Biologic comparison of inhaled insulin formulations: Exubera™ and novel spray-dried engineered particles of dextran-10.

Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize aerosol properties for pulmonary delivery. The current study was undertaken to investigate the in vitro and in vivo inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (w/v) dextran 10. Physical characterization revealed a "raisin like" particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 µm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (C max), 126 and 121 (µU/mL), and concentration-time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.

HS-GC-FID method for quantification of HFA-152a in cell culture media, and plasma from a range of species and regulatory compliant validations.

INTRODUCTION: 1,1-Difluoroethane (HFA-152a) is being developed as an alternative propellant in pressurized metered dose inhalers (pMDIs). As a part of the regulatory development pathway, pharmacology, toxicology and clinical studies have been conducted with inhaled HFA-152a. These studies require fit for purpose regulatory compliant (GxP validated) methods for quantification of HFA-152a from blood. METHODS: As HFA-152a is a gas at standard temperature and pressure, novel methods were developed to support the analysis across the wide range of species and concentrations required for regulatory filing. RESULTS: The developed methods utilized a headspace auto sampler coupled to a gas chromatograph (GC) with flame ionization detection. Key factors in the successful method included bringing together fit for purpose approaches to the head space vials, volume of matrix (blood), detection range required for species/study objective, handling / transfer of blood into head space vials and the stability/storage required for the analysis of the samples. The species-specific assays were fully validated under regulatory (GLP) conditions for mouse, rat, rabbit, canine and human and non-regulatory (non GLP) validations for guinea pig and cell culture media. DISCUSSION: Overall the novel approach of head space analysis of whole blood allowed for the development and validation of assays used to generate the toxicokinetic data that supported clinical testing of HFA-152a as a new pMDI propellant.

Characterization of respiratory deposition of fluticasone-salmeterol hydrofluoroalkane-134a and hydrofluoroalkane-134a beclomethasone in asthmatic patients.

BACKGROUND: Fixed combination fluticasone-salmeterol is the most used anti-inflammatory asthma treatment in North America, yet no studies report the actual respiratory tract dose or the distribution of drug within the lungs. Inflammation due to asthma affects all airways of the lungs, both large and small. Inhaled steroid delivery to airways results from a range of drug particle sizes, with emphasis on smaller drug particles capable of reaching the peripheral airways. Previous studies suggested that smaller drug particles increase pulmonary deposition and decrease oropharyngeal deposition. OBJECTIVES: To characterize the dose of fluticasone-salmeterol hydrofluoroalkane-134a (HFA) (particle size, 2.7 µm) delivered to asthmatic patients and examine the drug distribution within the lungs. The results were compared with the inhalation delivery of HFA beclomethasone (particle size, 0.7 µm). METHODS: A crossover study was conducted in asthmatic patients with commercial formulations of fluticasone-salmeterol and HFA beclomethasone radiolabeled with technetium Tc 99m. Deposition was measured using single-photon emission computed tomography/computed tomography gamma scintigraphy. RESULTS: Two-dimensional planar image analysis indicated that 58% of the HFA beclomethasone and 16% of the fluticasone-salmeterol HFA were deposited in the patient's lungs. The oropharyngeal cavity and gut analyses indicated that 77% of the fluticasone-salmeterol HFA was deposited in the oropharynx compared with 35% of the HFA beclomethasone. CONCLUSIONS: The decreased peripheral airway deposition and increased oropharyngeal deposition of fluticasone-salmeterol HFA was a result of its larger particle size. The smaller particle size of HFA beclomethasone allowed a greater proportion of lung deposition with a concomitant decrease in oropharyngeal deposition.

Particle size of inhaled corticosteroids: does it matter?

A question with respect to asthma therapy revolves around the issue of whether better efficacy occurs with an ultrafine-particle inhaled corticosteroid because of better lung deposition into the distal airways. This article reviews particle size and delivery devices of different steroids, clinical outcomes of small- versus large-particle steroids, and the issue of pharmacoeconomics.

Inhaled insulin is associated with prolonged enhancement of glucose disposal in muscle and liver in the canine.

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.

Inhalation of human insulin (exubera) augments the efficiency of muscle glucose uptake in vivo.

This study assessed the site of increased glucose uptake resulting from insulin inhalation, quantified its effect under steady-state glucose concentrations, and identified the time to onset of effect. Human insulin was administered to 13 beagles via inhalation (Exubera [insulin human (rDNA origin)] Inhalation Powder; n = 7) or infusion into the inferior vena cava (Humulin R; n = 6) using an algorithm to match plasma insulin levels and kinetics for both groups. Somatostatin and glucagon were infused. Glucose was delivered into the portal vein (4 mg x kg(-1) x min(-1)) and a peripheral vein, as needed, to maintain arterial plasma glucose levels at 180 mg/dl. Hepatic exposure to insulin and glucose and liver glucose uptake were similar in both groups. Despite comparable arterial insulin and glucose levels, hind-limb glucose uptake increased 2.4-fold after inhalation compared with infusion due to increased muscle glucose uptake. Glucose infusion rate, nonhepatic glucose uptake, and tracer-determined glucose disposal were about twice as great compared with intravenous insulin. The effect appeared after 1 h, persisting at least as long as arterial insulin levels remained above basal. Pulmonary administration of insulin increases nonhepatic glucose uptake compared with infusion, and skeletal muscle is the likely site of that effect.

Inhalation of insulin (Exubera) is associated with augmented disposal of portally infused glucose in dogs.

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 x kg(-1) x 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 x kg(-1) x 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.

Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers.

Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of ciclesonide. Technetium-99m (99mTc)-labeled ciclesonide (where the 99mTc-label is physically dissolved in the ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg ciclesonide for 2-D and 3-D imaging. The ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of ciclesonide produced no drug-related side effects. In conclusion, ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.

Respiratory Tract Deposition of HFA-Beclomethasone and HFA-Fluticasone in Asthmatic Patients.

BACKGROUND: The asthmatic patient's respiratory tract deposition of HFA fluticasone (Flovent HFA(™)) has not been established. There is a known large particle size difference with another commercial inhaled HFA steroid (QVAR(™)). This study compared the 2D and 3D respiratory tract deposition of each inhaled steroid. METHODS: This study was an open label, crossover study in eight patients diagnosed with asthma. The regional respiratory and oropharyngeal deposition of the two steroids were compared and contrasted using planar and SPECT imaging following delivery of the (99m)Tc-radiolabeled drug in each product. The SPECT images were merged with computed tomography images to quantify regional deposition within the patients. RESULTS: Two-dimensional (2D) planar images indicated that 24% of the Flovent HFA dose and 55% of the QVAR dose deposited in the lungs. 2D oropharyngeal deposition indicated that 75% of the Flovent HFA dose was deposited in the oropharynx, while 42% of the QVAR dose deposited in the oropharynx. Three-dimensional (3D) SPECT data indicated that 22% of the Flovent HFA dose and 53% of the QVAR dose deposited in the lungs. 3D oropharyngeal and gut deposition indicated 78% of the Flovent HFA dose was deposited in the oropharynx, while 47% of the QVAR dose deposited in the oropharynx. The increased lung deposition and decreased oropharynx deposition for both 2D and 3D image data of QVAR were statistically different from Flovent HFA. CONCLUSIONS: QVAR exhibited a significant increase in lung delivery compared to Flovent HFA. Conversely, QVAR delivered a significantly lower dose to the oropharynx than Flovent HFA. The findings were presumed to be driven by the smaller particle size of QVAR (0.7 microns MMAD) compared with Flovent HFA (2.0 microns MMAD).

Inhalation of insulin in dogs: assessment of insulin levels and comparison to subcutaneous injection.

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 microU/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 microU/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.

Alternative propellant aerosol delivery systems.

The year 2006 represents the 50th anniversary of the pressurized metered dose inhaler. With most technologies, 50 years represents a significant time span for technology evolution and modification, but with propellant-driven metered dose inhalers, the pace of change has been relatively slow. We are now in the era of alternative propellant aerosol delivery systems, but at this 50-year juncture, what are the characteristics of these systems and what are the prospects for future advances? This review will consider alternative propellant aerosol delivery systems broadly from their inception through future opportunities and challenges.

The CFC to HFA transition and its impact on pulmonary drug development.

The terms of the Montreal Protocol have eliminated chlorofluorocarbons (CFCs) and other ozone-depleting agents from commercial use, with the exemption of their use as propellants in metered-dose inhalers. Two new propellants have been approved for CFC substitutes: hydrofluoroalkane (HFA)-134a and HFA-227. An extensive safety program was conducted by the International Pharmaceutical Aerosol Consortium for Toxicity Testing (IPACT studies I and II), which found that the HFAs were as safe as or safer than the CFCs. The change from CFCs to HFAs in metered-dose inhalers was not a straightforward exchange. Indeed, substantial new technology had to be developed to make the HFAs suitable for use in metered-dose inhalers. Fortunately, with new understandings of respiratory diseases and the areas of the lungs that need to be targeted by medications, the new HFAs provided the opportunity to improve the performance of the beta-agonist products and created some entirely new ability for inhaled steroids to reach all the airways, both large and small, where asthma pathology resides. The transition from CFCs also spurred novel new drug-delivery technologies, improved dry powder inhalers, and highly dispersible engineered powders.

Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler.

The objective of this study was to determine the lung delivery of HFA-134a-beclomethasone dipropionate (HFA-BDP) from a breath-activated inhaler (QVAR Autohaler) compared with proper and improper press and breathe (QVAR P&B) metered dose inhaler (MDI) technique. The hypothesis was that that the smaller particles of BDP from HFA-BDP would stay suspended longer in the inspiratory air of patients and thus reduce the deleterious effects of inhaler discoordination. The study was an open label, four period, cross-over design. Asthmatic patients (n = 7) with a history of asthma symptoms, an FEV-1 of >70% of predicted normal, and a history of reversibility to a beta-agonist of >or=12% were utilized. BDP was radiolabeled with technetium-99m and delivered from the QVAR Autohaler or QVAR P&B device in patients trained to reproducibly utilize coordinated and discoordinated P&B MDI technique. Patients using Autohaler MDI exhibited 60% lung deposition of BDP. Patients using coordinated technique with the P&B MDI exhibited 59% lung deposition. Patients trained to consistently actuate the P&B MDI before inhaling exhibited 37% lung deposition. Patients trained to consistently actuate the P&B MDI late in the inspiration (i.e., 1.5 sec into a 3-sec inspiration) exhibited 50% lung deposition. In conclusion, the breath-activated Autohaler automatically provided optimal BDP lung deposition of 60%. Patients with good P&B MDI technique also received optimal lung deposition of 59%. The degree of lung deposition was decreased as patients demonstrated poor inhaler technique. However patients with poor technique still received a large lung dose of BDP (i.e., >or=37%) compared with lung deposition values of 4-7% for CFC-BDP MDIs previously published and confirmed in this study.

Nasal Deposition of HFA-Beclomethasone, Aqueous Fluticasone Propionate and Aqueous Mometasone Furoate in Allergic Rhinitis Patients.

BACKGROUND: The deposition of nasal aerosols from both aqueous formulations and propellant-based formulations has only minimally been described in rhinitis patients. This study quantified the regional nasal deposition of QNASL(™) (HFA-beclomethasone, nasal aerosol), Flonase(™) (fluticasone propionate, nasal spray) and Nasonex(™) (mometasone furoate monohydrate, nasal spray). METHODS: This study was an open label, crossover study in nine patients with allergic rhinitis. The regional nasal deposition of the three nasal products was compared and contrasted following delivery of the (99m)Tc-radiolabeled drug product in each product. The gamma images were merged with magnetic resonance images to quantify regional deposition within the patients. RESULTS: The HFA propellant-based formulation (QNASL) resulted in an increased retention of drug product in the nasal cavity compared with the two aqueous formulations (Flonase and Nasonex). The aqueous based formulations resulted in increased amount of the delivered dose that dripped from the nostril (6/8 patients for each of the aqueous formulations and 0/8 patients for the HFA propellant formulation) following administration. The percentage of delivered dose that deposited in the back of the throats of the patients was increased and variable (0.1% to 17.6% with Flonase and 0.0 to 4.7% for Nasonex) for the aqueous formulations when compared to dose delivered for the HFA propellant formulation (0.0% to 1.7% for QNASL). CONCLUSIONS: The regional deposition of the HFA propellant based formulation resulted in increased retention of drug product in the nasal cavity and decreased deposition in the back of the throat compared to the two aqueous formulations.

Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone : a cross-over study in healthy volunteers.

STUDY OBJECTIVES: To compare the lung deposition of radiolabeled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) with chlorofluorocarbon fluticasone propionate (CFC-FP) and chlorofluorocarbon beclomethasone (CFC-BDP). DESIGN: Six-day, open-label, nonrandomized, crossover study. SETTING: Clinical research laboratory. PARTICIPANTS: Nine healthy, nonsmoking, adult volunteers. INTERVENTIONS: On each study day, participants inhaled one or two puffs of 99mTc-labeled HFA-BDP, CFC-FP, or CFC-BDP. All products delivered 50 micro g per puff ex-valve. Subjects used a respiratory training and monitoring device to meet predefined, standardized inhalation patterns. Immediately after inhalation of radiolabeled study drug, planar gamma camera images were obtained. MEASUREMENTS AND RESULTS: Radiolabeled HFA-BDP had a higher deposition in the lungs (53% ex-actuator) compared with CFC-FP (12 to 13%) and CFC-BDP (4%). Conversely, CFC-FP and CFC-BDP had a much higher distribution to the oropharynx (72 to 78%, and 82%, respectively) than HFA-BDP (29%). HFA-BDP was deposited evenly throughout the lungs, while CFC-FP and CFC-BDP deposition was primarily in the large central and intermediate airways. Andersen particle size sampling gave mass median aerodynamic diameters for HFA-BDP, CFC-FP, and CFC-BDP of 0.9 micro m, 2.0 micro m, and 3.5 micro m, respectively. CONCLUSIONS: Lung deposition was greater with HFA-BDP compared with CFC-FP and CFC-BDP. Deposition values appeared to be related to the particle size distribution of each inhaler, with the smaller particles of HFA-BDP providing the greatest lung deposition and least oropharyngeal deposition.

A pilot study to assess lung deposition of HFA-beclomethasone and CFC-beclomethasone from a pressurized metered dose inhaler with and without add-on spacers and using varying breathhold times.

BACKGROUND: The study objective of this pilot study was to determine the lung delivery of HFA-134a-beclomethasone dipropionate (HFA-BDP; QVAR™) and CFC-beclomethasone dipropionate (CFC-BDP; Becloforte™) with and without the add-on spacers, Aerochamber™, and Volumatic™. The smaller particles of HFA-BDP were presumed to produce greater lung deposition using spacers, with and without a delay [i.e., metered dose inhaler (MDI) actuation into the spacer and subsequent inhalation 0 and 2 sec later], compared with the larger particles of CFC-BDP. The study included a comparison of breathhold effects (i.e., 1 and 10-sec breatholds) on lung deposition. METHODS: The study was an open-label design and utilized healthy subjects (n = 12 males). Each arm of the study contained three subjects; thus, outcomes were not powered to assess statistical significance. HFA-BDP and CFC-BDP were radiolabeled with technetium-99m and delivered to subjects. RESULTS: Results showed that the small particle HFA-BDP lung deposition averaged 52% and was not affected by the use of Aerochamber with or without a spacer delay. The oropharyngeal deposition of HFA-BDP was reduced from approximately 28% to 4% with the Aerochamber. Lung deposition with the large particle CFC-BDP was 3-7% and generally decreased with Aerochamber or Volumatic. A 2-sec time delay between actuation and breath plus the spacer reduced lung deposition slightly but reduced oropharygeal deposition substantially (84% down to 3-20%) using the Aerochamber or Volumatic with and without a spacer delay. HFA-BDP lung deposition was dependent on the breathhold. Lung deposition with HFA-BDP was reduced by 16% with a 1-sec versus 10-sec breathhold. The difference was measured in the increased exhaled fraction, confirming that smaller particles need time to deposit and are exhaled if there is a reduced breathhold. The large particle CFC-BDP lung deposition was not affected by breathhold. CONCLUSIONS: The use of Aerochamber or Volumatic spacers with HFA-BDP did not alter lung deposition but it did reduce oropharyngeal deposition. However, HFA-BDP displayed reduced oropharyngeal deposition without a spacer.

Inhalation aspects of therapeutic aerosols.

The pulmonary route of drug delivery can provide an excellent alternative to other routes both for local lung disease as well as systemic delivery. The year 2006 marks the 50th year since the invention of metered dose inhalers, yet inhalation is a very much underutilized route of delivery, possibly because inhalation drug development is perceived as being too difficult and expensive. However with proper knowledge these purported difficulties can be overcome. The process begins with identifying the target tissue and then utilizing technologies such as particle size adjustments through formulation techniques and delivery devices to most efficiently deliver the desired dose. There are a variety of new and existing inhaled excipients available to accomplish this goal. The active molecule can also be modified to increase solubility, decrease immunogenicity, and protect it from unwanted metabolism using PEGylation. Sustained release of an inhaled drug is also possible using biocompatible matrices such as oligolactic acid.

Inhalation of human insulin is associated with improved insulin action compared with subcutaneous injection and endogenous secretion in dogs.

This study compared the effects of endogenous (portal) insulin secretion versus peripheral insulin administration with subcutaneous or inhaled human insulin [INH; Exubera, insulin human (rDNA origin) inhalation powder] on glucose disposal in fasted dogs. In the control group, glucose was infused into the portal vein (Endo; n = 6). In two other groups, glucose was infused portally, whereas insulin was administered peripherally by inhalation (n = 13) or s.c. injection (n = 6) with somatostatin and basal glucagon. In the Endo group, over the first 3 h, the arterial insulin concentration was twice that of the peripheral groups, whereas hepatic sinusoidal insulin levels were half as much. Although net hepatic glucose uptake was greatest in the Endo group, the peripheral groups demonstrated larger increases in nonhepatic glucose uptake so that total glucose disposal was greater in the latter groups. Compared with s.c. insulin action, glucose excursions were smaller and shorter, and insulin action was at least twice as great after INH. Thus, at the glucose dose and insulin levels chosen, peripheral insulin delivery was associated with greater whole-body glucose disposal than endogenous (portal) insulin secretion. INH administration resulted in increased insulin sensitivity in nonhepatic but not in hepatic tissues compared with s.c. delivery.