Insulin Pharmacokinetics

Abstract

Where adjustments of diet, physical activity, and dosage of insulin are well known to diabetologists and diabetic patients, present-day knowledge of factors of importance to the pharmacokinetics of insulin is frequently ignored. The pharmacokinetics of insulin comprise the absorption process, the distribution including binding to circulating insulin antibodies, if present, and to insulin receptors, and its ultimate degradation and excretion. The distribution and metabolism of absorbed insulin follow that of endogenous insulin. The distribution and metabolism cannot be actively changed, except in the case of circulating insulin antibodies, which in rare cases also may cause insulin resistance. The use of insulin preparation of low immunogeneity will avoid or reduce this course of variation in action. The absorption process, the detailed mechanisms of which are still unknown, is influenced by many variables where some can be controlled, thereby reducing the intrapatient variability in insulin absorption, which may reach 35%, causing a corresponding metabolic lability. Besides the known differences in timing among different preparations, the size of dose, the injected volume, and the insulin concentration are determinants of absorption role. Fortuitous injection technique contributes to variance, as do changes in blood flow of the injected tissue. This may be induced by changes in ambient temperature, exercise of injected limb, or local massage. Regional differences are also due to differences in blood flow. Serum insulin peaks may peak up to 1 h after injection of soluble insulin into the thigh versus into the abdominal wall. Local degradation of insulin seems of less importance but may, in rare cases, be the cause of high insulin "requirements." Available evidence is reviewed and the importance of implementing the consequences in the daily care of the insulin-treated patient is emphasized.

Comparison of pharmacodynamic intrasubject variability of insulin lispro protamine suspension and insulin glargine in subjects with type 1 diabetes

“…The minimal clinically observed PD intrasubject variability of any insulin is w30% (1,4). For this study, the required sample size needed was 33 patients per arm in order to have w90% power to demonstrate noninferiority of PD intrasubject variability of ILPS compared with glargine, within a margin of 30% and aZ0.1.…”

Insulin analogues and their potential in the management of diabetes mellitus

“…One amino acid modification could lead to changes in the tridimensional structure of the insulin molecule and to major alterations in its biological properties [17]. The fact that insulin in concentrated neutral solution associates into dimers and hexamers [18] and the observation of a lag-phase in the s. c. absorption of soluble insulins [19,20] gave rise to the hypothesis that reduced propensity to self-association might lead to faster absorption of the insulin and shorter duration of action [16]. The approaches used in the creation of monomeric insulin analogues were charge repulsion (AspB28; AspB9,GluB27; Glu-B28,AspA21), decreased interface hydrophobicity (GluB16,-GluB27) and interference with hydrophobic contacts and beta-sheet formation (LysB28,ProB29) [16,21,22].…”

Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique

“…Unfortunately, the pharmacokinetics of these traditional insulin preparations do not match the profiles of endogenous insulin secretion. In particular, intermediate-acting insulin shows a peak-action profile [1] and, as with ultralente, a huge day-to-day variability in absorption after s.c. injection [2]. These undesirable effects result in large fluctuations in systemic exposure, and through this unfavourable insulin action profiles.…”