OBJECTIVE
<p>To
investigate the pharmacokinetic and pharmacodynamic properties, and safety of a
novel formulation of insulin aspart (AT247) versus currently marketed insulin
aspart formulations (IAsp and faster IAsp).</p>
<p> </p>
<p>RESEARCH
DESIGN AND METHODS</p>
<p>This
single-center, randomized, double-blind, three-period, crossover study was
conducted in 19 men with type 1 diabetes, receiving single dosing of trial
products (0.3 U/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics
were assessed during a euglycemic clamp lasting up to 8 hours. </p>
<p> </p>
<p>RESULTS</p>
<p>Onset of
insulin appearance was earlier for AT247 compared with IAsp (−12 minutes [95% CI
−14;−8] p=0.0004) and faster IAsp (−2 minutes [−5;−2] p=0.0003). Onset of
action was accelerated compared with IAsp (−23 minutes [−37;−15] p=0.0004) and
faster IAsp (−9 minutes [−11;−3] p=0.0006). Within the first 60 minutes, a
higher exposure was observed for AT247 compared with IAsp (AUC<sub>Asp,0-60min</sub>:
treatment ratio vs IAsp 2.3 [1.9;2.9]; vs faster IAsp 1.5 [1.3;1.8]), which was
underpinned by a greater early glucose-lowering effect (AUC<sub>GIR,0-60min</sub>:
treatment ratio vs IAsp 2.8 [2.0;5.5]; vs faster IAsp 1.7 [1.3;2.3]). Furthermore,
an earlier offset of exposure was observed for AT247 compared with IAsp (−32 minutes
[−58;−15] p=0.0015) and faster IAsp (−27 minutes [−85;−15] p=0.0017), while duration
of glucose-lowering effect, measured by t<sub>Late50%GIRmax</sub>, did not
differ significantly.</p>
<p> </p>
<p>CONCLUSIONS</p>
<p>AT247
exhibited an earlier insulin appearance, exposure and offset, with
corresponding enhanced early glucose-lowering effect compared with IAsp and
faster IAsp. It therefore represents a promising candidate in the pursuit for second
generation prandial insulin analogs to improve postprandial glycemic control.</p>
Role of Neural NO Synthase (nNOS) Uncoupling in the Dysfunctional Nitrergic Vasorelaxation of Penile Arteries from Insulin-Resistant Obese Zucker Rats
