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IOSR Journal of Pharmacy

Vol. 2, Issue 1, Jan-Feb.2012, pp. 057-061

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Greater Prevalence of Depression in Type I Diabetic Patients:
Correlation with Decreased Plasma Tryptophan

Saida Haider 1 , Saara Ahmad 2 , Saima Khaliq 3 , Saiqa Tabassum 4 , Zehra Batool 5 ,

Darakhshan J Haleem 6

1 (Neurochemistry and Neuropharmacology research unit, Department of Biochemistry, University of Karachi, Pakistan)

2 (Neurochemistry and Neuropharmacology research unit, Department of Biochemistry, University of Karachi, Pakistan)

3 (Department of Biochemistry, Federal Urdu University, Karachi, Karachi -7 5 3 00, Pakistan)

4 (Neurochemistry and Neuropharmacology research unit, Department of Biochemistry, University of Karachi, Pakistan)

5 (Neurochemistry and Neuropharmacology research unit, Department of Biochemistry, University of Karachi, Pakistan)

6 (Neurochemistry and Neuropharmacology research unit, Department of Biochemistry, University of Karachi, Pakistan)

ABSTRACT

The present study was designed to determine the frequency of major and minor depression in type I Diabetes and to relate the
occurrence of depression with plasma tryptophan levels. Study was conducted during the period January 2011 to September
2011 at two private hospitals of North Nazimabad in Karachi; Hanif hospital and Haleem hospital. 100 diabetic subjects were
selected out of which 50 were males and 50 were females. Likewise the controls were also in the same number. Patients with
type II diabetes mellitus and hypertension were excluded from the study. The study was done to evaluate major and minor
depression in diabetic and control subjects. Blood samples from all the participants were collected in fasting from anticubital
vein to determine plasma TRP levels. Plasma TRP levels were measured by HPLC-UV method. Our data showed that among
the control male subjects 5% were having minor depression while 95% were with no depression, while among test subjects
34% were having major depression, 66% were with minor symptoms of depression. However, among the female controls
13% were suffering with minor depression while 87% were with no depression. Among the female test subjects, 50% were
having major depression and 50% were having minor depression. Present study showed a significant (p<0.01) decrease in
plasma tryptophan levels in both male and female diabetic patients as compared to healthy non -diabetic controls. The present
finding suggests that frequency of major and minor depression is increased in diabetes. Present findings indicate that
decreased plasma TRP levels and lowered brain 5-HT levels may be responsible for depression seen in diabetics.

Keywords - 5-HT, Depression, Diabetes, Plasma TRP

1. INTRODUCTION

Depression is a psychological state caused by sad
mood, agitation, lack of interest and feelings of
worthlessness. The causes of depression are many like the
death of a loved one, unhealthy environmental condition,
seasonal variations and during post partum state. It is well
known that individuals with diabetes experience more
depression and diminished health status compared to those

without diabetes [1]. Depression is suggested to be prevalent
in persons with typel diabetes and may negatively affect
self-management and glycaemic control and increase the
risk of diabetic complications [2]. In depression it has been
studied previously that the neurotransmitters are altered in
the brain namely the monoamines. The most notable
monoamine that plays a vital role in the depression is
serotonin also known as 5-HT. Alterations in serotonin
levels and neurotransmission is associated with depressive
disorders. Role of 5-HT in depression is well documented
[3]. Decreased brain 5-HT has been associated with
depression [4]. It is also noted that the levels of serotonin is

decreased profoundly in those people suffering from
uncontrolled diabetes [5].

In diabetes the level of insulin is decreased. Insulin
is the hormone that maintains the blood glucose level and
helps in the gluconeogenesis in the body. Besides
gluconeogenesis insulin also helps in the transport of large
neutral amino acids including tryptophan, the precursor of
serotonin [6]. A decrease in insulin lowers the TRP/LNAA
ratio [7-9]. Synthesis of serotonin depends upon the uptake
of tryptophan to the brain. Decrease uptake of tryptophan
results in the decreased synthesis of serotonin in brain which
leads to agitation, depression, mood swings and memory
loss [10].

Based on the above consideration, the present
study was designed to initially investigate the prevalence of
depression in local population suffering from diabetes. Data
from both male and female subjects were calculated to
monitor the sex related differences. The present study also
determine plasma TRP levels and relates it with the
occurrence of major and minor depression commonly
observed in the diabetic subjects.

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Vol. 2, Issue 1, Jan-Feb.2012, pp. 057-061

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2. METHODOLOGY

2.1 Study design and setting:

A case control study was conducted between January
2011 to September 2011 in Hanif hospital and Haleem
hospital, North Nazimabad, Karachi.

2.2 Target Population:

The target population of the study was 100 diabetic
type I patients and 100 non diabetic healthy individual. Both
the groups had 50 male and 50 female subjects with the age
between 35 and 55 years. The patients coming to the
diabetic clinic in these hospitals with blood sugar levels
more than 120 mg/dl fasting and 200 mg/dl in random were
chosen as diabetic and it was also considered that diabetics
taken as test were on the hypoglycemic drugs. Similarly the
controls were free of signs and symptoms of diabetes and
also have the negative deranged blood sugar levels. Patients
with type II diabetes mellitus and hypertension were
excluded from the study. All the research involving human
subjects and material derived from human subjects in this
study was done in accordance to the ethical
recommendations and practices of these hospitals.

2.3 Data Collection:

Consent was taken and a questionnaire was asked from
the participant. This questionnaire was about the personal
information that is name, age, sex, race, dietary habits and
also asked for the symptoms of depression. Characteristics
of all the subjects participating in the study are shown in the
table 1. Type I diabetes was already diagnosed by the
standardized examination conducted by the specialist. The
non diabetics were of same age as of diabetics with normal
glucose tolerance test and they were not on any drug
treatment during the course of study. Blood samples from
all the participants were collected in fasting from anticubital
vein. Plasma was separated and used for the determination
of plasma TRP levels. Plasma TRP levels were measured by
HPLC-UV method. Samples for analysis were stored at -
70°C.

2.4 Analysis of depression:

In the questionnaire the patients were asked to answer
about depression. This was evaluated by asking them about
the persistent feeling of sadness, anxious and/or empty
mood with feelings of hopelessness, guilt, loss of interest in
daily tasks, easily fatiguiabilty, loss of appetite and weight,
thoughts of death and suicide and irritability. If five or more
symptoms are present daily affecting the routine activities
for two weeks then the person is labeled with depression.
Those with the long term depression and with almost all of
the signs of depression are listed as the cases of major

depression, those with five or less symptoms of depression
that do not occur daily nor consecutive for two weeks are
labeled cases of minor depression.

2.5 Statistical analysis:

Data are presented as means ± S.D. Neurochemical and
behavioral data were analyzed by student's Mest.

3. RESULTS

Table 1 shows general characteristic parameters of the
subjects which include age, sex, body weight, and blood
pressure and fasting blood glucose levels in both diabetic
and non-diabetic subjects.

TABLE 1: Age, sex, body weight, blood pressure and

fasting blood glucose level of participants suffering from

diabetes type I and controls (non-diabetics)

Non-diabetic

Diabetic patients

Parameters

patients (n=100)

(n=

100)

Males

Females

Males

Females

Age (years)

45

44

44

46

Weight (Kg)

±3.6

±4.0

±4.2

±4.6

75

70

69

67

±3.6

±3.5

±3.5

±3.5

Systolic BP

120.7

119.2

130.4

135.0

(mm Hg)

±3.5

±3.2

±4.2

±3.4

Diastolic BP

76.4

71.5

83.3

79.5

(mm Hg)

±1.3

±1.5

±2.8

±2.5

Fasting
Plasma

77

75.9

250.6

234.4

glucose

+ 5.0

+ 4.5

+ 3.7

+ 3.0

(mg/dl)

Effect of type I diabetes mellitus on depression in male
and female participant are shown in fig. 1. Our data showed
that among the control male subjects 5% were having minor
depression while 95% were with no depression, while
among test subjects 34% were having major depression,
66% were with minor symptoms of depression. However,
among the female controls 13% were suffering with minor
depression while 87% were with no depression. Among the
female test subjects, 53% were having severe depression
and 50% were having minor depression.

Effect of type I diabetes mellitus on plasma tryptophan
levels in male and female participants are shown in fig. 2.
Data analyzed by student's Mest showed a significant
(p<0.01) decrease in plasma tryptophan levels in both male
and female diabetic patients as compared to healthy non-
diabetic controls.

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Vol. 2, Issue 1, Jan-Feb.2012, pp. 057-061

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100 -i
90 -

1 70 -
■I 60 -

o

■s 50 -

& 40 -

Q 30 -

20 -

10 -

-L

96%

n

•■.■:,.

1%

5%

■ Non diabetic
□ Diabetic

34%

1%

IUU -
90 -

07% ■Non Diabetic

53 80 -

□ Diabetic

i 70 -

r 0J

a 60 -

50%

53%

■I 50 "

g 40 -
Q 30 -

^ 20 -

13%

10 -
n

| 1%

1%

No Depression Minor Depression Major Depression

No Depression

Minor Depression Major Depression

Fig. 1 Shows the occurrence of depression in terms of percentage in diabetic and non diabetic subjects evaluated by questionnaire.

(LNAA) that compete with TRP for entry into brain [8].
Evidence exists that diabetes is responsible for elevation of
the plasma levels of LNAA [18] that reduces brain
tryptophan uptake [19] due to which brain serotonin
synthesis rate declines.

6C

25 -

■ Non Diabetic

□ Diabetic

20 -

15 -

: 1

^

10 -

5 -

Male

Female

Fig. 2 shows the Plasma tryptophan (ug/ml) in diabetic and non
diabetic subjects analyzed by HPLC-UV. Values are presented as
mean + SD and significant differences are represented as
**=P<0.01

4. DISCUSSION

Increased depression is one of the most common and
dangerous complication of diabetes [11]. Studies have been
shown that the rate of depression in diabetics is much higher
than in the general population [12- 14] .This study showed
increased risk of major and minor depression in both male
and female diabetic patients as compared to the normal
population. The frequency of major and minor depression
was similar in male and female diabetic patients. It was also
found in this study that plasma tryptophan levels were
significantly decreased in male and female diabetic
participants as compared to the normal participants. The
present results provide a strong evidence for the association
between low plasma TRP levels and occurrence of major
and minor depression observed in diabetic patients as
compared to controls.

Tryptophan depletion might affect various behaviors
by affecting brain TRP levels, thereby decreasing 5-HT
synthesis. The present study has demonstrated a decrease in
plasma TRP levels in both male and female diabetic patients
and these patients also exhibited a greater incidence of
major and minor depression compared to healthy controls.
Several investigators have suggested that brain tryptophan
levels vary with the changes in free plasma TRP [15-17]. It
has also been reported that brain TRP levels are more
sensitive to the changes in total plasma TRP or to the ratio
of total plasma TRP to the sum of large neutral amino acids

Previous studies in humans and animals show that brain
5-HT synthesis is altered by the supply of TRP to the brain
[20, 21]. At normal circumstances, the brain enzyme TRP
hydroxylase is only 50% saturated with TRP therefore an
increase in brain TRP will automatically increases the
production of brain serotonin [22] and decreased plasma
TRP results in decreased 5-HT synthesis [23]. The decrease
in plasma TRP levels in the present findings may also be
attributed to the greater metabolism of TRP by alternative
pathways. Evidence shows that activity of liver TRP
oxygenase enzyme is increased in diabetes [24, 25]. Indeed
such metabolic alterations in diabetes may ultimately result
in decreased synthesis of brain 5-HT in diabetic patients.
Reports have shown that tryptophan uptake by brain was
decreased in diabetic condition leading to reduction in brain
tryptophan levels due to which synthesis and turnover of 5-
HT in brain was also decreased [26]. The pathogenesis of
depression is closely related to the monoaminergic system,
and particularly involves serotonergic mechanism [3, 27,
28]. Decreased brain 5-HT has been associated with
depression [29, 30]. Evidence exist suggesting low levels of
5-HT metabolism in depression [31, 32]. Several lines of
evidence have indicated that the prevalence of depression in
diabetic subjects is higher than in the general population. In
the present study, we report that patients with diabetes are at
increased risk of developing depression due to the alteration
in indoleamine levels. The study also shows that in diabetic
females the frequency of minor and major depression was
comparable but in male diabetics the frequency of minor
depression (66%) was more while major depression (34%)
was lower.

5. CONCLUSION

The present finding of decreased plasma tryptophan
levels suggests that greater prevalence of major and minor
depression commonly observed in diabetics may be due to
an altered brain 5-HT metabolism.

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