Time-dependent changes in glucose and insulin regulation during intermittent hypoxia and continuous hypoxia.

Hypoxia manifests in many forms including the short repetitive intermittent hypoxia (IH) of sleep apnoea and the continuous hypoxia (CH) of altitude, both of which may impact metabolic function. Based on our own previous studies and the available literature, we hypothesized that whereas acute exposure to IH and CH would lead to comparable metabolic dysfunction, with longer-term exposure, metabolism would normalize to a greater extent with CH than IH. Studies were conducted in lean C57BL/6J mice exposed to either IH or CH for 1 day or 4 weeks and compared to either intermittent air (IA) or unhandled (UN) controls, respectively. We utilized the frequently sampled intravenous glucose tolerance test and minimal model analyses to determine insulin-dependent (insulin sensitivity; S (I)) and insulin-independent (glucose effectiveness; S (g)) glucose disposal, as well as the insulin response to glucose (acute insulin response to glucose; AIR(g)). Our data show that 1-day exposure impaired the glucose tolerance and caused reductions in S (g) and AIR(g) in both the IH and CH groups, but only IH caused a significant decrease in S (I) (7.5 ± 2.7 vs. 17.0 ± 5.3 µU ml(-1) min(-1); p < 0.05). After 4-week exposure, there was evidence of metabolic adaptation in both hypoxic groups, however, in the CH group, there was a supranormal increase in S (I) relative to both UN and IH groups. We conclude that in lean mice, the marked metabolic dysfunction that occurs with acute exposure to hypoxia is reversed to a greater extent with chronic CH exposure than chronic IH exposure.

Simultaneous measurement of insulin sensitivity, insulin secretion, and the disposition index in conscious unhandled mice.

Of the parameters that determine glucose disposal and progression to diabetes in humans: first-phase insulin secretion, glucose effectiveness (Sg), insulin sensitivity (Si), and the disposition index (DI), only Si can be reliably measured in conscious mice. To determine the importance of the other parameters in murine glucose homeostasis in lean and obese states, we developed the frequently sampled intravenous glucose tolerance test (FSIVGTT) for use in unhandled mice. We validated the conscious FSIVGTT against the euglycemic clamp for measuring Si in lean and obese mice. Insulin-resistant mice had increased first-phase insulin secretion, decreased Sg, and a reduced DI, qualitatively similar to humans. Intriguingly, although insulin secretion explained most of the variation in glucose disposal in lean mice, Sg and the DI more strongly predicted glucose disposal in obese mice. DI curves identified individual diet-induced obese (DIO) mice as having compensated or decompensated insulin secretion. Conscious FSIVGTT opens the door to apply mouse genetics to the determinants of in vivo insulin secretion, Sg, and DI, and further validates the mouse as a model of metabolic disease.

Dynamic arterial blood gas analysis in conscious, unrestrained C57BL/6J mice during exposure to intermittent hypoxia.

Rodent models of chronic intermittent hypoxia (IH) are commonly used to investigate the pathophysiological sequelae that result from hypoxic exposure in patients experiencing obstructive sleep apnea (OSA). Despite the widespread use of IH models, little attention has been paid to carefully defining the degree of oxyhemoglobin desaturation that occurs during each hypoxic period. Therefore, we developed a rapid blood sampling technique to determine the arterial blood gas changes that occur in conscious unrestrained mice during a single IH event and hypothesized that the arterial Po(2) (Pa(O(2))) at the nadir level of the inspired oxygen profile causes oxyhemoglobin saturation to fall to between 80% and 90%. Mice were exposed to 120-180 cycles of IH at a rate of 60 cycles/h, and arterial blood samples were withdrawn (<3 s) at baseline and at 10-s time intervals over the course of a single IH cycle. The IH regimen caused a decline in the fraction of inspired oxygen from room air levels to a transient nadir of 6.0 +/- 0.2% over the 30-s hypoxic period. The Pa(O(2)) and arterial oxyhemoglobin saturation reached a nadir of 47 +/- 2 mmHg and 85 +/- 2% at 30 s, respectively. Arterial Pco(2) decreased to a nadir of 26 +/- 2 mmHg at 30 s, associated with a rise in arterial pH to 7.46 +/- 0.2. We conclude that the magnitude of oxyhemoglobin desaturation that is induced in our murine model of IH is consistent with the degree of hypoxic stress that occurs in moderate to severe clinical OSA.