TITLE OF PAPER

Serum Nesfatin-1 and Galanin concentrations in the adult with Metabolic syndrome:
relationships to insulin resistance and obesity
‫ و عالقتهم مع مقاومة األنسولين و‬:‫ والجالنين بمصل الدم في البالغين مع المتالزمة األيضية‬1-‫تركيز النسفاتن‬
‫السمنة‬
Maryam N. Alotibi 1, Amina M. Alnoury 2, Amani M. Alhozali 3
‫ أماني معتوق الهذلي‬،‫ أمينة محمد الغريب النوري‬،‫مريم نايف ضاوي العتيبي‬
1
Master's Degree in clinical biochemist, Faculty of Medicine, King Abdulaziz
University, Jeddah, Saudi Arabia
Email: mary.n_08@windowslive.com
2
Associate Professor, clinical biochemistry Department, Faculty of Medicine, King
Abdulaziz University, Jeddah, Saudi Arabia
Email: draminaalnoury@yahoo.com
3
MD, SSC-Med, Associate Professor of Internal Medicine, Consultant
Endocrinologist, Department of medicine, Head of Endocrinology unit, King
Abdulaziz University Hospital, Jeddah, Saudi Arabia
Email: ahuzali@hotmail.com

Address correspondence and reprint request to:

Maryam Naif Alotibi, clinical biochemistry Department, Faculty of Medicine, King
Abdulaziz University, PO Box 22383,
Jeddah 5417, Kingdom of Saudi Arabia,
E-mail: mary.n_08@windowslive.com

Disclosure. Authors have no conflict of interests, and the work was not supported or
funded by any drug company. This work was funded solely by the King Abdulaziz City
for Science and Technology, Kingdom of Saudi Arabia.

Number of authors: 3
Number of Words: 3030
Number of Tables: 3
Number of Figures: 0
Number of References: 39

1
 ABSTRACT
Objectives: To This study was performed to evaluate the circulating levels of nesfatin-
1 and galanin in metabolic syndrome (MetS) patients, and to investigate the
relationship between these two neuropeptides with and anthropometric and metabolic
parameters.
Methods: A total of 84 subjects participated in this case-control study, which was
conducted between in October 2014 and –June 2015 in the Internal Medicine
Outpatient Clinic of King Abdulaziz Abdul Aziz University Hospital (KAUH).
According to the American Heart Association, /National Heart, Lung, and Blood
Institute (AHA/NHLBI) and International Diabetes Federation (IDF) criteria for
metabolic syndromeMetS, they the participants were divided into 44 a MetSmetabolic
syndrome group (44 participants), and 40 age- and sex-matched control group (40
participants). Anthropometric measures were taken, and 12 12-hour- fasting blood
samples were taken for the measurement of nesfatin-1, galanin, and other
biochemical parameters.
Results: There was a significant decrease in serum levels of nesfatin-1 and significant
increase in serum levels of galanin in MetS patients when compared with the control
group (Pp < 0.05). Serum nesfatin-1 was negatively correlated with weight, waist
circumference (WC), and body mass index (BMI). Waist circumference WC was the
only independent predictor of serum nesfatin-1 levels, by explaining 11% of the total
variance according to the multiple regression model. Serum galanin was positively
correlated with fasting blood glucose (FBG), HbA1C, HOMA-IR, and triglycerides.
Fasting blood glucose FBG was the only independent predictor of serum galanin
levels, by explaining 12% of the total variance according to the multiple regression
model.
Conclusion: Our findings indicated a lower level of nesfatin-1 and a higher level of
galanin in patients with MetS, which might confer suggesting a role of these
neuropeptides in the pathogenesis of this disease.

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Introduction
Metabolic syndrome (MetS) denotes a group of metabolic risk factors for
cardiovascular diseases and diabetes, that includesing central obesity, elevated blood
glucose levels and/or hyperinsulinemia, dyslipidemia, and elevated blood pressure
(1). Its prevalence is rapidly increasing, and it has become an epidemic health
problem (2). The prevalence of metabolic syndrome MetS among Saudi- adults ranges
from 16% to 40% according to the study area and the definition utilized (3). Up to
now, the exact role of these physiopathological causes underlying metabolic
syndrome MetS has not been fully elucidated. The hypothalamus is the primary region
for energy homeostasis that incorporates many peptide hormones and neural satiety
signals (4,5). Numerous neuropeptides in the hypothalamus have been shown in many
peripheral tissues, including adipose tissue and the gastrointestinal tract. They play
essential roles in body weight regulation, feeding conduct, and body energy balance
(6). One of these neuropeptides is Nesfatinnesfatin-1 (Nes-1), which was recently
identified in 2006 as an anorexigenic neuropeptide, ; Nesfatinnesfatin-1 is a peptide
(82 amino acids) derived from the post post-translational processing of the N-
terminal fragment of nucleobindin-2 (NUCB2); ), the precursor protein expressed in
the hypothalamus (7). It is widely expressed in the central nervous system (CNS) and
several tissues, such as the pancreatic islet cells, pituitary gland, adipose tissue, and
stomach (8). It has a key role in regulating food intake, body weight, appetite
stimulation and body energy balance (9,10). Another neuropeptide is Galanin galanin
(GAL), a 29-amino acid peptide that was discovered in 1983 in the porcine intestine
as an orexigenic neuropeptide, ; which it is mainly synthesized in the central and
peripheral nervous systems and gastrointestinal tract (11,12). It acts exerts its effects
through the activation of GAL receptors (GalR1, GalR2, and GalR3) (13). It plays a
key role in the regulation of energy balance and modulation of food intake (13). It
also has a contributing role in the regulation of insulin sensitivity (14).
To our current knowledge, there has been very extremely little documentation
of the associations of these neuropeptides with various definitions of MetsMetS. This
study, aims to determine the levels of Galanin galanin and Nesfatinnesfatin-1 in
patients with MetS and to show their association with the parameters of the disease.
Methods. Study design and participants. This is a case-–control study which that was
conducted between October 2014 and June 2015 in the Internal Medicine Outpatient
Clinic of King Abdul Aziz University Hospital (KAUH). It included 84 participants
who were further divided into two groups; group 1 (included 44 metabolic syndrome
MetS patients) , and while group 2 (comprised 40 controls with less than three risk
factors). The participants’ ages of participants ranged between from 35 and to 75
years. Each subject was medically examined and interviewed using the standardized
questionnaire in relation to the history of disease and medications. Subjects with
renal disease, thyroid disorder, pregnancy or liver disease were excluded. Written
informed consent was obtained from all the subjects. The study protocol was
approved by the Unit of the Biomedical Ethics Research Committee of the Faculty of
Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Diagnostic criteria of MetS. MetS The metabolic syndrome was identified by using
the criteria of the American Heart Association/National Heart, Lung, and Blood
Institute (AHA/NHLBI) and International Diabetes Federation (IDF)AHA/NHLBI and
IDF, (as described by in (15). According to these criteria, at least three out of the

3
following five criteria characteristics must be present to diagnose a person clinically
as having the MetS:
1. Central obesity, as indicated by a waist circumference (WC) ≥ 94 cm for men and
≥ 80 cm for women.;
2. Triglycerides level (≥ 1.7 mmol/L or undergoing current treatment for
hypertriglyceridemia).;
3. High-density lipoprotein cholesterol (HDL-C) level (˂ 1.03 mmol/L for males and
˂ 1.3 mmol/L for females or undergoing current drug treatment for reduced HDL-
C).;
4. Hypertension (systolic and/or diastolic blood pressures ≥ 130/85 mmHg or
undergoing current antihypertensive drug treatment)).; and
5. Impaired fasting blood glucose (FBG; (≥ 5.5 mmol/L or undergoing current drug
treatment of for elevated glucose).

Anthropometric measurements. Body weight, height, and waist circumference WC

were performed determined for all the participants. Body Mass mass Index index
(BMI) was calculated by dividing of weight in kg kilograms by height in square
meters squared [(kg/m2]. ). Waist circumference WC was measured in centimeters.
Blood Pressure pressure was measured in millimeters of mercury (mmHg),
after the participants had rested for at least 5 minutes min of sitting, using a standard
digital sphygmomanometer (SureSigns VS3 monitor, Philips Medical Systems, USA).
Blood Sample sample collection and storage. Five milliliters of venous blood were
drawn from each participant after after an overnight fasting for (≈12-–14 hours) by a
certified phlebotomist using standard laboratory techniques. The Blood blood
samples were collected into a Vacutainer Serum Separator Tube (SST) and
centrifuged at 3,000 rpm for 10 min within 30 minutes min of sample collection.
Serum was separated immediately and stored in a clean, dry Eppendorf tubes at -–
80°C until the analysis was performed.
Biochemical analysis. Blood samples were analyzed for biochemical variables at
KAUH’s the clinical biochemistry laboratory of the KAU hospital according to the
standard procedures. Fasting blood glucose (FBG), glycated hemoglobin (HbA1c),
insulin, total cholesterol (TC), triglyceride (TG), high-density lipoprotein
cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were
measured using the Dimension Vista System (Dimension Vista1500, Healthcare
Company, New York, USA). FBG was measured using the hexokinase method,
whereas TC, TG, HDL-C and LDL-C were measured using an enzymatic method.
Glycated hemoglobin (HbA1c) was measured by a method based on a turbidimetric
inhibition immunoassay (TINIA). Serum insulin was determined by using direct
chemiluminescent technology immunoassay (ADVIA Centaur Insulin assay).
Insulin resistance was estimated by using homeostatic model assessment (HOMA-
IR) with the following formula: fasting plasma glucose (mmol/L) × fasting serum
insulin (µU/mL) divided by 22.5.

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Determination of Nesfatin-1 Concentration. The concentration of nesfatin-1 in
serum was determined using a Human Nesfatin-1 ELISA kit (CUSABIO
BIOTECH, Wuhan, China). This test kit is effective in the range of 31.25 to 2000
pg/ml.
Determination of Galanin concentration. The concentration of galanin in serum
was determined using a Human galanin (GAL) ELISA kit (CUSABIO BIOTECH,
Wuhan, China). This test kit is effective in the range of 4.7 to 300 pg/ml.

Statistical analysis. All statistical analysis was made by using the Statistical
Package for Social Science package (Version 20, SPSS INC, Chicago, Illinois,
USA). Descriptive data were given as mean ± standard deviation (SD). Comparison
of means between two groups was made with the Independent-sample t-test,
whereas the differences in percentages of categorical variables were assessed by a
chi-square test. The relationship between serum nesfatin-1, galanin concentrations
and components of the metabolic syndrome was calculated using Pearson’s method.
Multiple linear regression analysis with backward variable selection was done for
detection of independent predictors of nesfatin-1 and galanin levels. For all tests,
differences were considered statically significant at p value less than 0.05.
Results. A total of 84 subjects were enrolled in a case-control study. The subjects
were stratified into two groups (MetS group, n=44 and control group, n=40). The
clinical and biochemical characteristics of the groups are summarized in Table 1.
Significant differences (P<0.05) between participants with MetS and controls were
found for the components of MetS (waist circumference, systolic blood pressure,
triglycerides and fasting blood glucose. There was no significant difference
(P>0.05) between groups in age, height, BMI, diastolic blood pressure and HDL-C.
Regarding the analysis of serum nesfatin-1 and galanin levels, the data showed
significantly lower levels of nesfatin-1 in MetS patients than in control subjects,
p<0.05. On the contrary, the mean serum levels of galanin were significantly higher
in patients with MetS compared to the control subjects.
The prevalence of MetS risk factors among controls and MetS patients was
studied using the AHA/NHLBI and IDF criteria as shown in Table 2. The
prevalence of all risk factors (high FBG, hypertension, low HDL-C levels,
abdominal obesity and high TG) was significantly higher in MetS group than,
control group (P<0.001). Among individual components of MetS, the most
prevalent risk factors in patients were the high fasting blood glucose levels,
abdominal obesity and hypertension while the least prevalent were low serum HDL-
C and high serum TG. In the control group, the most prevalent risk factor was
abdominal obesity indicating increased obesity among studied population.
Table 3 revealed that galanin correlated positively with fasting blood glucose,
HbA1C, HOMA-IR and triglycerides (p<0.05). Nesfatin-1 correlated negatively with
weight, waist circumference and BMI(p<0.05). No correlation between galanin and
nesfatin-1was noticed.

Multiple backward linear regression analysis of the variables showed that

only fasting blood glucose (β= 0.38, p=0.002) was considered to be an independent
predictor of serum galanin level and explained approximately 12% (R2=0.12) of the

5
whole variance. Regarding nesfatin-1, only waist circumference (β = -0.33,
p=0.002) was considered to be an independent predictors of serum nesfatin-1 level
and explained approximately 11% (R2 =0.11) of the whole variance.
Discussion

Metabolic syndrome is one of the most complex and heterogeneous disorders. It

is characterized by abdominal obesity, hypertension, hyperglycemia and lipid
metabolic abnormalities. It has been identified as an independent CVD risk above
and beyond the sum of its individual components (1). The prevalence of MetS is
increasing in most countries; one possible reason is the epidemic of obesity in most
populations (2). Neuropeptides probably play a critical role in MetS. In the recent
years, the number and varieties of neuropeptides are growing, therefore
understanding the diverse effects of these identified neuropeptides is important
(4,5). Our primary aim is to investigate whether galanin and nesfatin-1 have a role
in the pathophysiological mechanism in patients with MetS as defined by IDF and
AHA/NHLBI criteria and to compare their serum levels to age- and sex-matched
controls. We also assessed the relationship between these two neuropeptides and
biochemical markers of MetS.

In the present study, TG and, FBG levels, SBP and WC (risk factors for the
MetS) were significantly higher in patients with MetS when compared to the control
group. Nevertheless, DBP and HDL-C were not significantly different between both
groups and this may be due to drug treatment of hypertension and dyslipidemia.
Our observations found that serum galanin concentrations were higher in
MetS patients than their age and sex-matched control subjects. To our knowledge,
there are no previous studies that measured galanin among adults with MetS, but
only in patients with individual components of the MetS. In this study, a significant
positive correlation was determined between serum galanin and FBG, HbA1C and
HOMA-IR (parameters indicating diabetes). This comes in accordance with
previous reports which showed a statistically significant positive correlation
between galanin concentrations and FBG content in healthy individuals and
patients with T2DM during the glucose tolerance test, pregnant women with
gestational diabetes mellitus (GDM) and non-pregnant women with T2DM (16,17).
Moreover, a positive association was showed between the plasma concentrations of
galanin and HbA1c in children with type 1 diabetes mellitus (18). Zhang group
showed a significant positive correlation between galanin and HOMA-IR (19).
These data seem to indicate that the raised galanin concentration may be a
consequence of increased serum glucose.
The correlation between serum galanin and lipid profile revealed a
significant positive correlation with TG, non-significant positive correlation with
LDL-C, TC and non-significant negative correlation with HDL-C. These results are
in agreement with those of Fang et al. 2016 who concluded that there is a
statistically significant positive correlation between galanin concentrations and TG
in obese subjects (14).
Our data didn’t show a correlation between serum galanin level and body
weight, BMI and waist circumference. In literature, a number of researches closely
related galanin to body weight and obesity via regulation of food intake in animals

6
and humans (20). Plasma galanin levels were reported to be increased in obese
female versus control subjects, particularly in individuals with BMI of >31. In
comparison, the concentrations of galanin were reduced in lean women compared
to healthy subjects, suggesting that circulating concentrations of galanin are
increased in individuals with greater visceral fat mass (21). These results are not in
agreement with results of this study which may be explained by a small number of
studied population or by the high percentage of obese persons in patients and
control groups (95.5% and 47.5% respectively).
The relationship between galanin and hypertension is not completely
elucidated. Some research studies reported the implication of galanin in the
regulation of blood pressure and heart rate in animals (22). A recent study reported
that the plasma galanin concentrations were reduced in obese individuals with
hypertension compared with age- and BMI-matched obese controls group.
Furthermore, the plasma galanin concentration was negatively correlative of
diastolic blood pressure in obese subjects with hypertension (23). However, our
study found no correlation between serum galanin level and the diastolic blood
pressure and non-significant negative correlation with systolic blood pressure.
To conclude, performing the multiple regression models indicated that
fasting blood glucose was the only independent predictors of serum galanin levels,
explaining 12% of the total variance.
Regarding the other neuropeptide, nesfatin-1, we observed significantly lower
nesfatin-1 concentrations in individuals with MetS versus age-sex-matched
controls. To the best of our knowledge, there has been only one previous study
which showed also lower levels of nesfatin-1 in MetS patients (24).
In the present study, we did not observe any correlation between nesfatin-1
level and FBG, HbA1C, fasting insulin and HOM-IR. The important role of
nesfatin-1 in the metabolism of glucose and insulin has been reported in several
studies. The results of these studies on the relationships between nesfatin-1 and
diabetes or insulin resistance have revealed inconsistent findings. Su et al. 2010
showed a decrease in plasma glucose levels after injection of nesfatin-1 in rats and
they suggested that the anti- hyperglycemic effect of nesfatin-1 probably occurs
through the insulin signal pathways but the exact mechanism was not elucidated
(25). Some studies have shown a reduced nesfatin-1 concentrations in the patient
with T2DM and high nesfatin-1 levels in patients with Type 1 DM when compared
to the healthy adults (26). Furthermore, nesfatin-1 concentrations were also
reported to be decreased in patients with GDM compared with control pregnant
women (27). Deniz et al. 2012 determined that serum nesfatin-1 concentrations
were lower in women with polycystic ovary syndrome who had insulin resistance
compared to the control group (28). However, other studies have observed a high
nesfatin-1 concentration in patients with T2DM and patients with IGT with a
positive correlation between plasma nesfatin-1 concentrations and FBG, plasma
insulin, 2nd-hour blood glucose after a glucose load and HOMA-IR (29).
Moreover, intravenous infusion of glucose significantly increased basal nesfatin-1
concentrations in healthy adult subjects (30).
Our study showed that there was a statistically significant negative
association between nesfatin-1 and body weight, BMI, waist circumference (obesity

7
parameters). Inconsistent findings have been obtained regarding the association
between nesfatin-1 levels and BMI. As available in literature, initial evidence
observed an inverse correlation between nesfatin-1 concentrations and BMI in non-
obese subjects (31). A significantly positive correlation between BMI and nesfatin-1
concentrations in obese and overweight individuals has been shown by Saldanha et
al. 2012 (10). In a study with obese children, nesfatin-1 levels were significantly
decreased compared to a control group. In that study, a negative significant
relationship was found between nesfatin-1 and BMI (32). Furthermore, another
study reported a significant decrease in the level of fasting nesfatin-1 concentration
in individuals with the highest BMI compared to non-obese individuals, and the
level of nesfatin-1 was inversely correlated with BMI, body fat weight and
percentage of body fat (33). In patients with non-alcoholic fatty liver disease, serum
nesfatin-1 concentrations in obese subjects were significantly reduced compared to
the non-obese subjects (34). Thus, all previous studies except one reported a
negative correlation between nesfatin1 level and BMI.
Regarding lipid profile, there has been no prior report in the literature
studying the relationship between the lipid profile and the nesfatin-1 concentrations
in MetS patients. One study found that nesfatin-1 was negatively correlated with TG
in patients with hypothyroidism (35). Another study found a positive correlation
between nesfatin-1 concentrations and the HDL-C in patients with T2DM (36). In
the current study, we did not observe any correlation between nesfatin-1
concentrations and HDL-C, LDL-C, TC or TG.
Regarding effect of nesfatin-1 on blood pressure, the results of different
studies are controversial. Intravenous injection of nesfatin-1 to rats and mice
resulted in a significant elevation of blood pressure (37). Zhao et al. 2015 found a
significant increase in plasma nesfatin-1 levels in patients with hypertension versus
controls subjects, and positive correlation with systolic blood pressures and diastolic
blood pressures, especially in overweight/obese hypertensive patients (38). That
study supported the relationship between nesfatin-1 and blood pressure. In contrast,
another study with obese individuals versus normal weight did not find any
relationship between nesfatin-1 and the systolic or diastolic blood pressures (39).
However, in the present study, no significant association was found between the
nesfatin-1 concentrations and the systolic or diastolic blood pressures.
The multiple regression models have shown that waist circumference is the
only independent predictors of serum nesfatin-1 levels, explaining 11% of the total
variance.
To our knowledge, this is the first study which investigated the relationship of
metabolic syndrome parameters with serum nesfatin-1and galanin in MetS patients
and control subjects aged between 35-75 years old. We investigated the hypothesis
that nesfatin-1 and galanin should be used as diagnostic markers for early
diagnosis of metabolic syndrome to improve patient outcomes. In our study, we
matched for age and gender to avoid any confounding that are usually encountered
in case-control studies design.
However, it should be mentioned that our study has some limitations. The
main limitation is a small sample size and recruitment of unhealthy controls
(having less than three risk factors) that might explain the absence of significant

8
difference when comparing some variables between the two groups. Other
limitation is that most patients take drugs for the treatment of different metabolic
risk factors of metabolic syndrome such as diabetes and hypertension which
influence the results.
In conclusion, our findings indicated a lower level of nesfatin-1 and a
higher level of galanin in patients with MetS when compared to the age-sex-
matched control group. Multiple regression models showed waist circumference to
be the only independent predictors of serum nesfatin-1 levels, explaining 11% of the
total variance and fasting blood glucose to be the only independent predictor of
serum galanin levels, explaining 12% of the total variance. No significant
relationship was found between nesfatin-1 and galanin. We recommend future
studies with a bigger sample size to clarify the exact role of these neuropeptides in the
metabolic syndrome process and to address the link of galanin and nesfatin-1 with
metabolic disturbances such as obesity and insulin resistance. To eliminate the
potential effect of certain medications, future studies should recruit as a control
group either healthy subjects or people who are at risk of developing MetS but not
taking any medications.

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