The Study Of Relationship Between Endoplasmic Reticulum Stress And Insulin Resistance In OSAS Patients

Objective:To explore the potential mechanisms of endoplasmic reticulum stress(ERS)-mediated insulin resistance(IR)in patients with obstructive sleep apnea/hypopnea syndrome(OSAS).Methods: The study subjects were consecutively recruited from September2021 to September 2022 at the outpatient clinic of the Sleep Center of the Second Affiliated Hospital of Kunming Medical University.The clinical relevant symptom indicators were collected prior to overnight polysomnography(PSG).The peripheral venous blood was drawn prior to meals in the early morning immediately following completion of PSG monitoring,and stored at-80℃ refrigerator after centrifugation.According to the 2015 Guidelines of the Diagnosis and Treatment of Obstructive Sleep Apnea Hypopnea Syndrome(Primary Edition),the study subjects were divided into non-OSAS group(AHI<5),mild OSAS group(5 ≤ AHI<15),and moderate OSAS group(15 ≤ AHI <30)and severe OSAS group(AHI ≥ 30).Serum8-hydroxydeoxyguanosine(8-OHd G),mitofusin-2(MFN2),fasting insulin(FINS),fasting blood glucose(FBG),protein kinase R-like endoplasmic reticulum kinase(PERK),eukaryotic translation initiation factor 2α(e IF2α),activating transcription factor 4(ATF4),C/EBP homologous protein(CHOP),tribbles homologous protein 3(TRB3),phosphorylated AKT(p-AKT)levels were measured by ELISA.The ANOVA and Kruskal-Wallis U signed rank tests were used to compare differences in levels of the above indicators between the different groups,and correlation analysis between serum indicators was analyzed using Pearson Correlation Analysis.A principal components analysis was used to address interprotein collinearity,followed by a multiple linear regression analysis to explore the quantified relationship between the serum indices and HOMA-IR.Results: A total of 156 subjects were recruited in this study among them 31,34,40,and 51 subjects were separately grouped in non-OSAS group,mild OSAS group,moderate OSAS group,and severe OSAS group.Demographic information such as gender,age,occupation,marital status et al did not differ significantly between the four groups(P=0.870,P=0.753).There were significant differences in clinical relevant symptoms such as daytime somnolence and fatigue between the normal group and those with OSAS groups(Ps<0.05).The HOMA-IR in non-OSAS group(1.75±0.62)did not significantly differ(P=0.331)from the mild OSAS group(1.98±0.73)in the present study,but the significant differences(Ps<0.001)between normal group and the remaining groups [moderate group(2.72±1.18)and severe group(3.87±0.88)] were detected.The HOMA-IR scale was positively correlated with the AHI scale(r=0.687,P<0.001).8-OHd G in Mild group(0.47±0.13 ng/m L),moderate group(0.82±0.24 ng/m L)and severe group(2.87±0.77 ng/m L)were statistically differed from each other(Ps<0.001),and the highly positive relationships between 8-OHd G and AHI(r=0.701,P<0.001),as well as 8-OHDG and HOMA-IR(r=0.467,P<0.001)were detected.MFN2 in non-OSAS group(3.77±1.66 ng/m L)differed significantly(Ps<0.001)from mild group(2.40±1.10 ng/m L),moderate group(1.89±0.87 ng/m L),and severe group(1.03±0.59 ng/m L).MFN2 was moderately negatively correlated with AHI(r=-0.560,P<0.001),HOMA-IR(r=-0.395,P<0.001),as well as with 8-OHd G(r=-0.540,P<0.001).PERK in non-OSAS group(321.65±118.56 pg/m L)differed significantly(Ps<0.001)from mild group(404.80± 134.30 pg/m L),moderate group(486.04 ± 137.14 pg/m L)and severe group(624.65±157.36 pg/m L).The e IF2α in non-OSAS group(181.36±87.94 pg/m L)did not significantly differ(P=0.012)from the mild group(236.72±119.6 pg/m L)but significantly differed(Ps<0.001)from the remaining groups [moderate group(262.40±139.53 pg/m L),severe group(386.06±160.11 pg/m L)].There was no difference(P=0.195)in ATF4 between normal group(186.42±68.85 pg/m L)and mild group(229.11±90.64 pg/m L),but the significant differences(Ps<0.001)between normal group and the remaining groups [moderate group(260.36±126.16 pg/m L)and severe group(383.37±181.78 pg/m L)] were detected.There was no difference(P=0.116)in the CHOP between the normal group(2.96±1.47 ng/m L)and the mild group(3.63±1.87ng/m L)in the present study,but the significant differences(Ps<0.001)between normal group and the remaining groups [moderate group(4.57±1.62 ng/m L)and severe group(7.27±1.86 ng/m L)] were detected.PERK(r=0.610,P<0.001),e IF2α(r=0.413,P<0.001),ATF4(r=0.512,P<0.001),CHOP(r=0.636,P<0.001)showed moderate positive correlation with AHI,and PERK(r=0.368,P<0.001),e IF2α(r=0.264,P<0.001),ATF4(r=0.461,P<0.001),CHOP(r=0.525,P<0.001)were positively correlated with HOMA-IR.TRB3 in normal group(0.59±0.36 ng/m L)differed significantly(Ps<0.001)from mild group(1.18±0.40 ng/m L),moderate group(2.22±0.99 ng/m L),and severe group(4.14±1.37 ng/m L)groups,and TRB3 was highly positively correlated with AHI(r=0.775,P<0.001),and TRB3 was positively correlated with HOMA-IR(r=0.597,P<0.001).Normal group(340.97±70.35 pg/m L),mild group(305.32±92.88 pg/m L),moderate group(201.8±53.25 pg/m L),and severe group(143.71±70.63 pg/m L)were statistically differed from each other(Ps<0.001),and p-AKT had a moderate negative correlation with AHI(r=-0.634,P<0.001),p-AKT and HOMA-IR(r=-0.453,P<0.001),and TRB3 and p-AKT(r=-0.721,P<0.001).Conclusion: 1.The OS and ERS maybe occur in OSAS patients due to CIH;2.The IR level of OSAS patients was significantly higher than that of non-OSAS patients;3.The potential mechanism of IR in OSAS patients may be: OS downregulates MFN2 expression and activates the PERK pathway,that is,PERK-el F2α-ATF4-CHOP,and the rise of CHOP drives the increase of TRB3,which hinders the phosphorylation of AKT and decreases p-AKT,thereby inhibiting the classical insulin metabolism pathway of PI3K-AKT leading to the emergence of IR;4.MFN2 may be a potential site for the treatment of complications in patients with OSAS.