Pioglitazone does not affect exogenous glucose oxidation or metabolic clearance rate during steady-state aerobic exercise at high altitude

Background: Hypoxia-induced insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR, proxy for peripheral glucose uptake) in native lowlanders exercising during the initial hours of high-altitude (HA) exposure compared sea level. These data suggest that administering an insulin sensitizing drug before HA exposure may increase exogenous glucose oxidation rate by stimulating peripheral glucose uptake. Objective: To compare the effects of pioglitazone (PIO) and placebo (PLA) on exogenous glucose oxidation and MCR during steady-state aerobic exercise at HA. We hypothesized that exogenous glucose oxidation and MCR would be higher with PIO than PLA. Methods: Using a randomized, crossover design, native lowlanders (n = 7 males, mean ± SD, age: 23 ± 6 y, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (1.43 ± 0.16 VȮ2 L/min) treadmill exercise at HA (460 mmHg) after being administered PIO (15 mg) or PLA (microcrystalline cellulose pill) daily for five days. Substrate oxidation and glucose turnover were determined using indirect calorimetry, oral 13C-glucose and [6,6-2H2]-glucose primed, continuous infusions. Results: Exogenous glucose oxidation rate was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation with PIO (1.65 ± 0.22 g/min) was the same as PLA (1.68 ± 0.32 g/min). There were no treatment effects on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min) disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), and MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Conclusion: These data do not support our hypothesis that exogenous glucose oxidation during exercise at HA can be restored through the short-term administration of PIO. Findings from this study may suggest that hypoxia-induced insulin resistance may be a symptom and not the primary etiology of dysregulated glucose metabolism during acute HA exposure. Supported by MOMRP; authors’ views not offcial US Army or DoD policy. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.