studies that serially measure volumetric coronary blood flow in conscious animals are currently in progress in an attempt to better define the effect of weight gain on both insulin-mediated cardiac glucose uptake and coronary vasodilation.
|
Acknowledgments |
|---|
This work was supported in part by grant 1RO1 HL-52205 from the National Institutes of Health, Bethesda, Md.
|
Footnotes |
|---|
Reprint requests to Albert P. Rocchini, MD, Division of Cardiology, Box 21, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614.
Received August 16, 1995; first decision September 29, 1995; accepted November 20, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Ferrannini E, Santoro D, Bonadonna R, Natali A, Parodi O, Camici PG. Metabolic and hemodynamic effects of insulin on human hearts. Am J Physiol. 1993;264:E308-E315.
2. Carlsten A, Hallgren B, Jagenburg R, Svanborg A, Werko L. Myocardial metabolism of glucose, lactic acid, amino acids and fatty acids in healthy human individuals at rest and at different work loads. Scand J Clin Lab Invest. 1961;13:418-428. [Medline] [Order article via Infotrieve]
3. Thomassen A, Nielsen TT, Bagger JP, Henningsen P. Cardiac metabolic and hemodynamic effects of insulin in patients with coronary heart disease. Diabetes. 1989;38:1175-1180. [Abstract]
4. Barrett EJ, Schwartz RG, Francis CK, Zaret BL. Regulation by insulin of myocardial glucose and fatty acid metabolism in the conscious dog. J Clin Invest. 1984;74:1073-1079.
5. Young LH, Zaret BL, Barrett EJ. Physiologic hyperinsulinemia stimulates lactate extraction by heart in the conscious dog. Metabolism. 1989;38:1115-1119. [Medline] [Order article via Infotrieve]
6.
Bing RJ. Cardiac
metabolism. Physiol Rev. 1965;45:171-202.
7.
Cheung JY, Conocer C, Regen DM, Whitfield C, Morgan
HE. Effect of insulin on kinetics of sugar transport in heart
muscle. Am J Physiol. 1978;234:E70-E78.
8. Park CR, Morgan HE, Henderson MJ, Regen DM, Cadenas E, Post RL. The regulation of glucose uptake in muscle as studied in the perfused rat heart. Recent Prog Horm Res. 1961;17:493-529.
9. Fisher RB, Lindsay DB. The action of insulin on the penetration of sugars into the perfused heart. J Physiol (Lond). 1956;131:526-561.
10.
Miller TB. A dual role for insulin in the
regulation of cardiac glycogen synthase. J Biol
Chem. 1978;253:5389-5394.
11. Rogers WJ, Russell RO, McDaniel HG, Rackley CE. Acute effects of glucose-insulin-potassium infusion on myocardial substrates, coronary blood flow and oxygen consumption in man. Am J Cardiol. 1977;40:421-428. [Medline] [Order article via Infotrieve]
12.
Natali A, Santoro D, Palombo C, Cerri M, Ghione S,
Ferrannini E. Impaired insulin action on skeletal muscle
metabolism in essential hypertension.
Hypertension. 1991;17:170-178.
13.
Baron AD, Brechtel G, Wallace P, Edelman SV.
Rates and tissue sites of non-insulin and insulin-mediated
glucose uptake in humans. Am J Physiol. 1988;255:E769-E774.
14.
Laakso M, Edelman SV, Brechtel G, Baron
AD. Effects of epinephrine on insulin-mediated
glucose uptake in whole body and leg muscle in humans: role of blood
flow. Am J Physiol. 1992;263:E199-E204.
15.
Baron AD, Laakso M, Brechtel G, Edelman SV.
Mechanism of insulin resistance in insulin-dependent diabetes
mellitus: a major role for reduced skeletal muscle blood flow.
J Clin Endocrinol Metab. 1991;73:637-643.
16. Laakso M, Edelman SV, Brechtel G, Baron AD. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes. 1992;41:1076-1083. [Abstract]
17. Julius S, Gudbrandsson T, Jamerson K, Shahab ST, Andersson O. The hemodynamic link between insulin resistance and hypertension. J Hypertens. 1991;9:983-986. [Medline] [Order article via Infotrieve]
18. Ferrannini E. Insulin and blood pressure: possible role of hemodynamics. Clin Exp Hypertens A. 1992;14:271-284. [Medline] [Order article via Infotrieve]
19.
Rocchini AP, Moorehead C, Katch V, Key J, Finta
KM. Forearm resistance vessel abnormalities and insulin
resistance in obese adolescents.
Hypertension. 1992;19:615-620.
20.
Jamerson KA, Julius S, Gudbrandsson T, Andersson O,
Brant DO. Reflex sympathetic activation induces acute insulin
resistance in the human forearm.
Hypertension. 1993;21:618-623.
21. Rocchini AP, Moorehead C, Wentz E, Deremer S. Obesity-induced hypertension in the dog. Hypertension. 1987;9(suppl III):III-64-III-68.
22.
Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holida
MD, Hartley CJ, Armstrong ML, Marcus ML, White CW. Transluminal,
subselective measurement of coronary artery blood flow velocity
and vasodilator reserve in man.
Circulation. 1985;72:82-92.
23.
Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson
DD. Effects of adenosine on human coronary
arterial circulation.
Circulation. 1990;82:1595-1606.
24. Wilson RF. Assessment of the human coronary circulation using a Doppler catheter. Am J Cardiol. 1991;67:44D-56D. [Medline] [Order article via Infotrieve]
25. Langer A, Wilson RF. Comparison of manual versus automated edge detection for determining degrees of luminal narrowing by quantitative coronary angiography. Am J Cardiol. 1991;67:885-888. [Medline] [Order article via Infotrieve]
26. Kolterman O, Insel J, Saekow M, Olefsky J. Mechanisms of insulin resistance in human obesity: evidence for receptor and post-receptor defects. J Clin Invest. 1980;65:1272-1284.
27. Liang CS, Doherty JU, Faillace R, Maekawa K, Arnold S, Gavras H, Hood WB Jr. Insulin infusion in conscious dogs: effects on systemic and coronary hemodynamic, regional blood flows and plasma catecholamines. J Clin Invest. 1982;69:1321-1336.
28. White CW, Wilson RF, Marcus ML. Measurement of coronary blood flow in humans. Prog Cardiovasc Dis. 1988;31:79-94. [Medline] [Order article via Infotrieve]
29.
Hodgson JMB, Cohen MD, Szentpetery S, Thames MD.
Effects of regional alpha- and beta-blockade on resting and
hyperemic coronary blood flow in conscious, unstressed
humans. Circulation. 1989;79:797-809.
This article has been cited by other articles:
 |
|
 |
|
  L. A Nikolaidis, A. Sturzu, C. Stolarski, D. Elahi, Y.-T. Shen, and R. P Shannon The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy Cardiovasc Res, February 1, 2004; 61(2): 297 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sundell and J. Knuuti Insulin and myocardial blood flow Cardiovasc Res, February 1, 2003; 57(2): 312 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Jagasia, J. M. Whiting, J. Concato, S. Pfau, and P. H. McNulty Effect of Non-Insulin-Dependent Diabetes Mellitus on Myocardial Insulin Responsiveness in Patients With Ischemic Heart Disease Circulation, April 3, 2001; 103(13): 1734 - 1739. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Iozzo, P. Chareonthaitawee, M. Di Terlizzi, D. J. Betteridge, E. Ferrannini, and P. G. Camici Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans Am J Physiol Endocrinol Metab, May 1, 2002; 282(5): E1163 - E1171. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||