Abstract
Diabetic patients treated with inhaled insulin exhibit reduced fasting plasma glucose levels. In dogs, insulin action in muscle is enhanced for as long as 3 h after insulin inhalation. This study was designed to determine whether this effect lasts for a prolonged duration such that it could explain the effect observed in diabetic patients. Human insulin was administered via inhalation (Exubera; n = 9) or infusion (Humulin R; n = 9) in dogs using an infusion algorithm that yielded matched plasma insulin kinetics between the two groups. Somatostatin was infused to prevent insulin secretion, and glucagon was infused to replace basal plasma levels of the hormone. Glucose was infused into the portal vein at 4 mg/kg/min and into a peripheral vein to maintain the arterial plasma glucose level at 160 mg/dl. Arterial and hepatic sinusoidal insulin and glucose levels were virtually identical in the two groups. Notwithstanding, glucose utilization was greater when insulin was administered by inhalation. At its peak, the peripheral glucose infusion rate was 4 mg/kg/min greater in the inhalation group, and a 50% difference between groups persisted over 8 h. Inhalation of insulin caused a greater increase in nonhepatic glucose uptake in the first 3 h after inhalation; thereafter, net hepatic glucose uptake was greater. Inhalation of insulin was associated with greater than expected (based on insulin levels) glucose disposal. This may explain the reduced fasting glucose concentrations observed in humans after administration of certain inhaled insulin formulations compared with subcutaneous insulin.
Footnotes
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↵1 On October 18, 2007, Pfizer Inc., announced that it would cease marketing Exubera because it did not meet the needs or financial expectations of customers. On April 9, 2008, Pfizer Inc., announced that it was updating the Exubera Product Insert to include the following statement: “In studies of Exubera in people with diabetes, lung cancer occurred in a few more people who were taking Exubera than in people who were taking other diabetes medicines. All of the people in these studies who developed lung cancer used to smoke cigarettes. There were too few cases to know if the lung cancer was related to Exubera.”
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This work was supported by Pfizer Inc.
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doi:10.1124/jpet.108.146985.
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ABBREVIATIONS: nonHGU, nonhepatic glucose uptake; ACE, angiotensin-converting enzyme; IVC, inferior vena cava; INH, inhalation group; IV, intravenous group; BK, bradykinin; AT, angiotensin; NHGB, net hepatic glucose balance; AUC, area(s) under the curve; peGIR, peripheral glucose infusion rate; NO, nitric oxide.
- Received October 3, 2008.
- Accepted December 16, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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