Abstract
Objective: Gestational diabetes mellitus (GDM) is a frequently occurring complication during pregnancy and has adverse effects on both mother and offspring. β-Cell dysfunction and inflammation play important roles in GDM pathogenesis. Cornuside (CNS) is an iridoid glycoside that exhibits anti-inflammation activities. In the present study, we explored the effects of CNS on β-cell and GDM. Design: MIN6 β-cell line cells were treated with varying concentrations of CNS. The content and secretion of insulin were measured. Methods: The expression of Pdx1, Rac1, Piezo, and NeuroD1 and cell proliferation in CNS-treated MIN6 cells were detected. CNS was administered to GDM mice, and the symptoms of GDM, expression of IL-6 and TNF-α, and activation of NF-κB in GDM mice were measured. Results: CNS promoted cell proliferation of MIN6 cells, enhanced insulin content and secretion, and expression of Pdx1, Rac1, Piezo, and NeuroD1 in MIN6 cells. CNS alleviated symptoms of GDM mice and decreased serum levels of IL-6 and TNF-α in GDM mice. CNS suppressed the expression of IL-6 and TNF-α, as well as the activation of NF-κB in the placenta of GDM mice. Conclusion: CNS ameliorates GDM symptoms by suppressing inflammation and enhancing β-cell functions.
Journal Section:
Research Article
References
1.
International Association of Diabetes and Pregnancy Study Groups Consensus Panel
Metzger
BE
, Gabbe
SG
, Persson
B
, Buchanan
TA
, Catalano
PA
, Damm
P
et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy
. Diabetes Care
. 2010
;33
(3
):676
–82
.2.
Reece
EA
, Leguizamón
G
, Wiznitzer
A
. Gestational diabetes: the need for a common ground
. Lancet
. 2009
;373
(9677
):1789
–97
.3.
Li
S
, Zhang
Y
, Sun
Y
, Zhang
G
, Bai
J
, Guo
J
et al. Naringenin improves insulin sensitivity in gestational diabetes mellitus mice through ampk
. Nutr Diabetes
. 2019
;9
(1
):28
.4.
Moyce
BL
, Dolinsky
VW
. Maternal beta-cell adaptations in pregnancy and placental signalling: implications for gestational diabetes
. Int J Mol Sci
. 2018
;19
(11
):3467
.5.
Vitoratos
N
, Valsamakis
G
, Mastorakos
G
, Boutsiadis
A
, Salakos
N
, Kouskouni
E
et al. Pre- and early post-partum adiponectin and interleukin-1beta levels in women with and without gestational diabetes
. Hormones
. 2008
;7
(3
):230
–6
.6.
Christian
LM
, Porter
K
. Longitudinal changes in serum proinflammatory markers across pregnancy and postpartum: effects of maternal body mass index
. Cytokine
. 2014
;70
(2
):134
–40
.7.
Pantham
P
, Aye
IL
, Powell
TL
. Inflammation in maternal obesity and gestational diabetes mellitus
. Placenta
. 2015
;36
(7
):709
–15
.8.
Yang
Y
, Liu
L
, Liu
B
, Li
Q
, Wang
Z
, Fan
S
et al. Functional defects of regulatory t cell through interleukin 10 mediated mechanism in the induction of gestational diabetes mellitus
. DNA Cel Biol
. 2018
;37
(3
):278
–85
.9.
Nordmann
TM
, Dror
E
, Schulze
F
, Traub
S
, Berishvili
E
, Barbieux
C
et al. The role of inflammation in beta-cell dedifferentiation
. Sci Rep
. 2017
;7
(1
):6285
.10.
Kolb
H
, Mandrup-Poulsen
T
. An immune origin of type 2 diabetes
. Diabetologia
. 2005
;48
(6
):1038
–50
.11.
Liu
T
, Zhang
L
, Joo
D
, Sun
SC
. Nf-κb signaling in inflammation
. Signal Transduct Target Ther
. 2017
;2
:17023
.12.
Kaminska
B
. Mapk signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits
. Biochim Biophys Acta
. 2005
1754
1–2
253
62
.13.
Feng
H
, Su
R
, Song
Y
, Wang
C
, Lin
L
, Ma
J
et al. Positive correlation between enhanced expression of tlr4/myd88/nf-κb with insulin resistance in placentae of gestational diabetes mellitus
. PLoS One
. 2016
;11
(6
):e0157185
.14.
Shen
Z
, Yang
C
, Zhu
P
, Tian
C
, Liang
A
. Protective effects of syringin against oxidative stress and inflammation in diabetic pregnant rats via TLR4/MyD88/NF-κB signaling pathway
. Biomed Pharmacother
. 2020
;131
:110681
.15.
Li
Y
, Xie
H
, Zhang
H
. Protective effect of sinomenine against inflammation and oxidative stress in gestational diabetes mellitus in female rats via TLR4/MyD88/NF-κB signaling pathway
. J Food Biochem
. 2021
;45
(11
):e13952
.16.
Shi
JZ
, Zheng
XM
, Zhou
YF
, Yun
LY
, Luo
DM
, Hao
JJ
et al. Cornuside is a potential agent against alzheimer's disease via orchestration of reactive astrocytes
. Nutrients
. 2022
14
.17.
Schiattarella
A
, Lombardo
M
, Morlando
M
, Rizzo
G
. The impact of a plant-based diet on gestational diabetes: a review
. Antioxidants
. 2021
10
.18.
Fedullo
AL
, Schiattarella
A
, Morlando
M
, Raguzzini
A
, Toti
E
, De Franciscis
P
et al. Mediterranean diet for the prevention of gestational diabetes in the COVID-19 era: implications of il-6 in diabesity
. Int J Mol Sci
. 2021
22
.19.
Lee
SO
, Kim
SY
, Han
SM
, Kim
HM
, Ham
SS
, Kang
IJ
. Corni fructus scavenges hydroxy radicals and decreases oxidative stress in endothelial cells
. J Med Food
. 2006
;9
(4
):594
–8
.20.
Choi
YH
, Jin
GY
, Li
GZ
, Yan
GH
. Cornuside suppresses lipopolysaccharide-induced inflammatory mediators by inhibiting nuclear factor-kappa b activation in raw 264.7 macrophages
. Biol Pharm Bull
. 2011
;34
(7
):959
–66
.21.
Kim
C
, Kim
N
, Bae
JS
. Anti-inflammatory and anti-oxidant functions of cornuside by regulating nf-[formula: see text]b, stat-1, and nrf2-ho-1 pathways
. Am J Chin Med
. 2022
;50
(5
):1349
–60
.22.
Jiang
WL
, Chen
XG
, Zhu
HB
, Hou
J
, Tian
JW
. Cornuside attenuates apoptosis and ameliorates mitochondrial energy metabolism in rat cortical neurons
. Pharmacology
. 2009
;84
(3
):162
–70
.23.
Yu
L
, Che
R
, Zhang
W
, Xu
J
, Lian
W
, He
J
et al. Cornuside, by regulating the AGEs-RAGE-IκBα-ERK1/2 signaling pathway, ameliorates cognitive impairment associated with brain aging
. Phytother Res
. 2023
;37
(6
):2419
–36
.24.
Wang
ZX
, Lian
WW
, He
J
, He
XL
, Wang
YM
, Pan
CH
et al. Cornuside ameliorates cognitive impairments in scopolamine induced ad mice: involvement of neurotransmitter and oxidative stress
. J Ethnopharmacol
. 2022
;293
:115252
.25.
Li
L
, Jin
G
, Jiang
J
, Zheng
M
, Jin
Y
, Lin
Z
et al. Cornuside inhibits mast cell-mediated allergic response by down-regulating MAPK and NF-κB signaling pathways
. Biochem Biophys Res Commun
. 2016
;473
(2
):408
–14
.26.
Coughlan
MT
, Permezel
M
, Georgiou
HM
, Rice
GE
. Repression of oxidant-induced nuclear factor-kappab activity mediates placental cytokine responses in gestational diabetes
. J Clin Endocrinol Metab
. 2004
;89
(7
):3585
–94
.27.
Liu
Z
, Yu
X
, Tong
C
, Qi
H
. Renal dysfunction in a mouse model of gdm is prevented by metformin through mapks
. Mol Med Rep
. 2019
;19
(5
):4491
–9
.28.
He
H
, Liu
Y
, Sun
M
. Nesfatin-1 alleviates high glucose/high lipid-induced injury of trophoblast cells during gestational diabetes mellitus
. Bioengineered
. 2021
;12
(2
):12789
–99
.29.
Zhang
M
, Yan
S
, Xu
X
, Yu
T
, Guo
Z
, Ma
M
et al. Three-dimensional cell-culture platform based on hydrogel with tunable microenvironmental properties to improve insulin-secreting function of min6 cells
. Biomaterials
. 2021
;270
:120687
.30.
Yamashita
H
, Shao
J
, Qiao
L
, Pagliassotti
M
, Friedman
JE
. Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in lepr(db/+) mice
. Pediatr Res
. 2003
;53
(3
):411
–8
.31.
Johns
EC
, Denison
FC
, Norman
JE
, Reynolds
RM
. Gestational diabetes mellitus: mechanisms, treatment, and complications
. Trends Endocrinol Metab
. 2018
;29
(11
):743
–54
.32.
Prakash
GT
, Das
AK
, Habeebullah
S
, Bhat
V
, Shamanna
SB
. Maternal and neonatal outcome in mothers with gestational diabetes mellitus
. Indian J Endocrinol Metab
. 2017
;21
(6
):854
–8
.33.
Li
S
, Zhu
Y
, Yeung
E
, Chavarro
JE
, Yuan
C
, Field
AE
et al. Offspring risk of obesity in childhood, adolescence and adulthood in relation to gestational diabetes mellitus: a sex-specific association
. Int J Epidemiol
. 2017
;46
(6
):2104
.34.
Torella
M
, Bellini
G
, Punzo
F
, Argenziano
M
, Schiattarella
A
, Labriola
D
et al. Tnf-α effect on human delivery onset by cb1/trpv1 crosstalk: new insights into endocannabinoid molecular signaling in preterm vs. Term labor. Analysis of the ec/ev pathway and predictive biomarkers for early diagnosis of preterm delivery
. Minerva Ginecol
. 2019
;71
(5
):359
–64
.35.
Liu
J
, Song
G
, Zhao
G
, Meng
T
. Association between tnf-α polymorphisms and gestational diabetes mellitus: a meta-analysis and trial sequential analysis
. Gynecol Endocrinol
. 2021
;37
(6
):506
–10
.36.
Li
L
, Jin
G
, Jiang
J
, Zheng
M
, Jin
Y
, Lin
Z
et al. Cornuside inhibits mast cell-mediated allergic response by down-regulating mapk and nf-κb signaling pathways
. Biochem Biophys Res Commun
. 2016
;473
(2
):408
–14
.37.
Liu
Y
, Hou
W
, Meng
X
, Zhao
W
, Pan
J
, Tang
J
et al. Heterogeneity of insulin resistance and beta cell dysfunction in gestational diabetes mellitus: a prospective cohort study of perinatal outcomes
. J Transl Med
. 2018
;16
(1
):289
.38.
Fakhrul-Alam
M
, Sharmin
J
, Mashfiqul
H
, Nusrat
S
, Mohona
Z
, Rakibul-Hasan
M
et al. Insulin secretory defect may be the major determinant of gdm in lean mothers
. J Clin Transl Endocrinol
. 2020
;20
:100226
.39.
Gurgul-Convey
E
, Mehmeti
I
, Lortz
S
, Lenzen
S
. Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stress-induced hydroxyl radical formation in mitochondria
. J Mol Med
. 2011
;89
(8
):785
–98
.40.
Eizirik
DL
, Cnop
M
. Er stress in pancreatic beta cells: the thin red line between adaptation and failure
. Sci Signal
. 2010
3
110
pe7
.41.
Cnop
M
, Welsh
N
, Jonas
JC
, Jörns
A
, Lenzen
S
, Eizirik
DL
. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities
. Diabetes
. 2005
54
Suppl 2
S97
107
.42.
Sachdeva
MM
, Claiborn
KC
, Khoo
C
, Yang
J
, Groff
DN
, Mirmira
RG
et al. Pdx1 (mody4) regulates pancreatic beta cell susceptibility to er stress
. Proc Natl Acad Sci U S A
. 2009
;106
(45
):19090
–5
.43.
Ye
Y
, Barghouth
M
, Dou
H
, Luan
C
, Wang
Y
, Karagiannopoulos
A
et al. A critical role of the mechanosensor piezo1 in glucose-induced insulin secretion in pancreatic beta-cells
. Nat Commun
. 2022
;13
(1
):4237
.44.
Romer
AI
, Singer
RA
, Sui
L
, Egli
D
, Sussel
L
. Murine perinatal beta-cell proliferation and the differentiation of human stem cell-derived insulin-expressing cells require neurod1
. Diabetes
. 2019
;68
(12
):2259
–71
.45.
Damacharla
D
, Thamilselvan
V
, Zhang
X
, Mestareehi
A
, Yi
Z
, Kowluru
A
. Quantitative proteomics reveals novel interaction partners of rac1 in pancreatic beta-cells: evidence for increased interaction with rac1 under hyperglycemic conditions
. Mol Cell Endocrinol
. 2019
;494
:110489
.46.
Gao
F
, Xia
SL
, Wang
XH
, Zhou
XX
, Wang
J
. Cornuside i promoted osteogenic differentiation of bone mesenchymal stem cells through pi3k/akt signaling pathway
. J Orthop Surg Res
. 2021
;16
(1
):397
.47.
Quaresima
P
, Saccone
G
, Pellegrino
R
, Vaccarisi
S
, Taranto
L
, Mazzulla
R
et al. Incidental diagnosis of a pancreatic adenocarcinoma in a woman affected by gestational diabetes mellitus: case report and literature review
. Am J Obstet Gynecol MFM
. 2021
;3
(6
):100471
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