American Journal of Therapeutics 15, 397–402 (2008)

Effect of Drugs Interacting With the Dopaminergic

Receptors on Glucose Levels and Insulin Release in
Healthy and Type 2 Diabetic Subjects

Freddy Contreras, MD,1 Christian Foullioux, MD,1

Betsy Pacheco, MD,1 Charbel Maroun, MD,1 Hector Bolı́var, MD,1
Mary Lares, MSc,1 Elliuz Leal, MD, PhD,2 Raquel Cano, MD, MSc,2
Valmore Bermúdez, MD, MPH, PhD,2 and Manuel Velasco, MD, PhD1*

Dopamine agonists play an important role in the regulation of the central nervous–cardiovascular, renal,
and hormonal systems through stimulation of dopaminergic (DA1 and DA2) and a- and b-adrenergic
receptors. Several studies have shown that in fat and diabetic mice. The aim of the present study was to
evaluate the interaction of the dopaminergic and endocrine systems by determining the effect of the
dopaminergic antagonist, metoclopramide, and dopamine on insulin secretion and cardiovascular
response by blockade and activation of dopamine receptors in healthy and type 2 diabetic subjects.
Healthy subjects (n =15) and subjects with type 2 diabetes (n = 15) of both genders, aged 18 to 60 years,
were recruited into this study. A comparative experimental design of 90 minutes was performed in
which placebo (0.9% saline) was infused intravenously for the first 30 minutes followed by
metoclopramide (7.5 mg/kg/min), a dopamine receptor antagonist for 30 minutes, and then
metoclopramide (7.5 mg/kg/min) plus dopamine (0.5–3 mg/kg/min) for 30 minutes. The following
clinical and biochemical parameters were measured at the beginning and then every 30 minutes of the
experimental period (30#, 60# and 90#): systolic–diastolic and mean arterial blood pressure, heart rate,
serum glucose, insulin, triacylglycerides, and total cholesterol. Baseline glycosylated hemoglobin was
measured and homeostasis model assessment for insulin resistance was calculated from insulin and
glucose levels. Twelve-lead electrocardiograms were also obtained at these points. Dopamine infusion
induced an increase in serum insulin, systolic blood pressure, and heart rate in healthy subjects but not in
subjects with type 2 diabetes. Infusion of metoclopramide induced a hypotensive effect in healthy
subjects, which was blunted by inclusion of dopamine in the infusion mixture. In subjects with diabetes,
metoclopramide had no effect on blood pressure, but addition of dopamine raised systolic blood
pressure. Neither metoclopramide nor dopamine altered significantly the lipid profile in healthy or
diabetic subjects. Dopaminergic drugs increase serum insulin probably by interacting with dopaminergic
receptors, but stimulation of b-adrenergic receptors cannot be ruled out. Stimulation of cardiovascular
dopamine receptors also caused modifications of hemodynamic parameters in healthy subjects, but
apparently these receptors are attenuated in patients with type 2 diabetes probably as a result of
endothelial dysfunction and alterations in the sympathetic nervous system sensitivity.

Keywords: type 2 diabetes mellitus, insulin, dopamine, dopaminergic receptors, hypertension,

dopaminergic agonists

1
Clinical Pharmacology Unit, Vargas Medical School, Central INTRODUCTION
University of Venezuela, Caracas, Venezuela; and 2Endocrine and
Metabolic Diseases Research Center, University of Zulia, School of Diabetes mellitus is one of the most prevalent diseases in
Medicine, Maracaibo, Venezuela. the world and a public health problem as a result of its
*Address for correspondence: Clinical Pharmacology Unit, Vargas
acute and chronic complications. It is estimated that in
Medical School, Central University of Venezuela, Caracas,
Venezuela. E-mail: veloscom@cantv.net
the year 2025, some 300 millions of people in the world
will have diabetes, mainly type 2 diabetes mellitus.1
1075–2765 Ó 2008 Lippincott Williams & Wilkins
398
It has been demonstrated that dopamine, a biogenic
amine synthesized in different areas of the peripheral
and central nervous systems, plays an important role in
the regulation of central nervous, cardiovascular, renal,
and endocrine systems through stimulation of a- and
b-adrenergic receptors and the specific dopaminergic
(DA1 and DA2) receptors.2–4 A number of investigators
have elucidated the role of dopamine in the pathogen-
esis and treatment of high blood pressure (BP).3–15
Furthermore, it has been established that dopamine at
dosages of 0.5 to 3 mg/kg/min is able to activate both
dopaminergic receptors in the cardiovascular and renal
systems. Activation of dopaminergic receptors in the
smooth muscle of arterioles induces vasodilatation,
and in the kidney, dopamine regulates sodium
excretion in renal tubules producing natriuresis, di-
uresis, increase in renal blood flow, and glomerular
filtration.5,7 Moreover, activation of DA2 receptors,
located in the presynaptic endings, reduces norepi-
nephrine release, thus causing vasodilatation and the
resulting decrease in heart rate and BP. At a high dose,
dopamine stimulates b-adrenergic receptors causing
inotropic and chronotropic effects, which result in an
increase in BP. At very high doses, activation of
dopamine receptors results in vasoconstriction.8,11
The activation of dopaminergic receptors may also
cause hormonal changes in the endocrine system.
Studies in diabetic and obese mice have shown that
dopaminergic agonists improve hyperglycemia and
hyperlipidemia. For example, treatment of diabetic db/db
mice with combined dopamine DA1/DA2 agonists, bro-
mocriptine and SKF 3893, reduced hyperglycemia and
hyperlipidemia and improved pancreatic b-cell islet
function, which stimulated insulin secretion.11 Bromo-
criptine and SKF3893 do not have direct stimulant
endocrine effects; nevertheless, these agents increase
plasma levels of steroids in addition to decreasing
glucose and lipid levels. The effect of dopamine on
pancreatic insulin release was shown by Martin et al.12
Administration of bromocriptine and SKF 3893 to obese
mice decreased food intake and body weight by 55%13
and also decreased plasma levels of glucose and free
fatty acids. It appears that dopaminergic agonists
increase lipolysis and gluconeogenic enzyme activities
in liver and also diminish hepatic glycogen levels and
5-xylose phosphate concentrations.
Metoclopramide is a dopaminergic-blocking agent15,16
that increases prolactin secretion by a dopaminergic-
blocking mechanism at the hypothalamic level in post-
partum patients.
The aim of the present study was to evaluate the
interaction of the dopaminergic and endocrine systems
by determining the effect of the dopaminergic antag-
onist, metoclopramide, and dopamine on insulin
American Journal of Therapeutics (2008) 15(4)
Contreras et al
secretion and cardiovascular response by blockade
and activation of dopamine receptors in healthy and
type 2 diabetic subjects.
PATIENTS, MATERIALS, AND
METHODS
A total of 30 subjects, 15 healthy and 15 with type 2
diabetes of both genders ranging in age between 25 and
53 years were selected through a survey of cardiovas-
cular risk factors in patients attending the outpatient
diabetes clinic of Victorino Santaella Hospital. Diabetes
mellitus was diagnosed according to the criteria of the
American Diabetes Association.17 All subjects gave
informed written consent for participation in the study.
The study was approved by the Institutional Review
Board and adheres to the ethical principles of the
Declaration of Helsinki (www.wma.net/e/policy/b3.
htm). All laboratory tests were preformed at no charge
and patients were not compensated.
The following inclusion criteria were used for the
selection of study subjects: 1) type 2 diabetes
(according to the American Diabetes Association
criteria; for the diabetic group); and 2) healthy subject
(for the control group) without any apparent patho-
logic condition. The following exclusion criteria were
used: 1) severe alcoholism; 2) body mass index 40
kg/m2 or less; 3) body mass index 19 kg/m2 or less;
4) any associated pathology such as thyrotoxicosis,
Cushing’s syndrome, rheumatoid arthritis, hemolytic
anemia, hepatopathy, hyperparathyroidism, Paget’s
disease, end-stage renal failure, gastrointestinal mal-
absorption syndrome, type 1 diabetes, acute coronary
heart disease, or high BP with target organ damage.
A series of laboratory and clinical examinations were
performed, including electrocardiogram, eye fundu-
scopy examination, serum glucose, blood urea nitro-
gen, creatinine, and urinanalysis, to rule out any of
the previously mentioned diseases and to confirm
the healthy state; and 5) use of certain drugs such
as levothyroxine, glucocorticoids, insulin, sildenafil,
labetalol, bromocriptine, agonists, or blockers of the
adrenergic receptors.
Anthropomorphic parameters (body weight and
height), BP, and resting heart rate were determined
and resting electrocardiogram was recorded for all
subjects. The body mass index (BMI) was calculated
from the formula: BMI = [body weight (kg)]/[height
squared (m2)]. BP was measured with a mercury sphyg-
momanometer and also with Dynamap (GE Medical
System Information Technologies, Milwaukee, WI)
heart rate was determined from the electrocardiogram.
A venous blood sample, during morning hours, was
Dopamine and Insulin Release in Healthy and Type 2 Diabetic Subjects
drawn to determine fasting glucose, insulin, and lipid
profile. All subjects were in a fasting state of 8 to 12
hours before the blood sample was taken and were off
any medication during the previous 15 days. The two
groups (control subjects and diabetic subjects) were
studied under a placebo comparative methodology for
a total of 90 minutes, not knowing treatment sequence
(Fig. 1). During the first 30 minutes, placebo (0.9%
saline) was infused, after that metoclopromide at a rate
of 7.5 mg/kg/min for the next 30 minutes, and then
dopamine at a dose of 0.5 to 5.0 mg/kg/min along with
metoclopramide (7.5 mg/kg/min) for the final 30
minutes. Blood was drawn and BP and heart rate
determined at 0, 30, 60, and 90 minutes after start of the
study. Most of the clinical chemistry determinations
were carried out on an autoanalyzer using the routine
analytical methods for blood glucose (enzymatic color-
imetric technique) and total cholesterol, triacylglycer-
ides, and high-density lipoprotein-cholesterol (HDL-c)
using commercial kits (CIENVAR, Venezuela). Low-
density lipoprotein-cholesterol (LDL-c) was calculated
by the Friedewald’s formula18: LDL-c = total choles-
terol – (triglycerides/5) – HDL-c. Plasma immunoreac-
tive insulin was determined by radioimmunoassay.19,20
Glycated hemoglobin A1c was measured by an ion
exchange resin21 method (Bioscience, Venezuela). Homeo-
stasis model assessment for insulin resistance, a simple
marker of insulin resistance, was calculated from fasting
plasma insulin and glucose levels as (insulin 3 glu-
cose)/22.5, in which the insulin concentration is reported
in milliunits per liter and glucose in millimolar concen-
tration calculated from normal values of insulin and
glucose.22
Statistical analysis
Biochemical and hemodynamic variables are expressed
as means 6 standard deviations, frequencies, and
percentage changes from baseline determination.
Kolmogorov-Smirnov test was used to assess normal-
ity distribution of quantitative variables. If variables
fulfilled normality distribution criteria, paired sample
FIGURE 1. Study protocol.
399
t test was used to compare means; if not, the Wilcoxon
rank sum test was used. Analysis of variance was
applied for variable data obtained at different times
(0, 30, 60, and 90 minutes) with Bonferroni post hoc test
to evaluate intergroup variations. Finally, glucose and
insulin relationship was appraised by Pearson’s cor-
relation test. Differences were considered significant
when the P value was , 0.05.
RESULTS
Subjects with diabetes were older than healthy vol-
unteers (mean age, 47.5 years versus 37.8 years). As
expected, serum glucose (88 6 9 mg/dL versus 120 6
48 mg/dL) and insulin levels (8.1 6 4.2 versus 15.6 6
8.5 um/mL), and hemoglobin A1c values (8.5 6 1.7%
versus 6.5 6 0.8%) were significantly higher in the
diabetic group as compared with the healthy group,
but there was no significant difference in BMI among
the two groups (Table 1). Homeostasis model assess-
ment for insulin resistance, a marker of insulin resis-
tance, was also significantly higher in subjects with
diabetes as compared with healthy subjects. Serum
triacyglycerides and total cholesterol were also higher
in subjects with diabetes when compared with the
healthy group (Table 1).
The effect of infusion of the dopaminergic antag-
onist, metoclopramide, and dopamine on glucose and
insulin levels is presented in Table 2. Infusion of
metoclopramide caused a significant increase in
insulin levels in healthy subjects; addition of dopa-
mine also augmented insulin release (P , 0.05). In
subjects with diabetes, metoclopramide had no effect
on insulin levels; however, addition of dopamine did
increase insulin levels. Metoclopramide infusion
raised glucose levels in the healthy subjects, which
was augmented by addition of dopamine to the
infusion mixture. Metoclopramide by itself had no
effect on glucose levels in the subjects with diabetes,
but metoclopramide plus dopamine raised glucose
levels. There was a significant relationship between
glucose and insulin levels in healthy subjects but not
in patients with diabetes.
Metoclopramide infusion caused a significant fall in
BP both in healthy individuals as well as in subjects
with diabetes (P , 0.05) when compared with placebo
(Table 3). However, addition of dopamine to metoclo-
pramide counteracted the BP-lowering response of meto-
clopramide. Actually, systolic BP became significantly
higher than baseline values in both groups of subjects.
There was no effect of metoclopramide or metoclo-
pramide plus dopamine on triglycerides levels or total
cholesterol in both groups of subjects.
American Journal of Therapeutics (2008) 15(4)
400 Contreras et al

Table 1. Clinical characteristics of the study subjects.

Healthy subjects Subjects with type 2

Parameter (n = 15) diabetes (n = 15) P

Age (years) 37.8 6 6.9 47.5 6 5.5 0.0001*

Gender
Males 7 (46.7%) 10 (66.7%) 0.447
Females 8 (53.3%) 5 (33.3%)
Body mass index (kg/m2) 28.5 6 4.2 28.3 6 4.1 0.815
Hemoglobin A1c (%) 6.45 6 0.84 8.53 6 1.70 0.001*
Homeostasis model assessment
for insulin resistance (mU/L.mM) 1.81 6 1.03 5.34 6 4.30 0.004*

*Significance at P , 0.05.

DISCUSSION a significant increase in insulin secretion in healthy

The aim of this study was to determine if dopaminergic
receptors are involved in the interaction of the
dopaminergic antagonist, metoclopramide, and dopa-
mine in healthy and diabetic subjects. In a previous
study, we had concluded that the pharmacologic effects
of metoclopramide + dopamine were carried out by the
activation of a- and b-adrenergic receptors rather than
by their specific dopaminergic receptors.23,24 In the
present study, we attempted to determine if infusion of
metoclopramide + dopamine in healthy and diabetic
subjects has any effect on glucose levels and insulin
secretion and if there is a correlation between glucose
and insulin levels. The results of this study show that
infusion with metoclopramide + dopamine produced
subjects and that insulin levels correlated with serum
glucose levels. However, in subjects with diabetes,
only a combination of metoclopramide and dopamine
increased serum levels of both insulin and glucose, and
there was no correlation between insulin and glucose.
The results of this study indicate that there is an
association between dopaminergic receptor activation
by dopamine and serum insulin levels. Previously, we
had reported a similar finding in patients with
hypertension pretreated with labetalol, an a- and b-
adrenergic receptor-blocking drug.16 The lack of effect
on insulin levels in subjects with type 2 diabetes in the
present study suggests that subjects with diabetes have
endothelial dysfunction and a sympathetic nervous
system defect.

Table 2. Effect of metoclopramide 6 dopamine infusion on serum glucose and insulin levels in healthy and type 2
diabetic subjects.

Healthy subjects (n = 15) Subjects with type 2 diabetes (n = 15)

Glucose levels Insulin levels Correlation Glucose levels Insulin levels Correlation
Time (mg/dL) (ng/mL) coefficient* (mg/dL) (ng/mL) coefficient*

0 minute 88 6 9 8.1 6 4.2 0.596§ 120 6 48 15.6 6 8.5 20.474

30 minutes 102 6 22 17.1 6 11.4 0.574§ 120 6 42 14.0 6 7.3 20.360
60 minutes† 113 6 31 26.3 6 16.5 0.791k 124 6 42 15.3 6 7.9 20.111
90 minutes‡ 147 6 20 35.4 6 20.6 0.852k 173 6 32 22.6 6 12.4 20.438

Glucose Insulin

Time: F = 103.418 (P , 0.05) Time: F = 41.066 (P , 0.05)

Groups: F = 4.284 (P , 0.05) Groups: F = 1.889 (P = NS)
Time 3 groups: F = 0.649 (P = NS) Time 3 groups: F = 15.019 (P , 0.05)

NS, nonsignificant.
*Correlation coefficient between glucose and insulin levels.
†After 30-minute infusion of metoclopramide (see text for dose).
‡After 30-minute infusion of metoclopramide + dopamine (see text for doses).
§Significant at P , 0.05.
k
Significant at P , 0.01.

American Journal of Therapeutics (2008) 15(4)

Dopamine and Insulin Release in Healthy and Type 2 Diabetic Subjects 401

Table 3. Effect of metoclopramide 6 dopamine infusion on blood pressure and heart rate in healthy and type 2
diabetic subjects.

Healthy subjects (n = 15) Subjects with type 2 diabetes (n = 15)

Systolic Diastolic Mean Systolic Diastolic Mean

blood blood arterial Herat blood blood arterial Heart
Infusion pressure* pressure* pressure* rate† pressure* pressure* pressure* rate†

Placebo 0.13 21.33 2.06 3.66 21.80 21.47 22.07 23.30

Metoclopramide 22.80 23.73 25.80‡ 25.50‡ 24.80 22.80 22.93 23.50
Metoclopramide +
dopamine 6.13* 3.73 4.73 4.73 7.67§ 0.27 3.40 3.90

*Change in blood pressure (mm Hg).

†Change in heart rate (beats per minute).
‡Significant at P , 0.05.
§Significant at P , 0.01.

The decrease in BP by infusion of metoclopramide in REFERENCES

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our studies, we may conclude the following:
1. Dopaminergic drugs such as dopamine activate
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More studies are needed to characterize dopaminer-
gic receptors in the pancreas using biochemical
methodology and to establish the significance of these
receptors in the control of insulin release from the
pancreas.
ACKNOWLEDGMENTS
We are grateful to Fonacit (Fondo Nacional de Ciencia
y Tecnololgı́a) for financial help (Project S12001000300).
We also appreciate the technical assistance of Ms. Maria
Carucci.
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