1752-P: Mechanistic Effects of Intermittent Hypoxia ?(IH) on? ß-Cells, Glucose Homeostasis, and Predisposition to Type 2 Diabetes (T2D)

The capacity of pancreatic β-cells to adapt to insulin resistance or stress conditions is the major determinant of developing Type 2 diabetes (T2D). Obstructive sleep apnea (OSA), a prevalent disorder associated with T2D, causes chronic intermittent hypoxia (IH). The mechanisms through which OSA/chronic IH cause abnormalities in glucose levels and T2DM are not known. Mechanistic responses to hypoxia in other tissues involve alterations in AMPK and mTORC1 signaling, but how these alterations affect tissues responsible for glucose homeostasis, including β-cells, is not known. It was hypothesized that IH leads to alterations in glucose homeostasis by inducing β-cell function via upregulation of mTORC1 signaling in β-cells. To examine the role of IH in glucose homeostasis and β-cell function, we used a system to induce IH in both in vivo and in vitro models. The fractional inspired O2 between 21% and 5% in 30 second intervals (~ 60 episodes/hr), for 12hrs/day for 7, 14, and 28-days in C57B6J mice. IH resulted in improved glucose tolerance and insulin sensitivity. Evidence of hypoxia at the β-cell level was seen by an increase in a common target of hypoxia inducible factor (HIF1), adrenomedullin, and an increase of the Hypoxyprobe marker, pimonidazole. At the mechanistic level, β-cells from IH exposed mice and islets exposed to IH in vitro displayed increase in mTORC1 activation, via activation of its downstream target pS6(240). Taken together, the current evidence showed that IH can induce improvements in glucose tolerance and insulin secretion, and this was associated to augmented mTORC1 signaling.