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

Abstract

The results of the present study, using the conscious beagle dog, demonstrate that inhaled insulin (INH; Exubera) provides better glycemic control during an intraportal glucose load than identical insulin levels induced by insulin (Humulin) infusion into the inferior vena cava (IVC). In the INH group (n ‫؍‬ 13), portal glucose infusion caused arterial plasma glucose to rise transiently (152 ؎ 9 mg/dl), before it returned to baseline (65 min) for the next 2 h. Net hepatic glucose uptake was minimal, whereas nonhepatic uptake rose to 12.5 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 (65 min). In the IVC group (n ‫؍‬ 9), arterial glucose rose rapidly (172 ؎ 6 mg/dl) and transiently fell to 135 ؎ 13 mg/dl (65 min) before returning to 165 ؎ 15 mg/dl (125 min). Plasma glucose excursions and hepatic glucose uptake were much greater in the IVC group, whereas nonhepatic uptake was markedly less (8.6 ؎ 0.9 mg ⅐ kg ؊1 ⅐ min ؊1 ; 65 min). Insulin kinetics and areas under the curve were identical in both groups. These data suggest that inhalation of Exubera results in a unique action on nonhepatic glucose clearance. Diabetes 54:1164 -1170, 2005 I nsulin delivered by inhalation is an alternative to injected insulin for patients with diabetes. Clinical studies comparing subcutaneous administration of insulin (Humulin) with insulin inhalation (Exubera) suggest that there is a unique glucose-lowering effect associated with inhaled insulin (1). 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.The difference in glycemic control resulting from inhalation verses subcutaneous administration of insulin could be explained by the different pharmacokinetic insulin profiles resulting from the two routes of administration, or by some unique aspect of insulin delivery by inhalation. To distinguish between these possibilities, we delivered insulin by inhalation (Exubera) or through infusion (Humulin) into the inferior vena cava (IVC) to create an identical pharmacokinetic profile to that resulting from insulin inhalation. We then examined the effects of both routes of insulin delivery on glucose disposal during a simulated oral glucose load. To further clarify the mechanism by which glucose disposal might be enhanced, we compared the role of the liver and nonhepatic tissues in glucose uptake. RESEARCH DESIGN AND METHODSExperiments were conducted on 22 healthy, conscious, 18-h-fasted, male beagle dogs (weight 8 -10 kg). Before the study, they were fed a standard diet once a day, and water was provided ad libitum. The surgical facility met the standards published by the American Association for the Accredi...

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).…”

Inhalation of Human Insulin Is Associated with Improved Insulin Action Compared with Subcutaneous Injection and Endogenous Secretion in Dogs

“…These observations raise the question whether there is a unique glucose-lowering effect associated with insulin delivered by inhalation, although that study was not specifically designed to test the bioefficacy of insulin delivered by inhalation compared with s.c. injection. Recently, we demonstrated that enhanced nonhepatic glucose clearance is indeed associated with the pulmonary route of insulin administration compared with intravenous insulin infusion (Edgerton et al, 2005). Therefore, the second aim of the present study was to further investigate the apparent unique effect of insulin inhalation on increased insulin sensitivity.…”

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

“…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].…”

“…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]. 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].…”