Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN304

Diabet Med. 1999 Apr;16(4):332-8. doi: 10.1046/j.1464-5491.1999.00081.x.


Aims: To compare the pharmacokinetic and pharmacodynamic properties of subcutaneously injected NN304, a novel long-acting insulin analogue, to NPH-insulin during euglycaemic glucose clamps in 11 healthy volunteers.

Methods: On three study days NN304 was injected in three different doses (0.15, 0.3, 0.6 U/kg body weight), while NPH-insulin (0.3 U/kg) was injected in identical dose on two other days.

Results: Injection of NN304 resulted in a linear and proportional increase in total NN304 concentrations (AUC0-1440 min: 0.15 U/kg: 344+/-43, 0.3 U/kg: 666+/-82, 0.6 U/kg: 1295+/-210 nmol/l; P<0.001). Maximal concentrations (609+/-140, 1046+/-283, 2033+/-460 pmol/l; P<0.001) were reached after 4-6 h. The metabolic response (expressed as maximal glucose infusion rates (GIR)) induced by subcutaneous injection of NN304 did not show the pronounced peak seen with NPH-insulin in an identical dose: GIRmax 3.2+/-1.1 vs. 4.4+/-1.8 mg/kg/min (P<0.05 for 0.3 U/kg NN304 vs. NPH-insulin; mean of both study days with NPH-insulin, all others not significant). NN304 also showed a slower onset of action, as indicated by a significantly higher tmax (446+/-162 vs. 359+/-175 min) and lower AUC0-240min (0.5+/-0.3 vs. 0.8+/-0.4 g/kg/240min; P<0.05, respectively). The three different doses of NN304 induced a significantly different glucose consumption in the first 720 min after injection (AUC0-720 min 1.1+/-0.6, 1.9+/-0.8, 1.7+/-0.8 g/kg; P<0.05 for 0.15 U/kg), but not over the whole study period (AUC0-1440 min 1.8+/-1.1, 3.1+/-1.3, 2.8+/-1.4 g/kg).

Conclusions: Injection of NN304 at different doses resulted in an increase in total NN304 concentration in a linear dose-response effect and a more even metabolic effect than NPH-insulin. However, we found no clear dose-response in its metabolic effect.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Adult
  • Carrier Proteins / pharmacokinetics
  • Carrier Proteins / therapeutic use*
  • Delayed-Action Preparations
  • Dose-Response Relationship, Drug
  • Glucose Clamp Technique
  • Humans
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use*
  • Injections, Subcutaneous
  • Insulin / analogs & derivatives*
  • Insulin / pharmacokinetics
  • Insulin / therapeutic use
  • Insulin Detemir
  • Insulin, Long-Acting
  • Linear Models
  • Male
  • Reference Values
  • Solubility


  • Carrier Proteins
  • Delayed-Action Preparations
  • Hypoglycemic Agents
  • Insulin
  • Insulin, Long-Acting
  • Insulin Detemir