Abstract
Sleep apnea syndrome (SAS) is a prevalent disorder characterized by recurrent apnea or hypoxia episodes leading to intermittent hypoxia (IH) and arousals during sleep. Currently, the relationship between SAS and metabolic diseases is being actively analyzed, and SAS is considered to be an independent risk factor for the development and progression of insulin resistance/type 2 diabetes (T2DM). Accumulating evidence suggests that the short cycles of decreased oxygen saturation and rapid reoxygenation, a typical feature of SAS, contribute to the development of glucose intolerance and insulin resistance. In addition to IH, several pathological conditions may also contribute to insulin resistance, including sympathetic nervous system hyperactivity, oxidative stress, vascular endothelial dysfunction, and the activation of inflammatory cytokines. However, the detailed mechanism by which IH induces insulin resistance in SAS patients has not been fully revealed. We have previously reported that IH stress may exacerbate insulin resistance/T2DM, especially in hepatocytes, adipocytes, and skeletal muscle cells, by causing abnormal cytokine expression/secretion from each cell. Adipose tissues, skeletal muscle, and the liver are the main endocrine organs producing hepatokines, adipokines, and myokines, respectively. In this review, we focus on the effect of IH on hepatokine, adipokine, and myokine expression.
Highlights
Sleep apnea syndrome (SAS) is a common disorder that causes repeated apnea and hypopnea due to the obstruction of the upper airway during sleep, and it occurs in about 13–33% of men and 5–19% of women [1,2]
Since we previously investigated the way in which intermittent hypoxia (IH) induces impaired insulin secretion/insulin resistance in in vitro experimental systems using pancreatic β cells, neuronal cells, hepatocytes, adipocytes, skeletal muscle cells, and cardiomyocytes [5,7,19,25,32,38], in this review, we focus on how IH induces insulin resistance
The relationship between hepatokine secreted by the liver and insulin resistance has been reported, and we examined the effects of IH on hepatokine expression and hepatocyte proliferation in vitro
Summary
Sleep apnea syndrome (SAS) is a common disorder that causes repeated apnea and hypopnea due to the obstruction of the upper airway during sleep, and it occurs in about 13–33% of men and 5–19% of women [1,2]. Abnormalities in hepatic lipid metabolism caused by insulin resistance lead to increased secretion of atherosclerosis-inducing lipoprotein abnormalities, inflammatory cytokines, and blood clot promoting factor, which promote atherosclerosis and create high-risk conditions for cardiovascular diseases [8,39]. Our in vitro study revealed that the gene expression of SeP and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) were increased via the downregulation of the miR-203 level in IH-treated hepatocytes. The RNA interference of HIP/PAP inhibited HepG2 cell proliferation measured by WST-8 assay, whereas the interference of other REG family genes such as REG Iα did not These results indicate that HIP/PAP, upregulated by IH, works as an autocrine/paracrine growth factor in hepatocyte proliferation. The overexpression of HIP/PAP could cause such hepatocytes to proliferate in SAS patients, leading to decreased insulin sensitivity. The most common complications in SAS patients are hypertension and diabetes, and IH, caused by SAS, reduced miR-203 in hepatocytes [5] and juxtaglomerular cells [63], resulting in increased Sep in hepatocytes, a diabetogenic hepatokine, and renin in juxtaglomerular cells, which induces hypertension, simultaneously
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