Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells

Hypoxia is a condition in which you breathe in less oxygen than is normal; normal oxygen levels are approximately 21% of the air we breathe. The effects of intermittent hypoxia are being tested in this study by administering a normal level of oxygen, followed by a hypoxic level (1% oxygen) at different time intervals. Intermittent hypoxia is a pathophysiological characteristic of obstructive sleep apnea, that can potentially cause decreased oxygen levels reaching the tissues, cellular stress responses, and cell dysfunction.

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This research is being done because obstructive sleep apnea is associated with an increased risk of diabetes and insulin resistance, but we are unaware of the reasons for this (Gu, et al, 1042-1043). There are many pathways and enzymes that are associated with glucose homeostasis in liver cells, some are insulin-dependent pathways and others are independent of the insulin pathways. These different pathways were studied using an in vitro model of humanHepG2cells and rat FAO cells (Gu, et al, 1042). For the purposes of my review, I am going to discuss the effects of intermittent hypoxia on the pathways and enzymes relating to the humanHepG2cells only. To make a very brief and broad generalization, the presence of insulin in hepatic cells should increase glycogen synthesis to reduce the amount of glucose in the blood and it decreases gluconeogenesis so that more glucose is not entering the blood.

In an incubator, human HepG2cell cultures were exposed to changing oxygen levels via a controlled gas delivery system with oxygen levels being monitored by an electrode. Each cycle consisted of oxygen levels starting at 21% and being reduced to 1% over 160 seconds; the cells remained at 1% oxygen levels for 60 seconds; over 200 seconds, the oxygen was reintroduced until reaching 21% again and remaining at this level for 60 seconds. Each hour, the cell cultures endured 7.5 hypoxic events. Cell cultures were exposed to a different number of hypoxic events to determine how extended intermittent hypoxia affects glucose homeostasis in liver cells. The control cell cultures were exposed to 21% oxygen levels for the entire time (Gu, et al, 1044).

When insulin binds to its receptor, a signaling cascade begins which includes the phosphorylation of AKT. The phosphorylation of AKT prompts the phosphorylation of GSK-3? which promotes glycogen synthesis. Insulin-stimulated cells were measured for AKT and GSK-3? phosphorylation after multiple cycles of intermittent hypoxia. As more cycles of intermittent hypoxia were administered, phosphorylation of AKT and GSK-3? was inhibited. This resulted in an unchanged presence of total AKT and GSK-3?, whereas, levels of these phosphorylated genes should have increased due to the insulin-stimulation. However, glycogen content was not significantly affected by intermittent hypoxia (Gu, et al, 1044-1045). Since GSK-3? is a precursor to glycogen synthesis, it would make sense that with an unchanged level of phosphorylated GSK-3? in the cell cultures, the glycogen content would remain constant. Could this suggest that glycogen synthesis is not fully dependent on phosphorylation of GSK-3??

FOXO1, located in the nucleus, upregulates transcription of two important enzymes involved in gluconeogenesis: G6Pase and PEPCK. Although, when insulin binds to its receptor, AKT phosphorylates causing the phosphorylation of FOXO1, as was seen in the control cell cultures. Phosphorylated FOXO1 leaves the nucleus and becomes inactive, which decreases the transcription of G6Pase and PEPCK enzymes. When HepG2cell cultures were tested after being exposed to a various number of intermittent hypoxic cycles, the results were mostly expected. As mentioned above, intermittent hypoxia decreased the concentration of phosphorylated AKT in the cells; it follows that phosphorylation of FOXO1 was also reduced, however, a decrease in overall FOXO1 expression was observed, which was not expected. This occurred for both insulin-stimulated and non-insulin cells. Transcription of PEPCK was reduced in a time-dependent manner while G6Pase was not altered(Gu, et al, 1045-1046). Since FOXO1 expression was reduced why wouldn’t the expression of G6Pase be reduced? There must be another factor involved in the transcription of this enzyme that is not affected by intermittent hypoxia and is not involved in PEPCK transcription. However, would it be useful in gluconeogenesis if only one of the major enzymes needed were present?

Once again, when insulin binds to its receptor, it phosphorylates IRS-1 which causes insulin signaling phosphorylation of JNK which directly interferes with insulin signaling when conditions of obesity and inflammation are present. JNK presence was examined afterHepG2cells were exposed to 360 cycles of intermittent hypoxia and phosphorylation of this protein had significantly increased. SomeHepG2cells were pretreated with a JNK inhibitor prior to any hypoxic exposure and after 360 cycles of intermittent hypoxia, phosphorylation of JNK was no longer observed (Gu, et al, 1046).

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