Of the parameters that determine glucose disposal and progression to diabetes in humans: first-phase insulin secretion, glucose effectiveness, insulin sensitivity, and the disposition index, only insulin sensitivity 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 insulin sensitivity in lean and obese mice. Insulin resistant mice had increased first-phase insulin secretion, decreased glucose effectiveness and a reduced disposition index, qualitatively similar to humans. Intriguingly, while insulin secretion explained most of the variation in glucose disposal in lean mice, glucose effectiveness and the disposition index more strongly predicted glucose disposal in obese mice. Disposition index curves identified individual diet-induced obese 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, glucose effectiveness and disposition index, and further validates the mouse as a model of metabolic disease.

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 Mice were exposed to 120-180 cycles of IH at a rate of 60 cycles/h, and arterial blood samples were withdrawn (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.

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; SI) and insulin-independent (glucose effectiveness; Sg) glucose disposal, as well as the insulin response to glucose (acute insulin response to glucose; AIRg). Our data show that 1-day exposure impaired the glucose tolerance and caused reductions in Sg and AIRg in both the IH and CH groups, but only IH caused a significant decrease in SI (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 SI 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.

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Optimizing glucose and insulin metabolism in sepsis and critical illness remains a clinical and scientific dilemma. We previously Rationale: demonstrated that mortality in a hyperglycemic mouse model of sepsis may be related to impaired pancreatic function. Using a novel frequently sampled intravenous glucose tolerance test (FSIVGTT) in conscious mice, we subsequently observed that endotoxemia leads to profound glucose intolerance and insulin resistance only under the condition of mild hyperglycemia. We now extend this work to further investigate the role of the pancreatic response in the metabolic dysfunction observed in critical illness.Adult male C57BL/6NTac mice were instrumented with chronic indwelling arterial and venous catheters. After 3 days recovery Methods: from surgery, four groups of mice were either infused with glucose (D50) to elicit mild hyperglycemia or saline at 100 ul/hr for 24 hours before acute intra-arterial administration of endotoxin (LPS, 1 mg/kg) or vehicle. Five hours after LPS administration, an FSIVGTT was performed by rapidly sampling arterial blood for glucose (and insulin) at (