Inhalation of Insulin in Dogs

Abstract

Pulmonary insulin delivery is being developed as a more acceptable alternative to conventional subcutaneous administration. In 15 healthy Beagle dogs (average weight 9.3 kg), we compared insulin distribution in arterial, deep venous, and hepatic portal circulation. Dogs received 0.36 units/kg s.c. regular human insulin (n ‫؍‬ 6) or 1 mg (2.8 units/kg) or 2 mg (5.6 units/kg) dry-powder human inhaled insulin (n ‫؍‬ 3 and 6, respectively). Postinhalation of inhaled insulin (1 or 2 mg), arterial insulin levels quickly rose to a maximum of 55 ؎ 6 or 92 ؎ 9 U/ml, respectively, declining to typical fasting levels by 3 h. Portal levels were lower than arterial levels at both doses, while deep venous levels were intermediate to arterial and portal levels. In contrast, subcutaneous insulin was associated with a delayed and lower peak arterial concentration (55 ؎ 8 U/ml at 64 min), requiring 6 h to return to baseline. Peak portal levels for subcutaneous insulin were comparable to those for 1 mg and significantly less than those for 2 mg inhaled insulin, although portal area under the curve (AUC) was comparable for the subcutaneous and 2-mg groups. The highest insulin levels with subcutaneous administration were seen in the deep venous circulation. Interestingly, the amount of glucose required for maintaining euglycemia was highest with 2 mg inhaled insulin. We conclude that plasma insulin AUC for the arterial insulin level (muscle) and hepatic sinusoidal insulin level (liver) is comparable for 2 mg inhaled insulin and 0.36 units/kg subcutaneous insulin. In addition, arterial peak concentration following insulin inhalation is two times greater than subcutaneous injection; however, the insulin is present in the circulation for half the time. Diabetes 53:877-881, 2004

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

“…Previous studies in dogs have shown that inhaled insulin has a higher and earlier peak of arterial insulin that clears more rapidly than subcutaneous insulin. Despite the similar arterial and hepatic insulin areas under the curve (AUCs) in the two groups, a 20% greater glucose infusion rate was required to maintain euglycemia in the inhaled insulin group relative to the subcutaneous insulin group (2). This finding was consistent with the unique glucose-lowering effect of inhaled insulin seen in human studies.…”

Use of Inhaled Insulin in a Basal/Bolus Insulin Regimen in Type 1 Diabetic Subjects

“…Although the reasons for this are not clear, it is possible that 1) the FPG decrease with inhaled insulin relates to IAbs functioning as a repository that slowly releases insulin (22) (however, no correlation between insulin binding and FPG has been observed to date with this preparation) or 2) the inhalation of insulin may increase insulin sensitivity or reduce endogenous glucose release (23,24).…”

Mealtime inhaled insulin lowers fasting glucose: a look at possible explanations

“…In a first trial, inhaled insulin as compared with insulin infused in the portal vein increased non-hepatic glucose clearance for up to 3 h [5]. In a second trial, the amount of glucose needed to maintain euglycaemia over 6 h was 20% higher in the inhaled group than in the group that received subcutaneous insulin, despite similar insulin AUCs [6]. In all, it therefore seems unlikely that either basal insulin supplementation or the pharmacodynamic properties of inhaled insulin can account for the difference in fasting glucose noted with the use of inhaled insulin.…”

“…The possibility that 'the inhalation of insulin may increase insulin sensitivity or reduce endogenous glucose release' comes from trials in dogs [5,6]. In a first trial, inhaled insulin as compared with insulin infused in the portal vein increased non-hepatic glucose clearance for up to 3 h [5].…”