Our study first reports GLUT4 gene SNPrs5417 allele is significantly associated with diagnosis of OSAS in hypertensive population. In addition, significant association is found between GLUT4 gene SNPrs5417 and males with OSAS. A allelic frequency in case group is lower than in control group. Significant relation is found between GLUT4 gene and males with OSAS in Han population, whereas the relation is not found in female subjects.
It is unanimously recognized that OSAS has familial aggregation and genetic susceptibility; however its genetic mechanism remains unknown so far. More than 72% in our study subjects have hypertension coupled with OSAS, and other epidemiological studies have indicated that prevalence of OSAS in hypertensive population is up to 50% ~ 60% . Hypertension and OSAS often coexist, and our previous study found patients merging with OSAS and hypertension are more likely to have metabolic disorders [23, 24]. These people are more likely to coexist insulin resistance, increased triglyceride and uric acid levels and decreased high density lipoprotein cholesterol. This study eliminated confounding factors of hypertension in OSAS patients by case–control design of particular subjects. In OSA, cycles of hypoxia and re-oxygenation facilitate the formation of reactive oxygen species (ROS) which impair endothelial function  and promote lipid and glucose peroxidation [26, 27] and increased formation of ROS can activate inflammatory responses . One of the major sources of cellular reactive oxygen species (ROS) is mitochondria, dysfunction of which contributes to several pathological conditions including vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. Shorter intermittent hypoxic exposures as pathophysiology of OSAS might preferentially activate inflammatory pathways and over-expression of such inflammatory factors as TNF-α, IL-6 and IL-8 , which influences normal insulin signaling of adipocytes and GLUT4, bringing about reduction of glucose assimilation triggering metabolic dysregulation . Furthermore, Insulin-stimulated GLUT4 translocation and glucose uptake are associated with NF- KB activation  which, a susceptible gene for OSAS  and nuclear receptor, plays a central role in inflammatory response and orchestrates over-expression of a range of factors including cytokines (TNF-a, IL-6 and IL-8) and adhesion molecules (intercellular adhesion molecule-1) [33, 34]. Overwhelming findings emphasize we gain full understanding about relation between OSAS and dysglycemia. In particular it is necessary to understand hereditary susceptibility of OSA and glucose metabolism. According to analysis of baseline data in this study, concentrations of FPG and hypersensitive C-reactive protein are higher in case group than in controls, indicating coupling reactions of dysimmunity caused by GLUT4 gene-related dysglycemia such as airway inflammatory cell invasion and high airway resistance leading to hypopnea and apnea during sleep.
Sushmita  reported prevalence of OSAS in T2DM is around 71%. IR acts as important role of pathogenesis of T2DM . Recently, total serum cholesterol/high-density lipoprotein cholesterol as evaluation index of IR has become a hotspot in cardiovascular diseases . Present study found significant difference of insulin resistance in OSAS patients comparing with controls using assessment indicators. FPG and fasting insulin of OSAS group was found to be higher than those of non-OSAS group after OGTT and insulin releasing test, explaining risk for impaired glucose tolerance of OSAS patients was higher, impaired fasting glucose reflecting basal insulin level secreted from β-cell is affected, and Punjabi  showed that severe OSAS is associated with function of pancreatic B cells. The two indicate intermittent hypoxia and re-oxygenation during OSAS bring about elevation of ROS. β cell is sensitive to ROS which generates dysfunction of β cell and even apoptosis. Therefore we can assume patients with OSAS experience a peak of ROS after nocturnal hypoxia, which affects β cell significantly, whereas intermittent hypoxia hardly exist daytime; thus there is no difference in dawn FPG and insulin levels of OSAS and non OSAS group. This is also the reason why dawn blood pressure is monitored in order to evaluate responsiveness of CPAP therapy; meanwhile this can explain why no significant differences are found in FPG and insulin levels of OSAS and non OSAS groups after activity and oxygen intake increasing. However β-cell damage increases with progress and severity of OSAS, and type 2 diabetes mellitus develops finally.
GLUT4 is an insulin-dependent glucose transporter protein, playing a pivotal part on IR by insulin signaling pathway . P38MAPK signaling pathway may improve insulin sensitivity through increasing intrinsic activity of GLUT4 and consequently increase glucose transportation and assimilation [40, 41]. Lu  ect found relative of p-p38MAPK and GLUT4 gene expression increased in IR rats of animal models. The latest study revealed P38MAPK is sensitive to ROS . Reduction of P38MAPK activity reduces tolerance of brain to anoxia . Intermittent hypoxia, the hallmark of OSAS, is implicated to promote formation of ROS and to induce oxidative stress, and brings about metabolic disorders such as hypertension, T2DM, insulin resistance, which aggregates OSAS. A part from inhibiting P38 MAPK, hypoxia also inhibits Akt-mTOR in differentiating myoblasts . Rena′s  research confirmed genetic and pharmacological evidence suggesting that suppression of Akt and mTOR activity is responsible for the loss of the myogenic action of insulinlike growth factors under hypoxia. Some other evidences indicate that selective suppression of PI3K/Akt /mTOR signaling pathway supresses inflammatory reaction caused by oxidative stress . Except for this, reduction of antioxidant enzymes in pancreas β cell is both an important target spot of ROS , and a direct factor of OSAS to generate IR. An observational cohort study found remarkable improvement of fasting and postprandial glucose in moderate to severe OSAS patients without obesity after CPAP therapy . Thus we can infer chronic oxidative stress secondary to OSAS and excessive reactive oxygen species influence activation of correlative signaling pathway and nuclear receptor to lead to abnormal activation and expression of GLUT4 gene. Treatment of OSAS contributes to regulate activity of reflective signaling pathway, increase activation of GLUT4 molecule, improve IR in OSAS patients, and decrease cardiovascular events.
Moreover, SNPrs5417 subtype of GLUT4 gene related to OSAS expressed significant difference in gender; C allelic of male case group was significantly higher than that of male control group, whereas this phenomenon does not exist in female subjects. Some animal experiments reported that melting GLUT4 of musculi soleus in male rats causes reduction of ATP and phosphocreatine, which is more obvious than those of female rats . GLUT4 mainly serves as its glucose transporter in skeletal muscle and liver, difference of which in males and females may bring about different expression in the same environment after influenced by intermittent hypoxia. However, a recent Turkish study reported OSAS-induced inflammation is more obvious in females . Prevalence of OSAS is dominant in males; clinical studies have been focused on males, which has lead to lack of data on females. This study did not find any relation between three locus’ mutation of GLUT4 and OSAS in female subjects, which may have some connections with sample size and racial difference. This aspect needs further molecular researches and longitudinal, large-sampled, population-based studies to explore. AA and AC types of SNP rs5417 were found to be independent protective factors for OSAS susceptibility, compared with CC type after adjustments for confounding factors using logistic regression analysis. Awake oxygen saturation and minimal oxygen saturation are higher in carriers of (AA + AC) types of GLUT4 rs5417 than in CC Homozygote types in male subjects with OSAS of Han population, which is consistent with findings from other studies. This result explains anoxia in C allelic carriers is more severe; although there is no difference in AHI of recessive genetic model, severity of OSAS in CC type carriers can be inferred. Since OSAS is a complex disease caused by genetic and environmental interaction, single mutation locus of GLUT4 is not sufficient to bring about intermediate phenotype and Phenotype change of OSAS. No association has been found between rs5415 and rs5435 gene types and OSAS, whereas haplotypes of combinations of rs5417, rs5415 and rs5435 reported to be associated with OSAS. Nair  ect found combined haplotypes of rs5417 and rs5418 of GLUT4 gene and combined haplotypes of rs5435 and rs5415 associated with T2DM. It is obvious that combination of GLUT4 gene and TaqSNPs increases genetic susceptibilities of OSAS and its related clinical co-morbidities.