5 Diabetes, hyperinsulinemia, and the hypoxic ventilatory response Netherlands) mass-flow controllers (EL-Flow, Bronkhorst High Tech, the Netherlands) provided a gas mixture consisting of nitrogen, carbon dioxide, and oxygen as desired. The software allows for the steering of the end-tidal gas concentrations (by varying the inspired concentration) and the collection of respiratory variables. Airflow was measured with a pneumotachograph/ pressure transducer system (#4813, Hans Rudolph, Shawnee, Kansas). Both inspiratory and expiratory concentrations for O2 and CO2 were continuously measured (ISA OR+Masimo Root Platform, Irvine, CA). Heart rate and oxygen saturation were obtained by pulse oximetry at the finger (Radical-7 Masimo Root Platform, Irvine, CA). Ventilation data were collected on a breath-tobreath basis. Respiratory Measurements Isocapnic ventilatory response to hypoxia The HVR was obtained at isocapnia (end-tidal PCO2 0.3-0.4 kPa above resting PCO2) by a rapid decrease in inspired oxygen fraction to 0.08 that was maintained for 5 min. Thereafter, the subjects were made hyperoxic (inspired oxygen fraction 0.4) for another 5 min. The HVR was calculated as VE/SpO2. Modified Dejour Test. The ventilatory response to 5 breaths of hyperoxia (inspired oxygen fraction 1.0) was obtained after 5 min of room air breathing. The decrease in ventilation in response to hyperoxia provides an indirect assessment of carotid sinus afferent nerve activity, which, in this context, is considered an indicator of carotid body activity or the carotid body's influence on resting ventilation. Modified Dejour The ventilatory response to 5 breaths of hyperoxia (inspired oxygen fraction 1.0) was obtained after 5 min of room air breathing. The decrease in ventilation in response to hyperoxia provides an indirect assessment of carotid sinus afferent nerve activity, which, in this context, is considered an indicator of carotid body activity or the carotid body's influence on resting ventilation. Hyperinsulemic-euglycemic clamp A manual hyperinsulinemic-euglycemic clamp was applied as described by de Fronzo et al.24 Insulin (100 IU/ml, Novorapid) was infused intravenously at 40 mU/body surface area (m2)/min, to achieve steady-state insulin levels (plasma levels ˜ 700 mU/mL). The body surface was calculated using Du Bois equation. Glucose 40% was infused to maintain blood glucose at a predetermined target level (fasting arterial blood glucose). Adjustments were performed at 5 min intervals, using arterial samples to determine glucose level using a blood gas analyzer (RAPID point 500e, Siemens Healthineers, Erlangen, Germany) for a total duration of 120 min. Respiratory measurements were performed during steady-state glucose infusion rates (coefficient of variation in blood glucose ≤ 103
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