OBJECTIVE —Both rapid-acting insulin analogs, insulin aspart and lispro, attenuate prandial glucose excursion compared with human soluble insulin. This trial was performed to study the pharmacokinetic and pharmacodynamic profiles of insulin aspart and insulin lispro in type 1 diabetic patients in a direct comparison and to investigate whether the administration of one analog results in favorable effects on prandial blood glucose control. RESEARCH DESIGN AND METHODS —A total of 24 type 1 diabetic patients (age 36 ± 8 years, 16 men and 8 women, BMI 24.3 ± 2.6 kg/m 2 , diabetes duration 17 ± 11 years, HbA 1c 7.9 ± 0.8%) on intensified insulin therapy were recruited into a single-center, randomized, double-blind, two-period, cross-over, glucose clamp trial. The subjects were given an individual need-derived dose of prandial insulin lispro or aspart immediately before a standard mixed meal. RESULTS —With respect to blood glucose excursions from time 0 to 6 h (Exc glu(0–6 h) ) and from time 0 to 4 h (Exc glu(0–4 h) ), the pharmacodynamic effect of insulin aspart and insulin lispro can be declared equivalent. This was supported by comparison with maximum postprandial blood glucose excursions ( C max(glu) ) (estimated ratio aspart/lispro ANOVA [90% CI]: 0.95 [0.80–1.13], 0.97 [0.82–1.17], and 1.01 [0.95–1.07] for Exc glu(0–6 h) , Exc glu(0–4 h) , and C max(glu) , respectively). For pharmacokinetic end points (maximum postprandial insulin excursions and area under the curve for insulin from time 0 to 6 h and from time 0 to 4 h), equivalence was indicated. No difference concerning absorption or elimination for time to maximal insulin concentration, time to half-maximum insulin concentration, and time to decrease to 50% of maximum insulin concentration was observed. CONCLUSIONS —These data suggest that in type 1 diabetic patients, both insulin analogs are equally effective for control of postprandial blood glucose excursions.

https://care.diabetesjournals.org/content/diacare/25/11/2053.full.pdf

A Direct Comparison of Insulin Aspart and Insulin Lispro in Patients With Type 1 Diabetes

OBJECTIVE —The rapid-acting insulin analogs aspart and lispro have now been developed in biphasic formulations. This trial compared the postprandial serum glucose control of biphasic insulin aspart 30 (BIAsp 30: 30% aspart, 70% protaminated aspart) with that of biphasic insulin lispro 25 (Mix25: 25% lispro, 75% protaminated lispro) and biphasic human insulin 30 (BHI 30: 30% regular insulin, 70% NPH insulin) in insulin-treated subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS —This was an open-labeled, randomized, single-dose, three-way crossover trial of 61 insulin-treated subjects with type 2 diabetes who had no significant late diabetic complications. BIAsp 30 and Mix25 were injected subcutaneously immediately before a test meal, and BHI 30 was injected 15 min before a test meal. The primary target of analysis was serum glucose excursion 0–5 h after a meal. RESULTS —The postprandial glycemic control with BIAsp 30, as assessed by the 5-h postmeal serum glucose excursion, was superior to that with both BHI 30 and Mix25 (16.6 ± 4.5 vs. 20.1 ± 4.9 and 18.9 ± 6.1 mmol/l per hour, respectively; P P max(SG) ] (−5%; P P P P max(SG) (−11 min; P CONCLUSIONS —This trial demonstrates that BIAsp 30 improves postprandial glycemic control compared with both Mix25 and BHI 30 in subjects with type 2 diabetes.

https://care.diabetesjournals.org/content/diacare/25/5/883.full.pdf

Improved Postprandial Glycemic Control With Biphasic Insulin Aspart Relative to Biphasic Insulin Lispro and Biphasic Human Insulin in Patients With Type 2 Diabetes

Several new insulin analogs that are prepared with recombinant DNA technology are available for clinical use [for a recent review, see Ref. (1)]. These agents have altered pharmacokinetics compared with regular human insulin. Insulin aspart (NovoLogTM; Novo Nordisk Pharmaceuticals) is homologous with regular human insulin except for a single substitution of aspartic acid for proline at position B28. This single substitution reduces the molecule’s tendency to form hexamers. Therefore, insulin aspart is absorbed more rapidly after subcutaneous injection and has both a faster onset of action and a shorter duration of action than regular insulin. A second short-acting recombinant insulin is insulin lispro (Humalog®; Eli Lilly and Company), which is a human insulin analog created by reversing the amino acids at positions 28 (Pro to Lys) and 29 (Lys to Pro) of the B chain. It is absorbed more rapidly than regular human insulin when administered subcutaneously and has a shorter duration of action.

A third recombinant insulin that is longer acting is insulin glargine (Lantus®; Aventis Pharmaceuticals), which differs from regular human insulin by the substitution of glycine for asparagine at position A21 and by the addition of two arginine residues to the COOH terminus of the B chain. These modifications lead to a slower, more prolonged absorption than regular insulin and a relatively stable concentration–time profile over 24 h. Insulin glargine is partially metabolized at the COOH terminus of the B chain in the subcutaneous depot to form two active metabolites, M1 and M2, with in vitro activity similar to …

Cross-Reactivity of Three Recombinant Insulin Analogs with Five Commercial Insulin Immunoassays

Insulin aspart is a novel rapid-acting insulin analogue with improved subcutaneous absorption properties when compared with soluble human insulin. Pharmacokinetic studies show an absorption profile with a time to reach peak concentration (tmax) about half that of human insulin, a peak plasma drug concentration (Cmax) approximately twice as high and shorter residence time. The potency and bio-availability of insulin aspart are similar to those of human insulin. The pharmacokinetics of insulin aspart have been studied in healthy Caucasian and Asian-Japanese volunteers, in patients with type 1 and 2 diabetes mellitus, and in children with diabetes, with both pre- and postprandial administration and during continuous subcutaneous insulin infusion (CSII). The pharmacokinetic profile was similar to that of another rapid-acting insulin analogue, insulin lispro, on the basis of published information for that agent. Pharmacodynamic studies show a smaller excursion of postprandial glucose with insulin aspart injected subcutaneously just before the meal compared with soluble human insulin injected 30 minutes before the meal in patients with type 1 diabetes mellitus, and an equivalent control in patients with type 2 diabetes displaying residual insulin production. In a treatment study, glucose excursions evaluated from 24-hour glucose profiles showed less variability with insulin aspart compared with human insulin. Adverse events, including hypoglycaemia-induced ventricular repolarisation and hypoglycaemic threshold and awareness, did not differ between insulin aspart and human insulin. The available data suggest that subcutaneous injections of insulin aspart just before meals better mimic the endogenous insulin profile in blood compared with human insulin, resulting in improved glucose control in a meal-related insulin regimen. This review summarises the clinical pharmacokinetics and pharmacodynamics of insulin aspart in relation to human insulin and insulin lispro.

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Aspart

Publisher Summary This chapter discusses the insulin-like peptides: structure, signaling, and function. Insulin-like peptides (ILPs) are paragons for the conservation of hormone structure and function among invertebrates and higher animals. They are encoded by multiple, distinct genes within each species and, upon secretion, serve as hormones, neurotransmitters, and growth factors during post-embryonic life stages. These diverse messages are transduced in target cells through an insulin receptor and a signaling network of activated proteins that directly affect biochemical pathways and gene expression. Of the diverse invertebrate groups, our accumulated knowledge of ILP endocrinology is the deepest and broadest for insects. This knowledge has revealed that essentially all of the proteins that make up the mechanisms for ILP processing, secretion, and signaling are remarkably similar to those of vertebrates, in effect conserving the pleiotropic effects of ILPs between insects and vertebrates.

Insulin-Like Peptides: Structure, Signaling, and Function

A new insulin immunoassay specific for the rapid-acting insulin analog, insulin aspart, suitable for bioavailability, bioequivalence, and pharmacokinetic studies.

A radioimmunoassay (RIA) for insulin was validated for reliable measurement of the human insulin analogue, insulin aspart, by correction of non-linear measurements. Specificity was equivalent for several species of insulin, except insulin aspart. A non-linear hyperbolic model fitted insulin aspart with a correction formula for non-linearity of: z = 1503y/(1398 - y), where y denotes measured concentration and z denotes true concentration. Matrix-effects were insignificant for human, porcine, and canine heparin-plasma and for human and porcine serum. The coefficient of variation was below 15% for 80–800 pmol/L human and porcine insulin and for 80–600 pmol/L insulin aspart. The limit of detection for insulin aspart was 11.5 pmol/L with a lower limit of quantification of 17.5 pmol/L. Dilution of serum with Pharmacia dilution media introduced no significant error. In conclusion, this paper demonstrates that a non-parallel radioimmunoassay can be used to estimate accurate concentrations of insulin aspart.

Declan Walsh

Papers

A new insulin immunoassay specific for the rapid-acting insulin analog, insulin aspart, suitable for bioavailability, bioequivalence, and pharmacokinetic studies.

Validity and use of a non-parallel insulin assay for pharmacokinetic studies of the rapid-acting insulin analogue, insulin aspart