Effects of Intermittent Hypoxia on Cytokine Expression Involved in Insulin Resistance

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.

Chronic Intermittent Hypoxia Increases Cell Proliferation in Hepatocellular Carcinoma

“…The results of the present study also suggest that chronic intermittent hypoxia leads to modulation in the glucose metabolism in the DEN-induced rat model. This is in accordance with previously reported studies showing chronic intermittent hypoxia-related alterations in fasting glucose levels and glucose metabolism in general [35][36][37].…”

Anorexigenic Effects of Intermittent Hypoxia on the Gut—Brain Axis in Sleep Apnea Syndrome

“…Our cellular studies have indicated that IH, a hallmark manifestation of SAS, is involved in the reduction in glucose-induced insulin secretion by down-regulation of CD38 in pancreatic β cells [ 6 ]; the up-regulation of selenoprotein P and HIP/PAP via down-regulation of miR-203 in hepatocytes [ 5 ]; the up-regulation of adipokines, such as CCL2, TNF-α, and RETN via down-regulation of miR-452 in adipocytes [ 78 ]; and the up-regulation of myokines, such as IL-8, osteonectin, and myonectin, in myocytes [ 79 , 80 , 81 ], all of which can contribute to obesity [ 82 ]. On the other hand, we have also revealed the IH-induced up-regulation of POMC and CART mRNA expression via GATA transcription factors in neuronal cells [ 104 ] and the up-regulation of PYY , GLP-1 , and NTS mRNAs through alteration in the chromatin structures of the PYY , GLP-1 , and NTS genes in enteroendocrine cells [ 106 ], both of which suggest possible anorexigenic effects of IH on the gut–brain axis.…”

“…Taken together, there is accumulating evidence indicating that IH induces the impairment of glucose tolerance and insulin resistance in pancreatic β cells, hepatocytes, adipocytes, and skeletal muscle cells, which may contribute to obesity [ 82 ] ( Figure 1 ).…”

“… The relationship between IH and insulin resistance, glucose intolerance, and diabetes. IH, frequently observed in SAS patients, is involved in the reduction in glucose-induced insulin secretion from pancreatic β cells via down-regulation of CD38 [ 6 ]; up-regulation of Reg I and hepatocyte growth factor in pancreatic β cells [ 76 ]; up-regulation of selenoprotein P and HIP/PAP in hepatocytes via down-regulation of miR-203 [ 5 ]; up-regulation of adipokines, such as CCL2, TNF-α, and RETN in adipocytes via down-regulation of miR-452 [ 78 ]; and up-regulation of myokines, such as IL-8, osteonectin, and myonectin in skeletal muscle cells [ 79 , 80 , 81 ], all of which can contribute to insulin resistance, glucose intolerance, and obesity [ 82 ]. …”

The Impact of Intermittent Hypoxia on Metabolism and Cognition

“…In conclusion, there is accumulating evidence indicating that IH induces impaired glucose tolerance and insulin resistance in pancreatic β cells, hepatocytes, adipocytes, and skeletal muscle cells by upregulating the genes responsible for insulin resistance [ 69 ] ( Figure 2 ).…”