Biological Activity of Nasally Administered Insulin in Normal Subjects

Abstract

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 less than .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 less than .01) than the former.(ABSTRACT TRUNCATED AT 250 WORDS)

Intra-individual variability of the metabolic effect of inhaled insulin together with an absorption enhancer.

“…In a previous study, we showed that inhalation of an insulin powder aerosol containing solid insulin particles (99 U) led to a relative bioavailability of 7.8 ± 3.5% and a relative bioefficacy of 7.6 ± 2.9% (2). This bioefficacy was comparable with that achieved with nasal insulin administration using absorption enhancers but implies that a large amount of insulin has to be used with either administration form to achieve a sufficient metabolic effect (3)(4)(5)(6)(7). Nevertheless, the time-action profile seen with inhalation of insulin showed promising properties (i.e., a rapid onset of action and a relatively long duration of action).…”

Insulin structure and function

“…Clinical studies have demonstrated that intranasal insulin results in an immediate but brief hypoglycemic response more closely resembling intravenous rather than subcutaneous insulin. 206 The rapid onset is desirable since it provides convenience and possibly greater efficacy given the more immediate suppression of hepatic glucose output. However, the short duration of action is less desirable as it does not fully cover a mealtime glucose excursion and precipitates the need for additional insulin administration.…”

Measurement of Insulin Absorption and Insulin Action

“…Metabolic activity can still be measured even after the blood insulin concentration has returned to basal values. [5][6][7][8][9] Investigation of only the pharmacokinetic properties of insulin preparations ignores this hysteresis, which is based on the series of events occurring between the increase of the intravascular insulin concentration and the resulting metabolic activity. The metabolic activity (ϭ increase of glucose utilization) of insulin administered by s.c. injection depends on:…”