Beruflich Dokumente
Kultur Dokumente
Review
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
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obesityinsulin
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resistance: lesson
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. . . . . . . . . . . . . . . . . . . . . . . . . . 63
. . . . . . . . . . . . . . . . . . . . . . . . . . 63
. . . . . . . . . . . . . . . . . . . . . . . . . . 67
learned from in vitro and in vivo69
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62
Table 1
The evidence of salivary ow rate in NIDDM from clinical studies.
Major ndings
Age
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
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
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
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
No difference in salivary ow
rate between groups
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
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
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
Ref.
Lin et al.
(2002)
64
Table 2
Evidence of salivary secretions in NIDDM from clinical studies.
Major ndings
Model
Age
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
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
Men
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
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
Ref.
Borg
Andersson
et al.
(1998)
Izumi et al.
(2015)
Meurman
et al.
(1998)
65
Table 2 (Continued)
Model
Age
Method
Major ndings
Interpretation
Control
Female: 30
Male: 30
NIDDM
Female: 30
Male: 30
Adult
NIDDM
HEX A: activity and output "
HEX B: activity and output "
GLU: activity and output "
Non-NIDDM: 38
Female: 20
Male: 18
NIDDM:35
Female: 17
Male: 18
43
45 13
years
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
Mussavira
et al.
(2015)
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
Abraham,
Rubino,
Sinaii,
Ramsey
and
Nieman,
(2013)
11
years
Goodson
et al.
(2014)
11
years
Obese:
Insulin "
CRP "
Adiponectin "
Leptin "
Goodson
et al. (2014)
11
years
Obese (n = 369)
Healthy (n = 60)
Normal
Underweight
Overweight
Obese
Children (n = 8319)
Body Mass Index (BMI) z-score was used to
classied the subjects into
Normal
Underweight
Overweight
Obese
Human
Normal weight: 30
Underweight: 2
Overweight: 12
Obese: 21
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)
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
Jang, Lee,
Kim, Kim
and Song,
(2012)
67
68
Table 4
The evidence of salivary gland alterations in the NIDDM and obesityinsulin resistance from in vivo studies.
Model
Age
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
6 weeks
5
Weeks of
dietary
program
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
Mozaffari
et al. (2011)
Jonsson,
Delaleu,
Brokstad,
Berggreen
and
Skarstein,
(2006)
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
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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