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Archives of Oral Biology 64 (2016) 6171

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Archives of Oral Biology


journal homepage: www.elsevier.com/locate/aob

Review

Is salivary gland function altered in noninsulin-dependent diabetes


mellitus and obesityinsulin resistance?
Jitjiroj Ittichaicharoena,b , Nipon Chattipakornb,c, Siriporn C. Chattipakorna,b,*
a

Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry Chiang Mai University, Chiang Mai, Thailand
Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
c
Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 6 October 2015
Received in revised form 23 December 2015
Accepted 5 January 2016

Salivary gland dysfunction in several systemic diseases has been shown to decrease the quality of life in
patients. In non-insulin dependent diabetes mellitus (NIDDM), inadequate salivary gland function has
been evidenced to closely associate with this abnormal glycemic control condition. Although several
studies demonstrated that NIDDM has a positive correlation with impaired salivary gland function,
including decreased salivary ow rate, some studies demonstrated contradictory ndings. Moreover, the
changes of the salivary gland function in pre-diabetic stage known as insulin resistance are still unclear.
The aim of this review is to comprehensively summarize the current evidence from in vitro,in vivo and
clinical studies regarding the relationship between NIDDM and salivary gland function, as well as the
correlation between obesity and salivary gland function. Consistent ndings as well as controversial
reports and the mechanistic insights regarding the effect of NIDDM and obesityinsulin resistance on
salivary gland function are also presented and discussed.
2016 Elsevier Ltd. All rights reserved.

Keyword:
Insulin
Obesity
Diabetes
Salivary gland function

Contents
1.

2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Search strategy and selection criteria for this review . . . . . . . . . . .
Salivary ow rate in NIDDM from clinical studies . . . . . . . . . . . . . .
1.2.
Salivary secretion in NIDDM from clinical studies . . . . . . . . . . . . . .
1.3.
Possible mechanisms of salivary gland dysfunction in NIDDM and
1.4.
studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Author contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
The salivary glands are important organs in the oral cavity and
are responsible for the secretion of saliva into the oral and

* Corresponding author at: Neurophysiology Unit, Cardiac Electrophysiology


Research and Training Center, Faculty of Medicine, Chiang Mai University
Department of Oral Biology and Diagnostic Science, Faculty of Dentistry Chiang
Mai University, Chiang Mai, 50200, Thailand.
Tel: +66 53 944 451; fax: +66 53 222 844.
E-mail addresses: scchattipakorn@gmail.com, siriporn.c@cmu.ac.th
(S.C. Chattipakorn).
http://dx.doi.org/10.1016/j.archoralbio.2016.01.002
0003-9969/ 2016 Elsevier Ltd. All rights reserved.

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learned from in vitro and in vivo69
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pharyngeal cavity. The main functions of saliva are to maintain oral


mucosa integrity, prevent oral infection and to promote appetite
(Hayward & Shea, 2009), resulting in a comfortable quality of life
(Amerongen & Veerman, 2002). The acinar cells of the salivary
glands are the secretory units that synthesize and secrete proteins,
while water and electrolytes can be pass though the acinar cells via
variety of mechanism (Proctor & Carpenter, 2007). Therefore, saliva
is mainly composed of 99% water and only a small portion of 1%
proteins. The activity of salivary glands is regulated by the
sympathetic and parasympathetic innervations (Garrett & Kidd,
1993). The activation of parasympathetic innervations in the

62

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

Table 1
The evidence of salivary ow rate in NIDDM from clinical studies.
Major ndings

Model (all human)

Age

 Obese with NIDDM


 Female: 11
 Male: 9
 Non-obese with NIDDM
 Female: 10
 Male: 10
 Healthy subject
 Female: 12
 Male: 10

38
 Fasting and unstimulated saliva No change in salivary ow rate in NIDDM had no effect on the
66 years
levels 5 min or 5 mL
all groups
salivary ow rate
 No medication details of
patients

 NIDDMa with hypoglycemic,


anti-hypertensive and anticholesterol medication
 Female: 12
 Male: 33
 Healthy subjects
 Female: 23
 Male: 13

20
 Each patient attended an out65 years
patient diabetes educational
program
 Fasting blood glucose (FBS)
 Unstimulated whole saliva and
citric acid-stimulated parotid
saliva

Men

59
 In study A, there was no change  NIDDM had no effect on stim Citric acid-stimulated parotid
77 years
saliva collection at 0, 15, 30, 45,
in salivary ow rate.
ulated salivary ow rates
60 and 120 min (interval 0.5
 In study B, there was no change
1 min)
in salivary ow rate between
 Patients in study A were not on
insulin-treated NIDDM patients
any medication
and medication-treated NIDDM
 OGTT was used to determine
patients
NIDDM and IGT in study A
 HbA1C was used to determine
treatment, either insulin or antidiabetic drug treatment, for the
patients in study B

 Study A
 Impaired glucose tolerance
(IGT): 10
 NIDDM: 10
 Control: 12
 Study B
 NIDDM patients
 Insulin treatment:15
 Anti-diabetic drugs: 9
 Control:12

Method

 NIDDM: Fasting blood sugar


(FBS) "
 No difference in unstimulated
and stimulated salivary ow
rate between all groups

Interpretation

Ref.
Aydin
(2007)

Dodds and
 NIDDM without xerogenic
medication had no inuence on Dodds
(1997)
salivary output
 Salivary ow rate was not
changed following the change of
FBS
 The glycemic control program
did not affect the salivary ow
rate

(Borg
Andersson
et al., 1998)

 NIDDM: 45
 Female: 13
 HbA1C: 9.2  2.2
 Male: 32
 HbA1C: 8.2  1.9
 Control: 86
 Female: 45
 Male: 32

5979
years

 Parasympathetic and sympa The medication use in NIDDM


and control subjects was
thetic neuropathies were sigrecorded
nicantly higher in NIDDM
 Unstimulated saliva was colpatients
lected at 1 h after meal for 5 min  No difference in unstimulated
 Parafn wax-stimulated whole
and stimulated salivary ow
saliva was collected for 5 min
rate among groups
 Deep breathing test (expiratory  An increase in the number of
to inspiratory (E/I) ratio),
drugs used daily resulted in a
 E/I  1.10 indicates parasymdecrease in both resting and
pathetic neuropathy
stimulated ow rate in the
 Orthostatic test (systolic
control subjects, but not in
blood pressure change)
NIDDM patients
 SBP decreased more than
30 mmHg: indicates sympathetic neuropathy

 The resting and stimulated saliva secretions were not different between the NIDDM
patients and the control subjects
 NIDDM did not seem to affect
salivary ow

Meurman
et al.,
(1998)

 Non-NIDDM: 38
 Female: 20
 Male: 18
 NIDDM:35
 Female: 17
 Male: 18

43
45  13
years

 Unstimulated whole saliva for


10 min
 Flow rate (mL/min)
 Salivary resistin (ng/mL)

 No difference in salivary ow
rate between groups

NIDDM had no effect on the


salivary ow rate

Yin et al.
(2012)

 OGTT, HbA1c
 Unstimulated whole saliva collection
 Unstimulated parotid saliva
collection using Carlson-Crittenden cup
 Stimulated parotid saliva collection
 All current medication use were
recorded

 No differences in salivary ow
rate between well-controlled
NIDDM and non-NIDDM.
 Poor-controlled DM:
 # salivary ow rate
 Taking xerostomia medication
in well-controlled and poorcontrolled NIDDM: # salivary
ow rate

 Poorly-controlled DM could be Chavez


et al.,
associated with salivary dysfunction
(2000)
 Xerogenic medication accelerated a decrease in salivary ow
rate in NIDDM

54
 Non-NIDDM
90 years
 Female: 14
 Male: 9
 Well-controlled NIDDM
 Female: 3
 Male: 8
 Poor-controlled NIDDM (HbA1C
> 9%)
 Female: 10
 Male: 8

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

63

Table 1 (Continued)
Model (all human)

Age

Method

Major ndings

Interpretation

 Healthy: 24
 Female: 13
 Male: 11
 NIDDM: 24
 Female: 13
 Male: 11

58.8
70.8
years

 Citric-acid stimulated salivary


ow rate
 Parotid gland (PS)
 Submandibular and sublingual gland (SS)
 Total protein
 Parotid gland (PS)
 Submandibular and sublingual gland (SS)

 Salivary ow rate (PS)


 Parotid gland: no change
 Submandibular and sublingual gland: #

 Diabetic patients showed a re- Izumi et al.


duction in salivary gland pro(2015)
duction and secretion in specic
salivary glands

 Group 1: NIDDM with xerostomia


 Female: 13
 Male: 23
 Group 2: NIDDM without xerostomia
 Female: 13
 Male: 23
 Control Group: no NIDDM
 Female: 1
 Male:23

56 years  Known xerogenic drugs were


 Group 1 had signicantly lower  Impaired salivary production
stopped 1 week before study.
UR values and ER values at the
and excretion were found in
 Fasting salivary uptake (UR)
1st and 15th minute, when
NIDDM patients with xeroswhich represents the function of
compared with controls and
tomic symptoms
salivary production
NIDDM patients without xeros Fasting salivary excretion ratio
tomia
(ER), which represents the
function of salivary excretion
 measured by scintigraphy

Ref.

Lin et al.
(2002)

All NIDDM patients without xerogenic medication.

salivary glands through the muscarinic acetylcholine receptors,


particularly M1 and M3 receptors causes uid secretion (Nakamura et al., 2004). On the other hand, the sympathetic stimulation
of salivary glands via b-adrenergic receptors leads to the release of
salivary proteins (Proctor & Carpenter, 2007). It has been
demonstrated that levels of alpha-amylase in saliva represents
the sympathetic activity of salivary glands (Enberg, Alho,
Loimaranta, & Lenander-Lumikari, 2001). The activation of
parasympathetic nerves results in a high salivary ow rate with
low salivary proteins. However, sympathetic activation leads to
secretion of a high level of salivary proteins without the reduction
in salivary ow rate (Carpenter, 2013). Therefore, salivary ow rate
is the direct result of parasympathetic function.
Non-insulin dependent diabetes mellitus (NIDDM) (also known
as Type 2 Diabetes Mellitus) is a chronic metabolic disorder,
characterized by insulin resistance, hyperglycemia, as well as
Langerhans islets beta-cells dysfunction (DeFronzo, 2004a, 2004b).
NIDDM causes complications in several organs, including salivary
glands (Al-Rawi, 2011; Desai & Mathews, 2014). Xerostomia is one
of the most common complaints in NIDDM patients (Albert et al.,
2012; Ali & Kunzel, 2011; Chomkhakhai, Thanakun, Khovidhunkit,
Khovidhunkit, & Thaweboon, 2009; Collin, Niskanen, et al., 2000;
Collin, Sorsa et al., 2000). Several clinical studies demonstrated
that NIDDM subjects had a reduction in salivary ow rate (Chavez,
Taylor, Borrell, & Ship, 2000; Izumi et al., 2015; Lin, Sun, Kao, & Lee,
2002). However, some studies showed contradictive ndings
(Aydin, 2007; Borg Andersson, Birkhed, Berntorp, Lindgarde, &
Matsson, 1998; Hartman et al., 2015; Meurman et al., 1998; Yin,
Gao, Yang, Xu, & Li, 2012). Currently, it is known that obesity is a
risk factor of developing insulin resistance and NIDDM (Arner &
Rydn, 2015; Esser, Legrand-Poels, Piette, Scheen, & Paquot, 2014;
Guo, 2014; Hardy, Czech, & Corvera, 2012; Leahy, 2005;
Vollenweider, von Eckardstein, & Widmann, 2015; Wellen &
Hotamisligil, 2005). Excess free fatty acids (FFAs) from an obese
condition has been shown to impair insulin signaling through both
cell autonomous mechanisms and inammatory process (Hardy,
Czech, & Corvera, 2012). It has been shown that obesityinsulin
resistance could cause the salivary gland dysfunction (Mozaffari
et al., 2011; Zalewska et al., 2014).
Despite these previous reports, the relationships between
NIDDM, obesityinsulin resistance, and salivary gland function are

still not clearly understood. In this review, the current evidence of


the available reports regarding the relationship between NIDDM,
obesityinsulin resistance and the alterations of the salivary glands
are comprehensively summarized. Controversial reports as well as
the mechanistic insights regarding the roles of NIDDM and obesity
on salivary gland function are also presented and discussed.
1.1. Search strategy and selection criteria for this review
Relevant publications in the PubMed database published before
August, 2015 were identied by using search terms NIDDM or
type 2 diabetes and salivary gland and obesityinsulin resistance
and salivary gland. Only articles published in English were
reviewed.
1.2. Salivary ow rate in NIDDM from clinical studies
NIDDM has been shown to lead to the development of systemic
inammation and that this inammation subsequently initiates
micro-angiopathy, macro-angiopathy and neuropathy in several
vital organs (Garcia et al., 2010; Lee et al., 2012; Rolo & Palmeira,
2006). The effects of NIDDM on the salivary gland function have
been widely studied; however these ndings are still controversial.
The salivary gland function has been evaluated by several methods,
including the measurement of salivary ow rate, alpha-amylase
activity, salivary cortisol levels, salivary adipokine levels and other
salivary inammatory biomarkers (Desai & Mathews, 2014).
However, the most common indicator for salivary gland function
is to measure salivary ow rate.
In NIDMM subjects, it has been shown that the salivary ow
rate in both adults and children was not signicantly different from
the normal subject group (Aydin, 2007; Borg Andersson et al.,
1998; Chavez, Borrell, Taylor, & Ship, 2001; Dodds, & Dodds, 1997;
Hartman et al., 2015; Meurman et al., 1998; Yin et al., 2012). These
studies measured the salivary ow rate by performing either
unstimulated saliva collection (Aydin, 2007; Borg Andersson et al.,
1998; Chavez et al., 2001; Dodds, & Dodds, 1997; Hartman et al.,
2015; Yin et al., 2012) or stimulated saliva collection (Borg
Andersson et al., 1998; Dodds, & Dodds, 1997; Meurman et al.,
1998). Since whole unstimulated salivary ow rate indicates the
function of the submandibular and sublingual glands which

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J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

Table 2
Evidence of salivary secretions in NIDDM from clinical studies.
Major ndings

Model

Age

 Obese with NIDDM (OD)


 Female: 11
 Male: 9
 Non-obese subjects with
NIDDM (NOD)
 Female: 10
 Male: 10
 Healthy subjects
 Female: 12
 Male: 10

 OD and ND subjects
38
 No medication
66 years  Plasma and saliva ghrelin levels
 Salivary glucose: "
were measured
 Total protein: "
 Plasma glucose levels were
 a-amylase activity: "
measured
 Total salivary protein was measured
 Amylase activity was measured

 Glucose was released into saliva Aydin


(2007)
of T2DM subjects
 Sympathetic stimulation was
increased regarding to the increase of a-amylase activity
 Parasympathetic stimulation
did not change

 NIDDMa with hypoglycemic,


anti-hypertensive and anticholesterol medication
 Female: 12
 Male: 33
 Healthy subjects
 Female: 23
 Male: 13

20
 NIDDM after glycemic control
 Each patient attended an out65 years
patient diabetes educational
program
 Amylase activity: #
program.
 No differences in salivary pro Fasting blood glucose (FBG)
 Unstimulated whole saliva and
teins among all groups
citric acid-stimulated parotid
saliva
 Parotid salivary protein, including proline-rich proteins (PRPs),
histatins, statherin and amylase
 Amylase activity compared between
 DM and control
 DM with glycemic control and
DM without glycemic control

 Amylase activity showed a pos- Dodds &


itive correlation with blood
Dodds
(1997)
glucose level
 The salivary proteins were not
changed along with the glycemic condition

Men

 Salivary glucose concentration


59
 Study A:
 Citric acid-stimulated parotid
77 years
saliva collection at 0, 15, 30, 45,
 IGT and NIDDM: salivary gluwas varied according to blood
60 and 120 min (interval 0.5
cose " compared with control
glucose concentration
1 min)
 The salivary glucose between
 Patients in study A were not on
IGT and NIDDM were not
any medication
signicantly different
 OGTT was used to determine
 Study B:
NIDDM and IGT in study A
 Both diabetic groups: salivary
 HbA1C was used to determine
glucose " compared with
treatment, either insulin or anticontrol
 The salivary glucose levels
diabetic drug treatment, for the
patients in study B
between IGT and NIDDM were
not signicantly different
 Both study A and study B
 Blood glucose: NIDDM > IGT >
Normal
 A positive correlation between salivary glucose and
blood glucose concentration
was found

 Study A
 Impaired glucose tolerance
(IGT): 10
 NIDDM: 10
 Control: 12
 Study B
 NIDDM patients
 Insulin treatment:15
 Anti-diabetic drugs: 9
 Control:12

Method

Interpretation

 Healthy: 24
 Female: 13
 Male: 11
 NIDDM: 24
 Female: 13
 Male: 11

58.8
70.8
years

 Citric-acid stimulated salivary


ow rate
 Parotid gland (PS)
 Submandibular and sublingual gland (SS)
 Total protein
 Parotid gland (PS)
 Submandibular and sublingual gland (SS)

 NIDDM: 45
 Female: 13
 Male: 32
 Control: 86
 Female: 45
 Male: 32

5979
years

 The history of medication use in  Salivary composition showed no  The resting and stimulated saNIDDM and control subject was
difference between groups.
liva secretions were not differrecord
 There were no statistically sigent between the NIDDM
 Unstimulated saliva was colnicant differences in the conpatients and the control sublected at 1 h after meal for 5 min
centrations of salivary secretion
jects
 Stimulated salivary secretion
 Parafn wax-stimulated whole
between well-glycemic consaliva was collected for 5 min
trolled patients and poor- glycan reect the quality of para Biochemical analyses:
cemic controlled patients (using
sympathetic and sympathetic
 Lysozyme
the median of HbA1c values to
activity
 Amylase
classify)
 Total protein, albumin, Ig (G,
M and A)
 Urea

 FBG of diabetic patient was


 NIDDM patients showed a resignicantly higher than control
duction in salivary gland pro Parotid gland
duction and secretion
 Total protein: no change
 Submandibular and sublingual
gland
 Total protein: #

Ref.

Borg
Andersson
et al.
(1998)

Izumi et al.
(2015)

Meurman
et al.
(1998)

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

65

Table 2 (Continued)
Model

Age

Method

Major ndings

Interpretation

 Control
 Female: 30
 Male: 30
 NIDDM
 Female: 30
 Male: 30

Adult

 Fasted for 2 h, unstimulated


saliva collection,
 colorimetric assay for
 Salivary exoglycosidases: Nacetyl-b-glucosaminidase
(HEX) activity, showing impaired epithelial membrane
structure
 b-D-glucuronidase activity
(GLU), showing degradation
of proteoglycans, representing salivary dysfunction

 NIDDM
 HEX A: activity and output "
 HEX B: activity and output "
 GLU: activity and output "

 There were functional changes Zalewska


et al.
in the salivary gland of DM
patients
(2013)
 There was a degeneration of the
salivary glands of NIDDM
patients
 There was local inammation in
the salivary glands of DM
patients

 Non-NIDDM: 38
 Female: 20
 Male: 18
 NIDDM:35
 Female: 17
 Male: 18

43
45  13
years

 Unstimulated whole saliva for


10 min
 Flow rate (mL/min)
 resistin (ng/mL)
 Unstimulated whole saliva

 Salivary resistin: "


 Salivary resistin can reect
 Salivary and serum resistin were
NIDDM condition
not affected by eating
 There was a positive correlation
between salivary and serum
resistin

Human parotid glands

42
Immunocytochemistry:
68 years immunogold labeling human
amylase and visualization with
transmission electron microscope
(TEM).

 NIDDM: 5
 Control:11

NIDDM patients:
 Controlled NIDDM: 27
 Uncontrolled NIDDM: 26
 Healthy group: 40

Ref.

Yin et al.
(2012)

 NIDDM showed only the in Changes in salivary gland mor- Piras et al.
crease of secretory granules, but
phology were found in NIDDM (2010)
the deposition of anti a-amy NIDDM showed only the inlase- labelled gold particle was
crease of secretory granules, but
not different when compared
the expression of a-amylase
with the control
was not different when com No signicant difference in the
pared with the control
number of lysosomes or lipid
droplets

33
 NIDDM:
 Unstimulated whole saliva
84 years  Chemicals: glucose, protein and
 high UA, GSH and total proUric acid (UA) assays
tein
 low AOA and CAT
 Salivary enzymatic antioxidants: catalase (CAT), superox-  Strong positive association beide dismutase (SOD)
tween
 salivary glucose and blood
 Salivary non-enzymatic parameters: antioxidant activity
glucose
 salivary glucose and GSH
(AOA), glutathione (GSH), UA,
glucose and total protein
 salivary glucose and UA

 Saliva can be used for the


diagnosis and the management
of DM

Mussavira
et al.
(2015)

All NIDDM patients without xerogenic medication.

maintain oral moisture during resting period (Falcao, da Mota,


Pires, & Bezerra, 2013), and that the salivary ow rate during the
resting period is commonly regulated by the parasympathetic
nervous system (Carpenter, 2013; Proctor & Carpenter, 2007),
those ndings suggested that the parasympathetic activity in
salivary glands of NIDDM patients has not been affected. This
suggestion has been supported by the study of Meurman and
colleagues who demonstrated that no signicant difference in
salivary ow rate or parasympathetic activity (measured by the
expiratory to inspiratory (E/I) ratio) was seen between NIDDM
and control groups (Meurman et al., 1998). In addition, the salivary
ow rate of the NIDDM subjects had no correlation with fasting
plasma glucose levels (Dodds & Dodds, 1997; Meurman et al.,
1998). Although the salivary ow rate did not change in NIDDM
patients, the amylase activity, which represents sympathetic
activity in salivary glands, signicantly increased (Aydin, 2007;
Dodds & Dodds, 1997). These ndings indicate that the diabetic
condition alters the salivary gland activity, particularly sympathetic activity, without changes in salivary ow rate. Interestingly,
these patients did not have any record of using xerogenic
medications.
Despite those reports, inconsistent ndings exist. Several
clinical studies demonstrated the reduction of salivary ow rate
in diabetes (Chavez et al., 2000; Izumi et al., 2015; Lin et al., 2002).

For example, the study of Chavez and colleagues demonstrated


that the poorly glycemic controlled NIDDM patients (HbA1C >9%)
had lower unstimulated salivary ow rate, compared with wellcontrolled NIDDM patients and the control group. In addition,
unstimulated salivary ow rate was signicantly reduced in poorcontrolled NIDDM patients and well-controlled NIDDM patients
who were taking xerogenic medications, when compared with the
non-NIDDM subjects (Chavez et al., 2000). Moreover, Izumi et al.
(2015) showed that the stimulated salivary ow rate and total
proteins produced by the parotid gland showed no rate of change
between diabetic patients and healthy control subjects, whilst the
stimulated salivary ow rate and total proteins collected from
submandibular and sublingual glands of diabetic patients showed
a signicant decrease, when compared with that of healthy control
subjects. Furthermore, Lin and colleagues demonstrated that
impaired salivary function was found in NIDDM patients with
xerostomia by the reduction of salivary secretory rate and
excretory rate (Lin et al., 2002). The reduction of salivary ow
rate in NIDDM patients from these previous studies (Chavez et al.,
2000; Izumi et al., 2015; Lin et al., 2002) may be associated with
the severity of NIDDM condition, the xerogenic medication, and
the specic salivary gland where saliva was collected from. The
comprehensive summary of reports on salivary ow rate in NIDDM
patients is shown in Table 1.

66

Table 3
The evidence of salivary ow rate and salivary secretions in obesityinsulin resistance from clinical studies.
Age

Method

Major ndings

Interpretation

Ref.

Human

50 years old

 Screening tests for Cushings syndrome:


 Dexamethasone suppression test (DST)
 Measurements of 24-h urine creatinine
and cortisol excretion (UFC)
 Measurement of bedtime salivary cortisol
 Analyzed all metabolic parameters

Salivary cortisol tended to rise as BMI


increased and correlated with an increase in
waist circumference

Obese people had an increase in salivary


cortisol levels

Abraham,
Rubino,
Sinaii,
Ramsey
and
Nieman,
(2013)

11
years

 3 mL Unstimulated whole saliva collection


 Flow rate (mL/h)
 Total protein (mg/dL)

 No differences in salivary ow rate among


groups
 No differences in total salivary protein
concentration among groups

 BMI did not affect salivary ow rate and


total salivary protein concentration

Goodson
et al.
(2014)

11
years

 3 mL Unstimulated whole saliva collection


 Insulin
 C-reactive protein (CRP)
 Adiponectin
 Leptin

 Obese:
 Insulin "
 CRP "
 Adiponectin "
 Leptin "

 Obese children tended to be metabolic


syndrome

Goodson
et al. (2014)

11
years

 Sjgrens syndrome related cytokines


 IL-4
 IL-10
 L12p70
 IL-17A
 IFN-g
 NIDDM related cytokines
 Insulin
 Ghrelin
 Myeloperoxidase (MPO)
 Vascular endothelial growth factor
(VEGF)

 OC: " CRP and IL-6, leptin


 NC: " CRP, IL-6, IL-10, IL-1b, MM-9 and
resistin
 OH: " IL-10 and adiponectin

 Many cytokines could be detected in saliva Goodson


 Those cytokines could be used as screening et al. (2014)
or adjunctive tool

 Obese (n = 369)
 Healthy (n = 60)

Children (n = 213 from total of 8319)


Body Mass Index (BMI) z-score was used to
classied the subjects into





Normal
Underweight
Overweight
Obese

Children (n = 8319)
Body Mass Index (BMI) z-score was used to
classied the subjects into





Normal
Underweight
Overweight
Obese

Children (n = 744 from total of 8319)









Obese healthy group (OH): 186


Obese with high insulin (OI): 186
Obese with high CRP (OC): 186
Non-Obese with high CRP (NC): 186
Non-Obese with high insulin (NI):186
Non-obese healthy group (NH): 186

Human





Normal weight: 30
Underweight: 2
Overweight: 12
Obese: 21

10.6  0.2 years  Salivary ow rate


 Salivary glucose: glucose oxidase method
using uorescent emission
 Plasma glucose analysis

 Blood pressure and fasting plasma glucose  Obesity had no effect on salivary ow rate
 Salivary glucose level could be a useful
showed no difference among groups
marker as a diagnostic screening tool for
 Salivary ow rate and salivary glucose
high plasma glucose levels in children
showed no difference among groups
 Salivary ow rate did not correlate with
fasting plasma glucose levels
 There was a signicant association between
plasma and salivary glucose levels

Hartman
et al. (2015)

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

Model

Metabolic syndrome
Female (5)
Male (7)
Healthy
Female (14)
Male (20)







Human

2070 years

 Blood pressure
 Waist circumference
 Fasting 12 h then collection of:
 Blood glucose
 Total cholesterol
 Triglycerides
 HDL, LDL, insulin
 HOMA-IR
 Unstimulated saliva collection (1112 pm)
 Salivary cortisol

There was a positive correlation between


Midnight salivary cortisol concentrations
midnight salivary cortisol and the metabolic
were signicantly and positively correlated
with abdominal circumference, fasting blood syndrome (MetS)
glucose and HOMA-IR

Jang, Lee,
Kim, Kim
and Song,
(2012)

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

67

1.3. Salivary secretion in NIDDM from clinical studies


The alterations of salivary secretion in NIDDM have been
demonstrated. It has been shown that increased amylase activity
was found in salivary glands of NIDDM patients (Aydin, 2007;
Dodds & Dodds, 1997). In a report by Piras and colleagues, they
found no signicant difference in amylase expression of salivary
gland isolated from NIDDM patients, when compared with that of
the control group (Piras, Hand, Mednieks, & Piludu, 2010).
However, amylase activity was not investigated in that study.
NIDDM patients also showed higher levels of salivary and serum
resistin (a peptide hormone) and pro-inammatory cytokines
which are produced by adipocytes and macrophages (Yin et al.,
2012), than non-NIDDM patients. Moreover, it has been shown that
there was an increase in salivary pro-inammatory cytokines,
including interleukins-1b, -6 and -8 (IL-1b, -6 and -8), tumor
necrosis factor-a (TNF-a) and matrix metalloproteinases (MMP)8 and -9 in NIDDM patients (Collin, Niskanen, et al., 2000; Collin,
Sorsa et al., 2000; Rathnayake et al., 2013). The positive correlation
of glucose levels between blood and saliva in impaired glucose
tolerance subjects and NIDDM subjects suggested the potential
role of plasma glucose on salivary gland function (Aydin, 2007;
Borg Andersson et al., 1998; Garcia et al., 2010; Yin et al., 2012). In
addition, Zalewska et al. (2013) showed that the salivary glands of
NIDDM patients exhibited greater changes in function and
morphology than those of control, by increasing salivary Nacetyl-b-glucosaminidase, representing impaired epithelial membrane structure, and salivary b-D-glucuronidase activity, representing the degradation of proteoglycans). All of these ndings
suggest that increased sympathetic activity, increased inammation, impaired insulin signaling, and the degradation of extracellular matrix occurs in salivary glands of NIDDM subjects. The
comprehensive summary of reports on salivary secretions in
NIDDM patients is shown in Table 2.
All of these clinical studies indicate that NIDDM can lead to
alterations in the salivary gland with or without a reduction in
salivary ow rate. The factors inuencing the salivary ow rate in
NIDDM could be dependent on the severity of the diabetic
condition, the use of xerogenic medication and the specic
collected salivary gland.
Salivary ow rate and salivary secretions in obesityinsulin
resistance or pre-diabetic condition from clinical studies
Evidence demonstrated that obesityinsulin resistance does
not have an effect on salivary ow rate (Borg Andersson et al., 1998;
Hartman et al., 2015). Impaired secretion of saliva is indicated
using the unstimulated salivary ow rate 0.2 mL/min in men and
0.18 mL/min in women (Chavez et al., 2000). In subjects with
impaired glucose tolerance (IGT or obesityinsulin resistance), it
has been shown that the unstimulated salivary ow rates were not
signicantly different from the control group (Borg Andersson
et al., 1998). Goodson and colleagues in 2014 evaluated twenty
biomarkers in fasting saliva samples taken from 11-year old
children who had been designated as underweight, normal healthy
weight, overweight and obese subjects. The study found that
salivary C-reactive protein (CRP), insulin and leptin levels of obese
subjects signicantly increased, when compared with those of
normal healthy weight subjects. However, salivary adiponectin
level in obese children signicantly showed a decrease, when
compared with levels in normal healthy weight subjects (Goodson
et al., 2014). Alterations in those biomarkers in plasma could be the
indicators of the development of the metabolic syndrome (MetS)
(Oh et al., 2014). In addition, Goodson's study showed that neither
total salivary protein level nor salivary ow rate were signicantly
different between body weight groups. The results of Goodsons
study suggested that obesity did not affect salivary protein levels or
salivary ow rate in this population, but the alteration of salivary

68

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

Table 4
The evidence of salivary gland alterations in the NIDDM and obesityinsulin resistance from in vivo studies.
Model

Age

Female mice (each group


n = 6)

20 weeks

Experimental
period

 Normal
 C57BL/6
 BALB/c
 Non-obese diabetic mice
(NOD mice):
 NOD/Lt
 NOD-scid
 NOD.B10.H

Methods

Major ndings

Interpretation

Ref.

 Stimulated saliva collection  TGFb1 " in NOD mice both  The salivary glands in dia- Yamachika
for 10 min: stimulated by
in saliva and lysated salibetic mice were destroyed et al.
either pilocarpine (0.5 mg/
vary gland
via increased proteolytic
(2000)
100 g) or isoproterenol
 MMP inhibitor can reduce
activities inside the salivary
(0.2 mg/100 g)
the expression of TGFb1
glands
 Protein analysis in saliva
 Decorin and biglycan were
and salivary glands by
degraded in the saliva of
detecting MMP, proteoglydiabetic mice
cans and TGFb1
 Detection of salivary decorin and biglycan

Decorin and biglycan maintain ECM structure in the


salivary gland and can be
destroyed by MMP
Male obese Zucker rats
 Lean (LZR) (n = 7-9)
 Obese (OZR)
 OZR- fed Cr 5 mg/kg (n = 7
9)
 OZR- fed Cr 10 mg/kg (n = 7
9)

6 weeks

 Fasting plasma glucose


6
Months after
 Insulin sensitivity by
chromium
QUICKI
administration  Western blot: NF-kB,
phospho-NF-kB, VCAM1 and ICAM-1 in salivary
glands

(Cr: Chromium picolinate for


glycemic control)

Male Wistar rats


 Normal diet (C): n = 9
 High fat diet (HFD): n = 9

5
Weeks of
dietary
program

Lacrimal gland (LG) and


submandibular gland (SG)
of male Wistar rats
 Young: 2 months old
 Old: 20 months old

Female mice
 NOD: n = 9
 BALB/c: n = 9

24 weeks 24 weeks

 OZR:
 " Plasma insulin levels
 " QUICKI
 " Lipid droplet
 " p-NF-kB/NF-kB ratio
 " ICAM-1
 OZR-fed Cr 10: showed a
benign expansion of the
secretory acinar units
 Histological features of
salivary glands: OZR similar
to LZR

Obesity led to an increase in


the inammation of the
salivary glands without
signicant morphological
changes

Mozaffari
et al. (2011)

 HFD-fed rats developed the


 Blood analysis: insulin,
glucose and fatty acid
insulin resistant condition
methyl esters
 HFD:
 Antioxidant prole of pa # SG peroxidase activity
rotid gland (PG) and sub # PG peroxidase activity
mandibular glands (SG)
 # total PG peroxidase
 Specic activity of salivary peroxidase
 Superoxide dismutase 2
(SOD2)
 CAT
 Uric acid (UA)
 Total antioxidant salivary
status (TAS)

 Obesityinsulin resistance Zalewska


led to the decrease of anti- et al.
oxidants in salivary glands (2014)
 Parotid and submandibular
glands responded differently to the insulin resistant
conditions
 The parotid glands seemed
to be more affected following the insulin resistant
condition
 The main source of antioxidants was in the parotid
glands

 Insulin tolerance test after


injection of 100 mL of
10 mM insulin
 Tissue collection: 3 min after injection of 100 mL of
10 mM insulin into the inferior vena cava
 Immunoblotting: IR, Shc
and STAT-1

 Aging induced a reduction Rocha et al.


in tyrosine phosphorylation (2003)
of insulin receptors in the
LG and SG, suggesting insulin resistance in the exocrine glands of aging rats

 Old rats: euglycemia and


hyperinsulinemia
 Old rats LG:
 # p-IR
 Old rats SG:
 # p-IR
 # p-STAT-1

 Pilocarpine-stimulated sal-  24-week-old NOD mice


ivary ow rate for 10 min
 Salivary ow rate #
 Evaluation of submandibu IL-4 "
lar salivary gland inam Granulocytemacromation by the number of
phage colony-stimulatmononuclear cells in H&Eing factor
stained slides and immu (GM-CSF) "
nohistochemistry analysis
 TNF-a "
(CD4+ T-cell).
 IL-5 #
 Salivary cytokine levels
 IFN-g: not detectable
 Serum cytokines levels

 The longer duration of insulin-resistant conditions


led to a lower salivary ow
rate and an increase in
salivary gland inammation

Jonsson,
Delaleu,
Brokstad,
Berggreen
and
Skarstein,
(2006)

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

biomarkers, including CRP, insulin, leptin and adiponectin, instead


of plasma biomarkers, may be useful indicators of the occurrence
of MetS in children (Goodson et al., 2014). In addition, Hartman and
colleagues demonstrated that salivary glucose levels may be useful
for the screening of high fasting plasma glucose levels in children
(Hartman et al., 2015). The recent study also showed that
signicant alterations in salivary adipocytokines were observed
in overweight and obese children, when compared with normalweight children (Shi et al., 2015). All of these ndings suggested
that salivary biomarkers in obese subjects could be useful tools to
predict the development or progression of MetS, particularly in
children.
An increase in salivary cytokines, including IFN-g, TNF-a, IL-1,
IL-4, IL-10, IL-12, and IL-17, have been shown to be associated with
oral dryness in primary and secondary Sjgren's syndrome
(Furuzawa-Carballeda et al., 2014; Kang, Lee, Hyon, Yun, & Song,
2011; von Bltzingslwen et al., 2007). These ndings suggested
that an increase in these particular salivary cytokines could be a
predictor of oral dryness.
Despite the unaltered salivary ow rate in obesityinsulin
resistance, both studies showed an increase in saliva glucose levels
(Borg Andersson et al., 1998; Hartman et al., 2015). These ndings
suggest that impaired insulin signaling might occur in the salivary
glands of obesityinsulin resistance.
In obese subjects, it has been demonstrated that saliva cortisol
levels were signicantly increased, compared to normal subjects
(Abraham, Rubino, Sinaii, Ramsey, & Nieman, 2013; Jang, Lee, Kim,
Kim, & Song, 2012). Several studies showed that there was an
increased level of salivary pro-inammatory cytokines in insulinresistant obese patients, including tumor necrosis factor-alpha

69

(TNF-a), interleukin-6 (IL-6), interferon gamma (IFN-g), macrophage inammatory protein-1 beta (MIP-1b) (Desai & Mathews,
2014) as well as an increased level of oxidative stress (Al-Rawi,
2011). These ndings suggest that obesityinsulin resistance
subjects developed impaired insulin sensitivity in the salivary
gland, increased level of salivary oxidative stress, and increased
level of inammation, possibly leading to salivary gland dysfunction. The comprehensive summary of reports on salivary gland
dysfunction in obesityinsulin resistance is shown in Table 3.
1.4. Possible mechanisms of salivary gland dysfunction in NIDDM and
obesityinsulin resistance: lesson learned from in vitro and in vivo
studies
Although alterations in salivary gland activity with or without a
change in salivary ow rate in NIDDM and obesityinsulin
resistance have been reported in clinical studies, the underlying
mechanisms responsible for these alterations have been documented from basic studies. Findings from in vivo studies supported
the clinical ndings from NIDDM and obesityinsulin resistance
for the occurrence of salivary gland dysfunction. NIDDM rats have
been shown to develop the degradation of salivary glands through
an increase in salivary decorin and biglycan levels (Yamachika,
Brayer, Oxford, Peck, & Humphreys-Beher, 2000). Decorin and
biglycan are parts of the extracellular matrix structure in the
salivary gland, and degradation can be caused by matrix metalloproteinases (MMPs) (Yamachika et al., 1998). An increase in
salivary decorin and biglycan represents the degradation of
salivary glands (Yamachika et al., 2000). In addition, Masago
and colleagues demonstrated the elevation of proapoptotic Bax

Fig. 1. The possible mechanisms of salivary gland dysfunction in NIDDM and obesityinsulin resistance.

70

J. Ittichaicharoen et al. / Archives of Oral Biology 64 (2016) 6171

and caspase 3 activation in glandular parenchyma of non-obese


diabetic mice (Masago et al., 2001). Thus, the degradation of
salivary gland in NIDDM and the obese-insulin resistant condition
could be due to the role of apoptosis in glandular parenchyma. It
has been shown that increased inammation correlates with TGFb1 expression (Imai, Hiramatsu, Fukushima, Pierschbacher, &
Okada, 1997). In addition, decorin and biglycan are known as the
reservoirs of TGF-b1 (Cs-Szabo, Roughley, Plaas, & Glant, 1995).
These ndings suggest that salivary gland inammation as well as
the degradation of the salivary gland develops in NIDDM. The
excessive inammation and degradation of salivary gland in
NIDDM could be responsible for salivary gland dysfunction,
resulting in the decrease of salivary ow rate. However, it is
possible that less severe salivary gland dysfunction might not alter
the salivary ow rate in NIDDM, as observed in several clinical
studies (Aydin, 2007; Borg Andersson et al., 1998; Chavez et al.,
2001; Dodds, & Dodds, 1997; Hartman et al., 2015; Meurman et al.,
1998; Yin et al., 2012).
Increased free fatty acid levels in the plasma are commonly
found in obesityinsulin resistance (DeFronzo, 2004a, 2004b). In
human parotid/submandibular gland epithelial cell lines, the
application of saturated fatty acids (SFAs) on them can lead to
increased IL-6 secretion, cell apoptosis and the degradation of
salivary gland cells (Shikama et al., 2013). These ndings suggested
that high levels of free fatty acid could cause salivary glands
damage. In addition, several in vivo studies support these ndings.
Zalewska et al. (2014) found that there was a reduction in antioxidants levels, by measuring peroxidase activity, in both the
submandibular and parotid glands in insulin-resistant obese rats
induced by high-fat diet, when compared with the control group.
Interestingly, the peroxidase enzyme activity in the submandibular
gland was still higher than that in the parotid gland of the high-fat
diet-fed rats. These ndings suggest that obesityinsulin resistance could lead to increased oxidative stress in the parotid glands,
rather the submandibular glands. In obese Zucker rats, an increase
in inammation, demonstrated by increased NFkB phosphorylation and ICAM-1 levels, was demonstrated in their salivary glands
(Mozaffari et al., 2011). However, no histological changes in the
salivary glands of these obese Zucker rats were found. A possible
explanation for this could be that the level of inammation in the
salivary glands of obese Zucker rats might not be high enough to
cause morphological changes. Rocha and colleagues also demonstrated that aged rats (20 months old) developed insulin
resistance, characterized by hyperinsulinemia with euglycemia,
and that the reduction of insulin receptor phosphorylation in
salivary glands also developed in these aged rats (Rocha, Carvalho,
Saad, & Velloso, 2003).
All of these ndings suggest that obesityinsulin resistance
leads to increased oxidative stress, inammation and decreased
insulin sensitivity in salivary gland, possibly leading to further
degradation of salivary glands. The comprehensive summary of
reports on salivary gland dysfunction in obesityinsulin resistance
and NIDDM from basic research is shown in Table 4.
2. Conclusion
Although the alterations of salivary ow rate in NIDDM have
been demonstrated previously (Chavez et al., 2000; Izumi et al.,
2015; Lin et al., 2002), several studies showed contradictory
ndings (Aydin, 2007; Borg Andersson et al., 1998; Chavez et al.,
2001; Dodds, & Dodds, 1997; Hartman et al., 2015; Meurman
et al., 1998; Yin et al., 2012). These inconsistent ndings could be
due to the difference in the severity of the diabetic condition, the
use of xerogenic medications and the different methods for saliva
collection in those studies. Changes in salivary gland activity with
or without an alteration in salivary ow rate can be found in

NIDDM and obesityinsulin resistance. The underlying mechanisms of salivary gland dysfunction could be due to hyperglycemia, hyperinsulinemia and dyslipidemia following NIDDM
and obesityinsulin resistance, resulting in increased oxidative
stress, inammation, increased sympathetic activity, and impaired insulin signaling in the salivary gland. High levels of
oxidative stress, inammation and insulin resistance in the
salivary gland can lead to the degradation of the salivary gland. In
addition, this degradation in NIDDM and obese patients can cause
a reduction in salivary ow rate. These potential mechanisms
responsible for salivary gland dysfunction in NIDDM and obesity
insulin resistance are summarized in Fig. 1. Since the development of salivary gland dysfunction could happen as early as the
development of obesityinsulin resistance (i.e. before the occurrence of NIDDM), future studies are needed and a suggested focus
is on the protection of salivary gland function in obesityinsulin
resistance.
Conict of interest
The authors declare that there is no conict of interest.
Author contribution
JI co-designed the study, analyzed the data and wrote the
manuscript. NC co-designed the study, and wrote the manuscript.
SCC co-designed the study, analyzed the data and wrote the
manuscript. All authors have read and approved the nal article.
Acknowledgments
This work was supported by grants from the Thailand Research
Fund TRF-BRG5780016 (SC), a CMU 50th Anniversary grant by
Chiang Mai University (JI and SC), National Research Council of
Thailand (SC), a NSTDA Research Chair Grant from the National
Science and Technology Development Agency Thailand (NC), and
the Chiang Mai University Excellent Center Award (NC).
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