BIOLOGICAL-ACTIVITY OF NASALLY ADMINISTERED INSULIN IN NORMAL SUBJECTS

Nasally administered (IN) insulin has been advocated as a potentially useful alternative to subcutaneously administered regular insulin because of its more rapid onset and time to peak action and its shorter duration of action. This study further defines the pharmacodynamics of IN insulin by using a euglycemic clamp technique to determine the bioavailability of IN insulin as compared with intravenous (IV) insulin, and to ascertain whether multiple sequentially administered doses of IN insulin alter pharmacodynamics. Eight normal volunteers received 2 control doses of IV insulin (0.05 U/kg), and 3 high doses (0.7 U/kg) and 3 low doses (0.35 U/kg) of IN insulin with an absorption enhancer (tauro-24,25 dihydrofusidate) given sequentially over a 2 day period. A euglycemic clamp was performed with a Biostator® (Ames) that infused dextrose to keep the subject's blood glucose at his fasting level. Analysis of dextrose infusion curves for the low and high doses of IN insulin revealed an onset of action of 9.4 ± 0.4 and 10.5 ± 0.3 minutes, time to peak action of 20.6 ± 5.6 and 23.7 ± 4.4 minutes and duration of action of 82.1 ± 5.2 and 95 ± 5.7 minutes respectively. Both the onset of action and time to peak action were slightly longer (P < .05) for the high as compared with the low dose IN insulin, although this should not represent a clinically significant difference. The total dextrose requirement was 21.9 ± 2.3 g for the low dose IN insulin and 34.1 ± 3.3 g for the high dose IN insulin, the latter value being significantly greater (P < .01) than the former. Relative to IN insulin, the IV insulin has a significantly (P < .01) shorter onset (77 ± 0.3 min) and time to peak action (16.7 ± 1.9 min), equivalent duration of action (99.6 ± 5.2 min) but slightly greater (P < .01) total dextrose requirement of 36.8 ± 3.5 g. When the bioavailability is derived from the insulin areas under the curve, the results were 7.1 ± 0.5% to 9.2 ± 0.6% (P < .05) for the high vs the low dose IN insulin. Calculated from the total dextrose requirement, the bioavailability of the intranasal insulin was 7.1 ± 0.5% (high dose) to 9.0 ± 0.9% (low dose) (P = ns). Based on the total dextrose requirements, the intrasubject coefficient of variation ranged from 11 to 82% for the low dose and 6 to 59% for the high dose. The total dextrose requirement was not affected by repetitive, sequential administration of IN insulin during the same day. We conclude that IN insulin has a pharmacologic profile similar to that of intravenous insulin. As such, its rapid onset of action and short time to peak action gives IN insulin obvious therapeutic advantages over conventional subcutaneous administration of insulin in the periprandial management of diabetes mellitus.