Measurement of Insulin Absorption and Insulin Action

Heinemann, Lutz; Anderson, James H.

doi:10.1089/dia.2004.6.698

Cited by 55 publications

(44 citation statements)

References 42 publications

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“…Similar bioavailability and biopotency values for AIR insulin (relative to insulin lispro) in healthy subjects have been previously reported (11) and have been corroborated by clinical experience in patients with diabetes (15). Further, the intrasubject variability values that were observed for AIR insulin-an important consideration in the context of an insulin's clinically reproducible metabolic effect (16,17)-are compatible with the potential use of this product in the treatment of diabetes.…”

Section: Safetysupporting

confidence: 83%

AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease

et al. 2007

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OBJECTIVE -In this open-label, randomized, crossover study, pharmacokinetic and glucodynamic responses were compared in healthy subjects versus subjects with moderate chronic obstructive pulmonary disease (COPD), following administration of 12 units equivalent AIR inhaled insulin versus 12 units subcutaneous insulin lispro.RESEARCH DESIGN AND METHODS -Three nonsmoking groups (n ϭ 15 each)-healthy subjects (baseline mean Ϯ SD age 38 Ϯ 13 years, forced expiratory volume in 1 s [FEV 1 ] 4.06 Ϯ 1.04 l), subjects with chronic bronchitis (aged 53 Ϯ 9 years, FEV 1 2.14 Ϯ 0.60 l), and subjects with pulmonary emphysema (aged 58 Ϯ 6 years, FEV 1 1.67 Ϯ 0.61 l)-were randomly assigned to one of three treatment sequences. Three euglycemic glucose clamp procedures were performed.RESULTS -In subjects with chronic bronchitis and emphysema, AIR inhaled insulin administration resulted in reduced insulin exposure (area under the serum insulin concentration curve from time zero until time of return to baseline [AUC 0 -tЈ ]) (55.7%, P ϭ 0.13 and 78.5%, P Ͻ 0.001, respectively) and reduced total insulin effect (total glucose infusion rate) (60.4%, P Ͻ 0.01 and 67.1%, P Ͻ 0.01, respectively) relative to healthy subjects. Subcutaneous insulin lispro administration resulted in similar responses across study groups for insulin exposure and metabolic effect. Intrasubject pharmacokinetic and glucodynamic variability ranged from 17 to 52% across groups. No significant differences were shown for pre-and postclamp pulmonary function tests. During clamps, FEV 1 and forced vital capacity declined modestly in both COPD groups, with no difference between AIR insulin and subcutaneous insulin lispro.CONCLUSIONS -Short-term exposure to AIR inhaled insulin was well tolerated by COPD subjects, showing similar time-exposure and time-action profiles, but with reduced insulin absorption and metabolic effect compared with healthy subjects. Further clinical evaluation is warranted in patients with comorbid diabetes and COPD. Diabetes Care 30:1777-1782, 2007I nhaled insulin has been approved recently in both Europe and the U.S. as an alternative to subcutaneous insulin injection in the treatment of patients with diabetes. A number of clinical trials in subjects with diabetes have demonstrated the feasibility and patient acceptance of administering insulin by the pulmonary route (1-6); however, there is little or no information on the acute or chronic effects of inhaled insulin exposure in patients with concomitant lung disease. Similarly, there are little data about how lung disease itself might alter pharmacokinetic and glucodynamic responses to inhaled insulin.AIR (a registered trademark of Alkermes, Cambridge, MA) is a newly developed inhaled insulin formulation that uses a novel technology to deliver a drypowder aerosol composed of large, lowdensity particles (2-5 m in aerodynamic diameter) of spray-dried human insulin in an excipient matrix (7). This type of formulation results in a high dispersibility of respirable particles (8) and allows for the use...

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Section: Safetysupporting

confidence: 83%

AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease

et al. 2007

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“…Finally, the results of the current study are relevant to the understanding of PD in clamp studies after subcutaneous injection of long-acting insulin analogs in T2DM (39,40). Distribution of the metabolic effect may be quite different if the insulin to be studied is injected in the morning compared with the evening.…”

Section: Discussionmentioning

confidence: 92%

Pharmacokinetics and Pharmacodynamics of Insulin Glargine Given in the Evening as Compared With in the Morning in Type 2 Diabetes

et al. 2014

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OBJECTIVETo compare pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration. RESEARCH DESIGN AND METHODSTen T2DM insulin-treated persons were studied during 24-h euglycemic glucose clamp, after glargine injection (0.4 units/kg s.c.), either in the evening (2200 h) or the morning (1000 h). RESULTSThe 24-h glucose infusion rate area under the curve (AUC 0-24h ) was similar in the evening and morning studies (1,058 6 571 and 995 6 691 mg/kg 3 24 h, P = 0.503), but the first 12 h (AUC 0-12h ) was lower with evening versus morning glargine (357 6 244 vs. 593 6 374 mg/kg 3 12 h, P = 0.004), whereas the opposite occurred for the second 12 h (AUC 12-24h 700 6 396 vs. 403 6 343 mg/kg 3 24 h, P = 0.002). The glucose infusion rate differences were totally accounted for by different rates of endogenous glucose production, not utilization. Plasma insulin and C-peptide levels did not differ in evening versus morning studies. Plasma glucagon levels (AUC 0-24h 1,533 6 656 vs. 1,120 6 344 ng/L/h, P = 0.027) and lipolysis (free fatty acid AUC 0-24h 7.5 6 1.6 vs. 8.9 6 1.9 mmol/L/h, P = 0.005; b-OH-butyrate AUC 0-24h 6.8 6 4.7 vs. 17.0 6 11.9 mmol/L/h, P = 0.005; glycerol, P < 0.020) were overall more suppressed after evening versus morning glargine administration. CONCLUSIONSThe PD of insulin glargine differs depending on time of administration. With morning administration insulin activity is greater in the first 0-12 h, while with evening administration the activity is greater in the 12-24 h period following dosing. However, glargine PK and plasma C-peptide levels were similar, as well as glargine PD when analyzed by 24-h clock time independent of the time of administration. Thus, the results reflect the impact of circadian changes in insulin sensitivity in T2DM (lower in the night-early morning vs. afternoon hours) rather than glargine per se.

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“…Subjects underwent automated euglycemic glucose clamp procedures (Biostator (glucose-controlled glucose infusion system); Life Science Instruments, Elkhart, IN, USA; (5,6)) at each of the four clamp visits. Subjects fasted for at least 8 h before and for the entire duration of each clamp procedure.…”

Section: Glucose Clamp Proceduresmentioning

confidence: 99%

Comparison of pharmacodynamic intrasubject variability of insulin lispro protamine suspension and insulin glargine in subjects with type 1 diabetes

Ocheltree¹,

Hompesch²,

Wondmagegnehu³

et al. 2010

European Journal of Endocrinology

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Objective: The objective of the study was to evaluate pharmacodynamic (PD) intrasubject variability of a single, s.c. dose of insulin lispro protamine suspension (ILPS) compared with insulin glargine in subjects with type 1 diabetes mellitus and additionally, to compare the intrasubject variability of pharmacokinetic parameters of both insulins. Design: This was a single-center, investigator-blinded and subject-blinded, two-arm, parallel, randomized, four-period study. During the replicate visits, subjects received a single s.c. 0.6 U/kg dose of either ILPS or glargine, and underwent 24-h euglycemic glucose clamps. Results: The intrasubject variabilities of the primary PD parameters, total amount of glucose infused (G tot ) and maximum glucose infusion rate (GIR; R max ), were statistically significantly lower for ILPS when compared with glargine (P!0.0001). Least-square (LS) mean estimates for G tot and R max were 2512.7 mg/kg and 3.740 mg/min per kg respectively for ILPS, and 1291.9 mg/kg and 1.793 mg/min per kg respectively for glargine. The LS mean estimates for G tot and R max were statistically greater (PZ0.0010 and P!0.0001 respectively) for ILPS compared with glargine, suggesting that ILPS had greater 24-h glucose-lowering activity. Glargine demonstrated a flatter GIR-time curve, and ILPS demonstrated a significantly shorter time of maximum GIR (tR max ) and earlier time to half-maximal GIR before tR max and time to half-maximal GIR after tR max . ILPS administration resulted in significantly greater exposure compared with glargine (area under the baseline-corrected serum concentration versus time curve from time 0 to 24 h (AUC 0-24 ): 77 150 vs 53 111 pmol min/l; maximum serum insulin concentration (C max ): 119 vs 68 pmol/l; ILPS versus glargine respectively), but the intrasubject variabilities for AUC and C max were comparable. Conclusion: Although glargine demonstrated a flatter GIR-time profile, the lower PD intrasubject variability of ILPS may provide a more predictable response.

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Measurement of Insulin Absorption and Insulin Action

Cited by 55 publications

References 42 publications

AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease

AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease

Pharmacokinetics and Pharmacodynamics of Insulin Glargine Given in the Evening as Compared With in the Morning in Type 2 Diabetes

Comparison of pharmacodynamic intrasubject variability of insulin lispro protamine suspension and insulin glargine in subjects with type 1 diabetes

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