Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner

Abstract

Background/Aims: Obstructive sleep apnea is associated with diabetes and insulin resistance, but the underlying mechanisms remain unclear. The purpose of the current study was to determine the molecular effects of intermittent hypoxia (IH) on hepatic insulin signaling and glucose homeostasis, and whether c-Jun NH₂-terminal-kinase (JNK) contributed to metabolic responses to IH in liver cells. Methods: The human HepG₂ cells and rat FAO cells were exposed to 10, 30, 120, 240 or 360 cycles of IH (1% O₂ for 60 s followed by 21% O₂ for 60s, 7.5 cycles per hour) or normoxia as a control. In a subgroup, we exposed cells to 360 cycles of IH with the JNK inhibitor SP600125. After IH exposure, cell glycogen content and glucose output were measured using colorimetric assay kits. Canonical insulin signaling and gluconeogenic genes were measured by western blot and quantitative polymerase chain reaction. Results: IH decreased insulin-stimulated protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) phosphorylation in a time-dependent manner, while inhibiting forkhead box protein O1 (FOXO1) expression and phosphoenolpyruvate carboxykinase (PEPCK) transcription independent of insulin signaling. JNK inhibitor SP600125 partially restored AKT/ GSK-3β phosphorylation and glycogen synthesis, but did not affect other IH-induced glucose metabolic changes. Conclusion: IH in vitro impaired insulin signal transduction in liver cells as assessed by inhibited AKT/GSK-3β phosphorylation via JNK activation. IH inhibited FOXO1 and gluconeogenesis in an insulin-independent manner.

Relationship Between Intermittent Hypoxia and Type 2 Diabetes in Sleep Apnea Syndrome

“…Furthermore, IH increases not only glucose supply from hepatocytes but also gene expression of several gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (EC 4.1.32) and glucose 6-phosphatase (EC 3.1.3.9) in the liver, contributing to fasting hyperglycemia and development of type 2 DM [53]. Gu et al report that IH disrupts glucose homeostasis in hepatocytes in an insulin-dependent and independent manner [54]. Recently, several proteins that are exclusively or predominantly secreted by the liver, called hepatokines, were confirmed as directly affecting glucose and lipid metabolism [55,56].…”

The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis

“…FOXO1 is a regulator of the phosphoenolpyruvate carboxykinase gene (PEPCK), which plays a pivotal role in gluconeogenesis. However, nor the intrahepatic glycogen concentration nor the production of glucose in the hepatocytes after intermittent hypoxia were significantly impaired (67). On the other hand, other studies did show an increased glucose production in hepatocytes when the duration of intermittent hypoxia was increased (68).…”

Ameliorative effect of bayberry leaves proanthocyanidins on high sugar diet induced Drosophila melanogaster

“…They were reported to alleviate insulin resistance in type 2 diabetes mellitus via modulating second messenger signaling pathways, including PI3K-AKT, MAPK, and JNK signaling. What’s more, BLPs downregulated dFOXO-PEPCK expression, resulting in gluconeogenesis inhibition, which subsequently contributed to a reduction of glucose output ( Gu et al, 2018 ).…”