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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 Contreras et al

It has been demonstrated that dopamine, a biogenic secretion and cardiovascular response by blockade
amine synthesized in different areas of the peripheral and activation of dopamine receptors in healthy and
and central nervous systems, plays an important role in type 2 diabetic subjects.
the regulation of central nervous, cardiovascular, renal,
and endocrine systems through stimulation of a- and
b-adrenergic receptors and the specific dopaminergic PATIENTS, MATERIALS, AND
(DA1 and DA2) receptors.2–4 A number of investigators METHODS
have elucidated the role of dopamine in the pathogen-
esis and treatment of high blood pressure (BP).3–15 A total of 30 subjects, 15 healthy and 15 with type 2
Furthermore, it has been established that dopamine at diabetes of both genders ranging in age between 25 and
dosages of 0.5 to 3 mg/kg/min is able to activate both 53 years were selected through a survey of cardiovas-
dopaminergic receptors in the cardiovascular and renal cular risk factors in patients attending the outpatient
systems. Activation of dopaminergic receptors in the diabetes clinic of Victorino Santaella Hospital. Diabetes
smooth muscle of arterioles induces vasodilatation, mellitus was diagnosed according to the criteria of the
and in the kidney, dopamine regulates sodium American Diabetes Association.17 All subjects gave
excretion in renal tubules producing natriuresis, di- informed written consent for participation in the study.
uresis, increase in renal blood flow, and glomerular The study was approved by the Institutional Review
filtration.5,7 Moreover, activation of DA2 receptors, Board and adheres to the ethical principles of the
located in the presynaptic endings, reduces norepi- Declaration of Helsinki (www.wma.net/e/policy/b3.
nephrine release, thus causing vasodilatation and the htm). All laboratory tests were preformed at no charge
resulting decrease in heart rate and BP. At a high dose, and patients were not compensated.
dopamine stimulates b-adrenergic receptors causing The following inclusion criteria were used for the
inotropic and chronotropic effects, which result in an selection of study subjects: 1) type 2 diabetes
increase in BP. At very high doses, activation of (according to the American Diabetes Association
dopamine receptors results in vasoconstriction.8,11 criteria; for the diabetic group); and 2) healthy subject
The activation of dopaminergic receptors may also (for the control group) without any apparent patho-
cause hormonal changes in the endocrine system. logic condition. The following exclusion criteria were
Studies in diabetic and obese mice have shown that used: 1) severe alcoholism; 2) body mass index 40
dopaminergic agonists improve hyperglycemia and kg/m2 or less; 3) body mass index 19 kg/m2 or less;
hyperlipidemia. For example, treatment of diabetic db/db 4) any associated pathology such as thyrotoxicosis,
mice with combined dopamine DA1/DA2 agonists, bro- Cushing’s syndrome, rheumatoid arthritis, hemolytic
mocriptine and SKF 3893, reduced hyperglycemia and anemia, hepatopathy, hyperparathyroidism, Paget’s
hyperlipidemia and improved pancreatic b-cell islet disease, end-stage renal failure, gastrointestinal mal-
function, which stimulated insulin secretion.11 Bromo- absorption syndrome, type 1 diabetes, acute coronary
criptine and SKF3893 do not have direct stimulant heart disease, or high BP with target organ damage.
endocrine effects; nevertheless, these agents increase A series of laboratory and clinical examinations were
plasma levels of steroids in addition to decreasing performed, including electrocardiogram, eye fundu-
glucose and lipid levels. The effect of dopamine on scopy examination, serum glucose, blood urea nitro-
pancreatic insulin release was shown by Martin et al.12 gen, creatinine, and urinanalysis, to rule out any of
Administration of bromocriptine and SKF 3893 to obese the previously mentioned diseases and to confirm
mice decreased food intake and body weight by 55%13 the healthy state; and 5) use of certain drugs such
and also decreased plasma levels of glucose and free as levothyroxine, glucocorticoids, insulin, sildenafil,
fatty acids. It appears that dopaminergic agonists labetalol, bromocriptine, agonists, or blockers of the
increase lipolysis and gluconeogenic enzyme activities adrenergic receptors.
in liver and also diminish hepatic glycogen levels and Anthropomorphic parameters (body weight and
5-xylose phosphate concentrations. height), BP, and resting heart rate were determined
Metoclopramide is a dopaminergic-blocking agent15,16 and resting electrocardiogram was recorded for all
that increases prolactin secretion by a dopaminergic- subjects. The body mass index (BMI) was calculated
blocking mechanism at the hypothalamic level in post- from the formula: BMI = [body weight (kg)]/[height
partum patients. squared (m2)]. BP was measured with a mercury sphyg-
The aim of the present study was to evaluate the momanometer and also with Dynamap (GE Medical
interaction of the dopaminergic and endocrine systems System Information Technologies, Milwaukee, WI)
by determining the effect of the dopaminergic antag- heart rate was determined from the electrocardiogram.
onist, metoclopramide, and dopamine on insulin A venous blood sample, during morning hours, was
American Journal of Therapeutics (2008) 15(4)
Dopamine and Insulin Release in Healthy and Type 2 Diabetic Subjects 399

drawn to determine fasting glucose, insulin, and lipid t test was used to compare means; if not, the Wilcoxon
profile. All subjects were in a fasting state of 8 to 12 rank sum test was used. Analysis of variance was
hours before the blood sample was taken and were off applied for variable data obtained at different times
any medication during the previous 15 days. The two (0, 30, 60, and 90 minutes) with Bonferroni post hoc test
groups (control subjects and diabetic subjects) were to evaluate intergroup variations. Finally, glucose and
studied under a placebo comparative methodology for insulin relationship was appraised by Pearson’s cor-
a total of 90 minutes, not knowing treatment sequence relation test. Differences were considered significant
(Fig. 1). During the first 30 minutes, placebo (0.9% when the P value was , 0.05.
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 RESULTS
metoclopramide (7.5 mg/kg/min) for the final 30
minutes. Blood was drawn and BP and heart rate Subjects with diabetes were older than healthy vol-
determined at 0, 30, 60, and 90 minutes after start of the unteers (mean age, 47.5 years versus 37.8 years). As
study. Most of the clinical chemistry determinations expected, serum glucose (88 6 9 mg/dL versus 120 6
were carried out on an autoanalyzer using the routine 48 mg/dL) and insulin levels (8.1 6 4.2 versus 15.6 6
analytical methods for blood glucose (enzymatic color- 8.5 um/mL), and hemoglobin A1c values (8.5 6 1.7%
imetric technique) and total cholesterol, triacylglycer- versus 6.5 6 0.8%) were significantly higher in the
ides, and high-density lipoprotein-cholesterol (HDL-c) diabetic group as compared with the healthy group,
using commercial kits (CIENVAR, Venezuela). Low- but there was no significant difference in BMI among
density lipoprotein-cholesterol (LDL-c) was calculated the two groups (Table 1). Homeostasis model assess-
by the Friedewald’s formula18: LDL-c = total choles- ment for insulin resistance, a marker of insulin resis-
terol – (triglycerides/5) – HDL-c. Plasma immunoreac- tance, was also significantly higher in subjects with
tive insulin was determined by radioimmunoassay.19,20 diabetes as compared with healthy subjects. Serum
Glycated hemoglobin A1c was measured by an ion triacyglycerides and total cholesterol were also higher
exchange resin21 method (Bioscience, Venezuela). Homeo- in subjects with diabetes when compared with the
stasis model assessment for insulin resistance, a simple healthy group (Table 1).
marker of insulin resistance, was calculated from fasting The effect of infusion of the dopaminergic antag-
plasma insulin and glucose levels as (insulin 3 glu- onist, metoclopramide, and dopamine on glucose and
cose)/22.5, in which the insulin concentration is reported insulin levels is presented in Table 2. Infusion of
in milliunits per liter and glucose in millimolar concen- metoclopramide caused a significant increase in
tration calculated from normal values of insulin and insulin levels in healthy subjects; addition of dopa-
glucose.22 mine also augmented insulin release (P , 0.05). In
subjects with diabetes, metoclopramide had no effect
Statistical analysis
on insulin levels; however, addition of dopamine did
Biochemical and hemodynamic variables are expressed increase insulin levels. Metoclopramide infusion
as means 6 standard deviations, frequencies, and raised glucose levels in the healthy subjects, which
percentage changes from baseline determination. was augmented by addition of dopamine to the
Kolmogorov-Smirnov test was used to assess normal- infusion mixture. Metoclopramide by itself had no
ity distribution of quantitative variables. If variables effect on glucose levels in the subjects with diabetes,
fulfilled normality distribution criteria, paired sample 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
FIGURE 1. Study protocol. 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


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

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American Journal of Therapeutics (2008) 15(4)