Asian Journal of Medical Sciences 5(1): 09-18, 2013
ISSN: 2040-8765; e-ISSN: 2040-8773
© Maxwell Scientific Organization, 2013
Submitted: August 09, 2012
Accepted: September 03, 2012
Published: February 25, 2013
Serum Prolactrin and Blood Glucose Levels Before and After an Oral Glucse-load in
Patients with Diabetes Mellitus and Liver Cirrhosis
1
Tahia H. Saleem, 2Howaida A. Nafady and 1Housny A. Hassan
1
Departments of Biochemistry,
2
Departments of Internal Medicine, Faculty of Medicine, Assuit University, Egypt
Abstract: Serum prolactin and blood glucose levels were measured in 13 patients with type II diabetes mellitus and
nine patients with liver cirrhosis (Bilharzial or post-hepatic or mixed) in addition to 13 normal controls. Basal serum
prolactin levels in diabetic patients did not differ significantly from levels reported for control, while those of liver
cirrhosis patients were significantly higher than those of both diabetic patients and controls. After oral glucose load,
all the patients showed decreased glucose tolerance accompanied with hyperprolactinemia that was more apparent
and persistent in liver-cirrhosis patients. Serum insulin levels that were feasible to be measured in six liver-cirrhosis
patients, showed concomitant delayed insulin rise following the glucose load that was maintained longer than in
control. These findings of glucose intolerance and hyperprolactinemia were discussed and interpreted on a
suggestion to be secondary to various mechanisms including peripheral insulin resistance, gluconeogenesis and/or
altered response of pancreatic B-cells to glucose loading.
Keywords: Blood glucose, liver cirrhosis, serum prolactin, type II diabetes mellitus
certain dietary factors may either directly or indirectly
modify the prolactin response. Prolactin release
following hypoglycemia is impaired in presence of
massive obesity (Koplemanet al., 1979).
Chronic suppression of prolactin during winter or
summer did not significantly alter the amount of insulin
released, nor did it significantly alter body composition,
so that elevated levels of prolactin in summer do not
enhance the release of insulin to glucose (McMahon
et al., 1997). Prolactin improves glucose homeostasis
by increasing β-cell mass in certain conditions such as
pregnancy whereas hyperprolactinemia due to a
pituitary gland adenoma tumor exacerbates insulin
resistance.
However, previous studies have not evaluated how
prolactin modulates β-cell function and insulin
sensitivity at different dosages (Landgrafet al., 1975).
The mechanisms by which lactogenic hormones
promote β-cell expansion remain poorly understood.
Because Prolactin (PRL) up-regulates β-cell glucose
transporter 2, glucokinase and pyruvate dehydrogenase
activities, Glucose availability might mediate or
modulate the effects of PRL on β-cell mass through
expression of cell cyclins, cell cycle inhibitors and
various other genes known to regulate β-cell
replication, including insulin receptor substrate 2, IGFII, menin, forkhead box protein M1, tryptophan
hydroxylase 1 and the PRL receptor (John Wiley and
Sons, 2011). Differential effects on gene expression are
associated with synergistic effects of glucose and PRL
on islet DNA synthesis. PRL up-regulates β-cell
INTRODUCTION
Pituitary hormone and cytokine Prolactin (PRL) is
one of the mediators of the bidirectional
communication between neuroendocrine and immune
systems. It participates in many immunomodulatory
activities, affects differentiation and maturation of both,
B and T lymphocytes and enhances inflammatory
responses and production of immunoglobulins.
Hyperprolactinemia has been described in many
autoimmune diseases and the activity of PRL has been
intensively studied. Nevertheless, no data on PRL
contribution to pathogenesis of diabetes mellitus is
available, although the effect of PRL on beta cells of
the pancreas and insulin secretion has been observed
(Cejkovaet al., 2009).
The effects of (PRL) on lactation and reproductive
organs are well known. However, its effects on other
target organs and its physiological consequences remain
poorly understood. Prolactin was shown earlier to act as
a stimulating factor for the immune system and thus it
might influence the development of autoimmune
diseases, as in type-1 diabetes mellitus. PRL might
affect the associated immunological changes occurring
in theearly phases of developing type-1 DM (Hala
et al., 2010).
Among the various physiological factors known to
augment prolactin, insulin induced hypoglycemia which
results in significant release of prolactin in normal
subjects. This effect is similar to the response of
thyrotropine releasing hormone on chlorpromazine,
Corresponding Author: Howaida A. Nafady, Department of Internal Medicine, Faculty of Medicine, Assuit University, Egypt
9
Asian J. Med. Sci., 5(1): 09-18, 2013
glucose uptake and utilization, whereas glucose
increases islet PRL receptor expression and potentates
the effects of PRL on cell cycle gene expression and
DNA synthesis. These novel targets for prevention of
neonatal glucose intolerance and gestational diabetes
and may provide new insight into the pathogenesis of βcell hyperplasia in obese subjects with insulin
resistance (Arumugam et al., 2011). Glucose
intolerance and hyperinsulinemia frequently occur in
patients with chronic liver failure. Immunoreactive
insulin was significantly higher in cirrhotic patients
than in controls both before and during the oral glucose
tolerance test. As basal C-peptide values were
significantly higher and C-peptide/Immunoreactive
insulin ratio was significantly lower in cirrhotic patients
than in the control subjects. In chronic liver disease
investigators failed to establish a pathogenetic role of
hormones involved in the glucose counter regulating
system. Free fatty acids may play an important role in
glucose intolerance in chronic liver failure (Riggio
et al., 2004).
The association between prolactin and diabetic
retinopathy has been always a matter of controversy.
Considerable number of studies performed on this issue
and demonstrated increased, decreased, or normal
prolactin in patients with diabetic retinopathy (Triebel
et al., 2011). Prolactin is the main source vasoinhibins,
study of vasoinhibins in animal models demonstrated
that these proteins, derived from prolactin hormone
could decrease vasopermiability and antagonize the
proangiogenic effects of vascularendothelial growth
factor and they concluded that diabetic patients had
lower levelof this protein (Garcia et al., 2008).
The present study screens the changes in the level
of serum prolactin after overnight fasting and following
a glucose load dose (tolerance dose) in normal, diabetic
patients (who were decided to be treated with
hypoglycemic drugs) and liver cirrhosis (Bilharzial or
post- hepatic or mixed), also to investigate the
implication of prolactin in glucose intolerance.
a different day with a value in the diabetic range is
necessary to confirm the diagnosis (Keen, 1998).
American Diabetes Association (ADA) issued
diagnostic criteria for diabetes mellitus in 1997, with
follow-up in 2003 and 2010. The diagnosis is based on
one of four abnormalities: hemoglobin A1C (A1C),
Fasting Plasma Glucose (FPG), elevated random
glucose with symptoms, or abnormal Oral Glucose
Tolerance Test (OGTT) (Alberti and Zimmet, 1998).
They decided to be treated by oral hypoglycemic drugs.
The study conducted from April to December 2011.
The second group involved nine males representing the
group of patients suffering from liver cirrhosis
(Bilharzial or post-hepatic or mixed form) proved by
clinical laboratory tests (liver function tests), abdominal
ultrasound and liver biopsy. Their ages varied between
35 and 60 years. All patients in our study were
normotensive, had normal renal functions with no
history of use of drugs that can affect serum prolactin
level. All were chosen from the newly administered
inpatients of internal medicine department of Assuit
University hospital.
The control group comprised of 13 volunteers (nine
males and four females) and was more or less matching
the patients in age and socioeconomic class. This study
is carried out after approval of the research ethics
committee of Faculty of Medicine, Assuit University
and after taking consent from the participants.
After an overnight fast an oral glucose load dose
(1.5 g/kg body weight) were given to all participants
(patients and control). At 9.0 a.m. blood samples were
taken just before the oral glucose load (0 time, i.e.,
basal level) and 30 and 90 min after the ingestion of the
load dose. Blood glucose was determined by glucose
oxidase method using the kits provided by bio Matrix
Laboratory reagents and products. For determination of
serum prolactin, blood samples were withdrawn
without the use of anticoagulant, sera were separated
and the concentrations were determined by
immunometric assay methods. Catalog LKPR1 Glun
Rhonwy, ianberis, Gwynedd, United Kingdom.
It was also possible in this study to follow the
pattern of serum insulin concentration in six
participants of the control group and another six
belongs to the liver cirrhosis group and their data will
be included separately in the results. Insulin
concentrations were determined by radioimmunoassay
method using the human serum insulin kits purchased
from Immuno Nuclear Corporation Cat No. 06-l2 Post
No. xpo. 297, 5 I/USA TER; MI NN ESO TA, USA.
SUBJECTS AND METHODS
The subjects of the present study included two
groups of patients and a control group. The first group
included 13 patients (six males and seven females)
representing the group of patients suffering from
diabetes mellitus. None of the female participants were
pregnant or lactating Their ages varied between 40 and
65 years and proved to have type-II DM according to
the new WHO criteria for diagnosis of diabetes mellitus
and hyperglycemia which is fasting plasma glucose
to ≥7.0 mmol/L with symptoms are typical of diabetes,
or 2 h post-glucose or casual postprandial plasma
glucose level of ≥11.1 mmol/L. If there are no
symptoms, or symptoms are equivocal, at least one
additional glucose measurement (preferably fasting) on
Statistical analysis: Data obtained in this study were
analyzed by statistical analysis using both student ''t''
test and paired ''t'' test. Using SPSS program and p
value less than 0.05 is considered significant.
10 Asian J. Med. Sci., 5(1): 09-18, 2013
load at 30 min there was negative correlation (r = -0.61)
and return positive correlation at 90 min (r = 0.57)
(Table 2). No significant difference was found in the
level of serum prolactin between males and females
(data not showed).
The results of blood glucose (mg/100 mL) in the
diabetic group at 0, 30 and 90 min after glucose
ingestion revealed significant increase in blood glucose
after 30 and 90 min of glucose ingestion (p<0.001 and
p<0.01), respectively (Table 3 and Fig. 2a). On the
other hand, Prolactin levels significantly increased from
the basal at 30 min (p<0.001). After 90 min, the level
was decreased significantly from that of 30 min
(p<0.01) and although it appeared higher than basal, the
difference was insignificant (Table 3 and Fig. 2b).
RESULTS
The results of blood glucose (mg/100 mL) in the
control group showed significant increase of blood
glucose after 30 min ingestion compared to ''0'' min,
(p<0.001), Ninety minutes after, blood glucose level
showed the tendency to return to the basal levels, where
the difference from basal was not significant (Table 1
and Fig. 1a). On the other hand, following glucose load
individual values of serum prolactin showed variable
response at the 30 and 90 min time (increase, decrease
or no change), but the mean value did not differ
significantly from the basal (Table 1 and Fig. 1b).
There was positive correlation between glucose and
prolactin in the basal state (r = 0.44) while after glucose
Table 1: The individual, mean, standard deviation and standard error values of blood glucose (mg/100 mL) and prolactin (ng/mL) obtained from
control group
Blood glucose (mg/100 mL)
Prolactin (ng/mL)
-------------------------------------------------------------------------------------------------------------------------------------------Number
0
30
90
0
30
90
1
83
116
80
6.370
3.910
3.720
2
65
118
59
6.430
7.820
5.230
3
91
116
95
7.970
7.200
8.680
4
78
116
83
6.460
6.590
5.530
5
75
120
80
3.600
4.280
5.110
6
73
150
73
6.340
9.170
5.260
7
82
132
113
6.190
6.190
5.050
8
80
103
90
4.430
7.140
5.540
9
66
84
69
3.660
3.660
4.800
10
65
122
94
4.710
6.890
6.990
11
80
120
77
2.620
3.290
7.940
12
77
45
88
6.740
6.280
7.020
13
68
88
80
7.250
8.190
6.650
Mean
75.615
113.846
83.154
5.595
6.596
5.949
S.D.
7.964
17.893
13.459
1.615
1.827
1.398
S.E.
2.963
3.733
0.448
0.507
0.507
0.388
p-value
NS
<0.001
NS
NS
NS
NS
Table 2: Correlations between blood glucose (mg/100 mL) and prolactin (ng/mL) in control and diabetic
Control
---------------------------------------------------------------------------------------------------------Glucose
Prolactin
Insulin
---------------------------------------------------------------------------------------------0
30
90
0
30
90
0
30
90
Glucose
1
1
1
0.44
-0.61
0.57
0.023
0.41
0.50
Prolactin
0.44
-0.61
0.57
1
1
1
-0.69
0.16
0.32
113.846
83.154
75.615
60
40
20
0
1: Basal value
2: After 30 min
3: After 90 min
6.596
100
80
7.0
Prolactin (ng/mL)
Blood glucose (mg/100 mL)
120
1: Basal value
2: After 30 min
3: After 90 min
Diabetic
-------------------------------------------------------------------Glucose
Prolactin
-------------------------------------------------------------0
30
90
0
30
90
1
1
1
-0.13
-0.43
-0.12
-0.13
-43
-0.12
1
1
1
1
2
6.5
5.595
5.5
5
3
(a)
5.949
6.0
1
2
3
(b)
Fig. 1: Mean values of blood glucose (mg/100 mL) and prolactin (ng/mL) in control group (a) blood glucose level after 30 min
after ingestion of glucose load p<0.001, (b) prolactin (ng/mL) in control group p value NS
11 Asian J. Med. Sci., 5(1): 09-18, 2013
450
1: Basal level
2: After 30 min
3: After 90 min
16
387.462
Serum prolactin (ng/mL)
Blood glucose (mg/100 mL)
Table 3: The individual, mean, standard deviation and standard error values of blood glucose (mg/100 mL) and prolactin (ng/mL) in diabetic
patients
Blood glucose (mg/100 mL)
Prolactin (ng/mL)
------------------------------------------------------------------------------- ---------------------------------------------------------------Number
0
30
90
0
30
90
1
206
290
220
7.230
22.030
9.190
2
220
310
230
5.910
11.110
6.520
3
154
246
220
6.430
12.590
7.820
4
336
437
400
14.890
21.850
13.850
5
270
390
284
7.630
12.860
7.630
6
400
600
510
3.820
9.020
5.480
7
130
340
230
6.740
22.400
12.430
8
88
219
229
10.090
14.710
8.830
9
179
325
290
9.020
20.280
8.090
10
319
539
430
3.600
10.490
6.990
11
140
311
243
5.820
11.050
6.460
12
230
534
384
7.570
10.060
9.140
13
330
496
370
6.030
8.620
7.390
Mean
230.923
387.462
310.769
7.290
14.390
8.372
S.D.
94.412
122.386
96.908
2.903
5.296
2.355
S.E.
26.185
33.944
26.878
0.805
1.496
0.653
p-value
NS
<0.001
<0.01
NS
<0.001
<0.01
400
350
300
310.769
230.923
250
200
150
100
50
0
14
2
14.39
12
10
8
8.372
7.29
6
4
2
0
1
1: Basal level
2: After 30 min
3: After 90 min
3
1
(a)
2
3
(b)
Fig. 2: Mean values of blood glucose (mg/100 mL) and serum prolactin (ng/mL) in diabetic patients (a) blood glucose after 30
and 90 min of glucose ingestion (p<0.001 and p<0.01), (b) prolactin levels at 30 min (p<0.001). After 90 min, the level
was decreased significantly from that of 30 min (p<0.01)
15
222.556
Serum prolactin (ng/mL)
Blood glucose (mg/100 mL)
250
200
132.333
150
100
86.222
50
0
1
2
(a)
13.27
11.542
10.247
10
5
0
3
1: Basal level
2: After 30 min
3: After 90 min
1
2
3
(b) Fig. 3: Mean values of blood glucose (mg/100 mL) and serum prolactin (ng/mL) in liver cirrhosis (a) blood glucose after 30 min
p<0.001 and after 90 min p<0.01, (b) prolactin after 30 min p<0.001 and after 90 min p<0.01
There was negative correlation between glucose and
prolactin at '0', at 30 and 90 min after glucose load
(r = -0.135, -0.43, -0.12) (Table 2).
The results of blood glucose (mg/100 mL) and
serum prolactin (ng/mL) in liver cirrhosis patients at 0,
30 and 90 min after glucose ingestion showed
12 Asian J. Med. Sci., 5(1): 09-18, 2013
230.923
250 1: Control group
2: Diabetic group
3: Liver Cirrhosis group
200
150
100
86.222
75.615
50
0
1
2
Blood glucose values (mg/100 mL)
Blood glucose (mg/100 mL)
Table 4: The individual, mean, standard deviation and standard error values of blood glucose (mg/100 mL) and prolactin (ng/mL) in liver
cirrhosis patients
Blood glucose (mg/100 mL)
Prolactin (ng/mL)
---------------------------------------------------------------------------------------------------------------------------------------------Number
0
30
90
0
30
90
1
75
250
155
8.590
9.790
8.400
2
65
230
100
20.620
12.830
13.420
3
76
232
108
8.430
9.940
5.690
4
95
300
145
10.690
11.110
7.290
5
75
275
160
6.890
9.880
8.150
6
96
262
110
18.490
17.170
17.570
7
83
110
153
14.890
23.260
14.460
8
94
194
154
6.460
9.790
5.050
9
117
150
117
8.830
15.660
12.190
Mean
86.222
222.556
132.3330
11.542
13.270
10.247
S.D.
15.802
61.186
23.3240
5.195
4.642
4.324
S.E.
5.267
20.396
7.7875
1.372
1.547
1.441
p-value
NS
<0.001
<0.001
NS
NS
NS
3
500
1: Control group
2: Diabetic group
3: Liver Cirrhosis group
387.462
400
300
222.556
200
113.846
100
0
1
2
Blood glucose values (mg/100 mL)
(a)
3
(b)
250 1: Control group
2: Diabetic group
210.769
3: Liver Cirrhosis group
200
150
100
132.333
83.154
50
0
1
2
3
(c)
Fig. 4: Glucose tolerance in the three studied groups (a) fasting blood glucose (mg/100 mL) in the three studied groups in group
2: basal value p<0.001, (b) blood glucose values 30 min after ingestion of load dose in the three studied groups p<0.001
in diabetic and liver cirrhosis, (c) blood glucose values 90 min after ingestion of load dose in the three studied groups
p<0.001 in diabetic and liver cirrhosis
significant rise in blood glucose at 30 and 90 min
(p<0.001) and (p<0.001), respectively (Table 4 and
Fig. 3a). This change was not accompanied with a
significant change in serum prolactin level (Table 4 and
Fig. 3b). There was positive correlation at '0' state
(r = 0.03) meanwhile there were negative correlations
afterglucose load at 30 and 90 min r = -0.12 and -0.49,
respectively.
The comparison between blood glucose levels in
all studied groups showed that basal glucose levels of
patients with liver cirrhosis did not differ significantly
from those of control. Those of diabetic patients were
found to be significantly higher than control (p<0.001)
and than those of liver cirrhosis (Table 5 and Fig. 4a).
Statistical comparison between these two groups
ofpatients showed that the mean values of diabetic
13 Asian J. Med. Sci., 5(1): 09-18, 2013
Serum prolactin (ng/mL)
14
12
1: Control
2: Diabetic group
3: Liver Cirrhosis group
Serum prolactin levels (ng/mL)
Table 5: Glucose levels (mg/100 mL) (glucose tolerance) in the three groups studied
Group
Item
Fasting (mg/100 mL)
Control (n = 13)
Mean
75.615
S.D.
7.864
S.E.
2.209
Diabetic patients (n-13)
Mean
230.923
S.D.
99.412
S.E.
26.165 p<0.001
Liver cirrhosis patients (n-9)
Mean
86.222
S.D.
15.802
S.E.
5.267 p<0.001
11.542
10
7.29
8
6
5.595
4
2
0
1
2
30 min (mg/100 mL)
113.846
17.893
4.963
387.462
122.386
33.944 p<0.001
222.556
61.186
20.396 p<0.001
1: Control group
2: Diabetic group
16 3: Liver Cirrhosis group 14.39
14
90 min (mg/100 mL)
83.154
13.459
3.733
210.769
96.908
26.878 p<0.001
132.333
23.224
7.775 p<0.001
13.27
12
10
3
8
6.96
6
4
2
0
1
2
(a)
3
(b)
1: Control group
2: Diabetic group
10 3: Liver Cirrhosis group
Serum prolactin level (ng/mL)
12
10.247
8.388
8
6
5.949
4
2
0
1
2
3
(c)
Fig. 5: Prolactin levels (ng/mL) at various periods (glucose tolerance) in the three groups studied (a) fasting prolactin levels
(ng/100 mL) in the three studied groups p<0.001 in diabetic and p<0.01 in liver cirrhosis, (b) prolactin levels (ng/mL) 30
after ingestion of load dose in the three studied groups, p<0.01 in diabetic group and p<0.001 in liver cirrhosis group, (c)
prolactin levels (ng/mL) 90 min after ingestion of load dose in the three studied groups, p<0.001 in liver cirrhosis
patients were significantly higher than those reported
for liver cirrhosis patients at both the 30 and 90 min
(p<0.001 and p<0.001), respectively. In the meantime,
the glucose levels of patients (diabetic or cirrhotic)
were significantly higher than those reported for control
group at 30 and 90 min (p<0.001, 0.001 and p<0.001),
respectively (Table 5 and Fig. 4b and c).
Comparison between serum prolactin at various
periods of glucose tolerance in all groups studied
revealed that the basal serum prolactin levels of the
diabetic patients although were higher than those of
control, they did not differ significantly. Those of
livercirrhosis patients were significantly higher than
those of control (p<0.001) (Table 6 and Fig. 5a). In
diabetic patients, glucose load resulted in a significant
rise in serum prolactin at 30 and 90 min comparing to
the control group (p<0.001 and p<0.01), respectively.
Similarly on comparison of 30 and 90 min serum
prolactin levels of liver cirrhosis patients versus those
obtained from control revealed that both levels were
significantly higher (p<0.001 and p<0.01), respectively
(Table 6 and Fig. 5b and c).
Statistical comparison of the serum prolactin levels
for the liver cirrhosis patients versus those of diabetes
showed that the basal level of Liver cirrhosis group was
significantly higher than the diabetic group, (p<0.05)
14 Asian J. Med. Sci., 5(1): 09-18, 2013
Table 6: Prolactin levels (ng/mL) at various periods
tolerance) in the three groups studied
Fasting
30 min
Group
Item
(ng/mL)
(ng/mL)
Control
Mean
5.595
6.960
(n = 13)
S.D.
1.615
1.827
S.E.
0.448
0.507
Diabetic
Mean
7.290
14.390
Patients
S.D.
2.903
5.296
(n-13)
1.496
S.E.
0.805
p<0.001
p<0.001
Liver cirrhosis Mean
11.542
13.270
Patients (n-9)
S.D.
5.195
4.642
S.E.
1.732
1.547
p<0.01
p<0.001
(glucose
serum insulin level was markedly raised to a peak level
at 30 min period (p<0.001) then decreased to reach its
mean basal level at 90 min (Table 7 and Fig. 6).
Therewere negative correlations between insulin,
glucose and prolactin in fasting state (r = -0.23 and
-0.69), respectively meanwhile there were positive
correlations after glucose load at 30 and 90 min
(r = 0.61, 0.16, 0.42, 0.41, -0.57, 0.505, 0.50 and 0.31)
(Table 8).
In liver cirrhosis patients, the mean fasting serum
insulin level appeared to be higher than that of control,
but the difference was not significant, following
glucose load, there was a delayed insulin response thatmaintained till the 90 min period. The 30 min level
appeared to be significantly lower than those of control,
(p<0.001) while that at 90 min was significantly higher
(p<0.001) (Table 9 and Fig. 6 and 7). There were
negative correlations between insulin, glucose and
prolactin at '0' state (r = -0.636 and -0.44) and return
90 min
(ng/mL)
5.949
1.398
0.388
8.372
2.355
0.653
p<0.01
10.247
4.324
1.441
p<0.001
(Table 6 and Fig. 5a), while levels at 30 and 90 min
following glucose load did not differ significantly
(Table 6 and Fig. 5b and c).
Serum insulin levels determined in six control and
six liver cirrhosis patients, the data showed that in the
control participants, following glucose load, the mean
Table 7: Glucose levels (mg/100 mL) and prolactin (ng/mL) and insulin (U/mL) in six males normal subjects
Blood glucose (mg/100 mL)
Prolactin (ng/mL)
Insulin (U/mL)
----------------------------------------------------------------------------------------------------- --------------------------------------------Number
0
30
90
0
30
90
0
30
90
1
83
116
80
6.370
3.910
3.720
12
32
16
2
65
118
59
6.430
7.820
5.230
12
40
12
3
91
116
95
7.970
7.200
8.680
12
58
21
4
78
116
83
6.460
6.590
5.350
8
46
10
5
75
120
80
3.600
4.280
5.110
18
71
24
6
73
150
73
6.340
9.170
5.260
9
62
11
Mean
77.500
122.667
78.333
6.195
6.495
5.558
11.883
51.500
15.667
S.D.
8.894
13.486
11.894
1.419
2.050
1.647
3.488
14.666
5.750
S.E.
3.631
5.508
4.856
0.579
0.637
0.673
1.424
5.988
2.348
p-value
NS
<0.001
NS
NS
NS
NS
NS
<0.001
NS
Table 8: Correlations between blood glucose (mg/100 mL), prolactin (ng/mL) and insulin (U/mL) in control and liver cirrhosis patients
Glucose
Prolactin
Insulin
---------------------------------------------------------------------------------------------------- -------------------------------------------0
30
90
0
30
90
0
30
90
Control
Glucose
1
1
1
0.44
-0.61
0.57
-0.023
0.41
0.50
Prolactin
0.44
-0.61
0.57
1
1
1
-0.690
0.16
0.32
Insulin
-0.02
0.16
0.50
-0.69
0.16
0.31
1
1
1
Liver cirrhosis
Glucose
1
1
1
0.03
-0.10
-0.12
-0.630
0.23
0.34
Prolactin
0.03
-0.01
-0.49
1
1
1
-0.440
0.18
-0.55
Insulin
-0.63
0.23
0.34
-0.44
0.18
0.23
1
1
1
Table 9: Glucose levels (mg/100 mL) and prolactin (ng/mL) and insulin (U/mL) in six males with liver cirrhosis
Blood glucose (mg/100 mL)
Prolactin (ng/mL)
Insulin (U/mL)
--------------------------------------------------- ----------------------------------------------------------------------------------------------Number
0
30
90
0
30
90
0
30
90
1
75
250
155
8.590
3.910
3.720
12
32
16
2
65
230
100
20.620
7.820
5.230
12
40
12
3
76
232
108
8.430
7.200
8.680
12
58
21
4
95
300
145
10.680
6.590
5.350
8
46
10
5
75
275
160
6.890
4.280
5.110
18
71
24
6
96
262
110
18.490
9.170
5.260
9
62
11
Mean
80.333
258.167
129.667
12.283
11.787
10.087
14.333
35.667
39.500
S.D.
12.420
26.806
26.583
5.800
2.883
4.491
2.733
10.328
24.329
S.E.
5.071
10.944
10.853
2.368
1.177
1.834
1.116
4.216
9.932
p-value
NS
<0.001
<0.001
NS
NS
NS
NS
<0.001
<0.001
15 Asian J. Med. Sci., 5(1): 09-18, 2013
60
Insulin (uU/mL)
50
1: Basal level
2: After 30 min
3: After 90 min
are more or less combatable with the previous studies
(Garcia-Webb and Peter Moore, 1999; Charles et al.,
1996). After 30 min of glucose ingestion, there is a
significant rise in both blood glucose and serum insulin
levels (p<0.001) and p<0.001). On the other hand,
serum prolactin showed insignificant rise. After 90 min
of glucose ingestion, the three parameters of the study
return nearly to their basal levels.
In the diabetic group, the basal glucose level
showed significant rise (p<0.001) comparing to the
control group, whereas serum prolactin showed no
significant variation. After 30 min of glucose ingestion,
both blood glucose and serum prolactin showed
significant rise (p<0.01) respectively comparing to their
basal level. At 90 min, the blood glucose level showed
significant rise (p<0.01) comparing to its basal level,
but serum prolactin showed insignificant rise. It showed
that after a glucose load diabetic patients exhibited a
markedly reduced glucose tolerance accompanied with
hyperprolactinemia.
Patients with liver cirrhosis seem to suffer from
hyperglycemia despite the abnormal raised insulin
level. Glucose load led to glucose intolerance aided by
delayed insulin response that was apparently
insufficient to allow proper utilization. The response to
glucose load in liver cirrhosis patients was shown by
rise in the serum prolactin at 30 min that was variable
among individuals, but the mean was not significantly
different from the basal level. After 90 min individual
levels tended to return to their basal levels or even
lower, but the mean serum prolactin was insignificantly
lower than the basal level.
The pattern of the 24 h level of plasma prolactin in
a group of relatively stable insulin-dependent diabetic
patients ''juvenile diabetes' was found by Hanssen et al.
(1978) to be similar to that of non diabetes and was
unaffected by somatostatin infusion. They also found
that plasma prolactin in the normal showed a number of
small rises during day and night and that the mean night
level was significantly higher than the day time level.
Chronic suppression of prolactin during winter or
summer did not significantly alter the amount of insulin
released, nor did it significantly alter body composition.
Furthermore, acute administration of prolactin did not
significantly enhance the release of insulin, during
winter or summer treatment periods. Elevated levels of
prolactin in summer do not enhance the release of
insulin to glucose (McMahon et al., 1997).
In vitro lactogen treatment, in the form of oral
prolactin alters insulin secretary behavior and B cell
junctional communication and supports our hypothesis
that lactogen, insulin secretion and junctional
communication among B cells are related (Sorenson
et al., 1987). Hyperprolactinemia decreases glucose
tolerance via an increase in insulin resistance.
The role of prolactin in the pathogenesis of a
human diabetogenic syndrome has been suggested by
the studies of Landgrafet al. (1975). These investigators
studied the blood glucose and insulin levels during Oral
51.5
40
30
20
15.667
11.883
10
0
1
2
3
Fig. 6: Insulin (uU/mL) in six males normal subjects serum
insulin level was markedly raised to a peak level at 30
min period (p<0.001)
45
Insulin (uU/mL)
40
1: Basal level
2: After 30 min
3: After 90 min
35.667
39.5
35
30
25
20
15
10
5
0
14.333
1
2
3
Fig. 7: Insulin (uU/mL) in six males with liver cirrhosis
p<0.001 after 30 and 90 min
positive correlation at 30 min (r = 0.23, 0.18) and
returnnegative correlation betweeninsulin and prolactin
at 90 min (r = -0.55) (Table 8).
DISCUSSION
The effect of raised prolactin levels on glucose
homeostasis and insulin release is still not well known.
However, its effects on other target organs and its
physiological consequences remain poorly understood.
Prolactin was shown earlier to act as a stimulating
factor for the immune system and thus it might
influence the development of autoimmune diseases, as
in type-1 diabetes mellitus. Prolactin might affect the
associated immunological changes occurring in the
early phases of developing type-1 as indicated by the
significant reduction of IL-1b and IFN-g (Hala et al.,
2010).
Shokoofehet al. (2012) demonstrated that all
diabetics had higher level of circulatingprolactin than
the control subjects and those without retinopathy had
higher concentration compared with patients with
proliferative retinopathy and those who had severe non
proliferative retinopathy had lower prolactin
concentration.
Our studies showed that the basal glucose level,
serum prolactin and serum insulin in the control group
16 Asian J. Med. Sci., 5(1): 09-18, 2013
Glucose Tolerance Test (OGTT) glucose and insulin
levels were measured in 26 patients with prolactinproducing pituitary tumors. The basal glucose and
insulin levels were similar to the control despite chronic
hyperprolactinemia. However, GTT was impaired and
accompanied by a relative peripheral insensitivity as
reflected by the associated hyperinsulinaemia. Even
both glucose intolerance and hyperinsulinemia
improved after suppression of prolactin release
following treatment by bromocriptine.
Prolactin injections promoted β-cell mass by
increasing β-cell proliferation and neogenesis through
the potentiation of phosphorylation of signal transducer
and activator of transcription-5 and decreased menin
expression. However, only the low-dose prolactin
injection potentates glucose-stimulated insulin secretion
through glucokinase and glucose transporter-2
induction. In addition, low-dose prolactin decreased
hepatic glucose output in hyperinsulinemic states,
indicating an improvement in hepatic insulin resistance.
However, high-dose prolactin injection exacerbated
whole body and hepatic insulin resistance. In contrast to
the normal adaptive increases in glucose-stimulated
insulin secretion through expanded β-cell mass and
insulin sensitivity realized with moderately increased
prolactin levels, high levels of prolactin exacerbate
insulin resistance and impairs insulin secretary capacity
(John Wiley and Sons, 2011).
Glucose intolerance and hyperinsulinemia
frequently occur in patients with chronic liver failure.
Immunoreactive insulin was significantly higher in
cirrhotic patients than in controls both before and
during the oral glucose tolerance test. Both
hyperproduction and hypo degradation seem to be
responsible for the high insulin levels. High basal
growth hormone and free fatty acids values were
observed in the cirrhotic group. In chronic liver disease
free fatty acids may play an important role in glucose
intolerance in chronic liver failure (Manabu and
Takao, 1996).
Prolactin is known to have renal sodium retention
properties in man, since hyperprolactinemia is
frequently observed in liver disease, Alain et al. (1994).
The mechanisms by which lactogenic hormones
promote β-cell expansion remain poorly understood.
Because Prolactin (PRL) up-regulates β-cell glucose
transporter 2, glucokinase and pyruvate dehydrogenase
activities, glucose availability might mediate or
modulate the effects of PRL on β-cell mass.
liver, enhanced peripheral resistance to insulin and/or
altered response of the pancreatic B cells to glucose
loading. Prolactin (PRL) up-regulates β-cell glucose
transporter 2, glucokinase and pyruvate dehydrogenase
activities, glucose availability might mediate or
modulate the effects of PRL on β-cell mass.
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18