title: Inhaled insulin is associated with prolonged enhancement of glucose disposal in muscle and liver in the canine.
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.
authors.affiliation: Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 710 Robinson Research Building, Nashville, TN 37232-0615, USA. dale.edgerton@vanderbilt.edu
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
authors.forename: Doss W
authors.initials: DW
authors.lastname: Neal
authors.forename: Melanie
authors.initials: M
authors.lastname: Scott
authors.forename: Margaret
authors.initials: M
authors.lastname: Lautz
authors.forename: Nancy
authors.initials: N
authors.lastname: Brown
authors.forename: Jeff
authors.initials: J
authors.lastname: Petro
authors.forename: Charles H
authors.initials: CH
authors.lastname: Hobbs
authors.forename: Chet
authors.initials: C
authors.lastname: Leach
authors.forename: Angelo
authors.initials: A
authors.lastname: Del Parigi
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Strack
mesh_terms: D000280:Administration, Inhalation; D000465:Algorithms; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy; D004285:Dogs; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007260:Infusion Pumps; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: C473734:Exubera; D007328:Insulin; D011994:Recombinant Proteins; D005947:Glucose