Role of the iNOS/IRS1/AKT/GSK-3β signaling pathway in chronic intermittent hypoxia-induced insulin resistance
10.19405/j.cnki.issn1000-1492.2025.02.004
- Author:
Meina Jin
1
;
Xueli Zhou
1
;
Haibo Li
1
;
Wei Bai
1
;
Chuxuan Jia
1
;
Li Gao
1
;
Lijue Ren
2
;
Qingyu Chen
3
;
Rui Wang
4
;
Hua Li
5
;
Cuiying Wei
1
Author Information
1. Dept of Geriatrics , The First Afiliated Hospital of Baotou Medical College , Baotou 014000
2. Dept of Endocrinology , The First Afiliated Hospital of Baotou Medical College , Baotou 014000
3. Dept of Stomatology , The First Afiliated Hospital of Baotou Medical College , Baotou 014000;
4. Animal Research Laboratory , Baotou Medical College , Baotou 014000
5. People ′s Hospital of Gushang County , Baotou , Inner Mongolia Autonomous Region , Baotou 014200
- Publication Type:Journal Article
- Keywords:
chronic intermittent hypoxia-reoxygenation;
insulin resistance;
inducible nitric oxide synthase;
IRS1 / AKT/GSK-3β signaling pathway;
SD rat;
liver
- From:
Acta Universitatis Medicinalis Anhui
2025;60(2):210-217
- CountryChina
- Language:Chinese
-
Abstract:
Objective :To pathological changes and inducible nitric oxide synthase(iNOS), phosphorylated insulin receptor substrate 1 serine 307(p-IRS1ser 307), phosphorylated protein kinase B serine 473(p-AKTser 473), glycogen synthase kinase-3β(GSK-3β), and gluconeogenic synthase(GS) proteins were observed in the liver of rats under the condition of chronic intermittent hypoxia-replicated oxygen in control. And to explore the role of iNOS/IRS1/AKT/GSK-3β signaling pathway in chronic intermittent hypoxia-induced insulin resistance.
Methods :Forty SD rats were randomly divided into a control group(NC group) and an experimental group(CIH group), with 20 rats in each group. The NC group was placed in a normoxic environment for 12 weeks, while the CIH group was first subjected to intermittent hypoxia for 8 weeks, and then resumed normoxic rearing until the 12th week. Fasting blood glucose(FBG) and fasting insulin(FINS) were measured at baseline, week 8 and week 12, and liver tissues were taken for pathology and measurement of iNOS, p-IRS1ser 307, p-AKTser 473, GSK3β and GS levels, to compare the differences between groups.
Results:t baseline, there was no significant difference in liver pathology between the two groups, and the observed indexes were not statistically significant(P>0.05); at 8 weeks, compared with the NC group, liver pathology in the CIH group showed significant disorganization of hepatic blood sinusoids and hepatocyte cords, obvious hepatocyte edema, smaller nuclei, increased lymphocyte infiltration, and a small number of fat vacuoles, significantly higher levels of FBG, FINS, insulin resistance index(HOMA-IR), iNOS mRNA, p-IRS1ser 307 protein, GSK-3β protein levels, and decreased p-AKTser 473 protein and GS protein levels, all of which were statistically significant(allP<0.05). IRS1ser 307 protein, GSK-3β protein levels were increased, p-AKTser 473 protein and GS protein levels were decreased, and the differences were statistically significant(allP<0.05); at 12 weeks, no lymphocyte infiltration was seen in the CIH group compared with that of the NC group and fat vacuoles significantly increased, and there was no improvement in the other pathological damage that had already occurred, and the levels of p-AKTser 473 protein significantly increased. AKTser 473 protein level significantly increased, p-IRS1ser 307 protein and GS protein levels were significantly reduced, all of which were statistically significant(allP<0.05), and the rest of the observational indexes were not statistically significant. Pearson′s correlation analysis showed that HOMA-IR of CIH group was significantly positively correlated with the levels of iNOS mRNA, p-IRS1ser 307 protein, and GSK-3β protein at 8 weeks(r=0.874, 0.817,0.872;allP<0.05), and significantly negatively correlated with the levels of p-AKTser 473 protein and GS protein(r=-0.886,-0.879;allP<0.05).
Conclusion:Chronic intermittent hypoxia can lead to hepatic pathological damage that cannot be reversed even by reoxygenation interventions and may mediate the development of insulin resistance by upregulating the IRS1/AKT/GSK-3β signaling pathway through the upregulation of iNOS mRNA expression.
- Full text:2026012209345315368iNOS_IRS1_AKT...歇低氧致胰岛素抵抗中的作用_靳美娜.pdf
