Newer insulin analogues and inhaled insulin

Diabetes is a metabolic disease with high prevalence worldwide. Exogenous insulin is used in the management of this condition. The development of human insulin has provided tighter control of glycaemia in diabetic patients. Insulin analogues like insulin lispro and aspart were developed to closely match its profile with physiological secretion. The newer additions to this armamentarium are insulin glulisine, insulin detemir and albulin. Insulin glulisine is a short acting analogue with a rapid onset of action. The antiapoptotic property, mediated through insulin substrate receptor-2 has a favourable protective action on beta cells. Insulin detemir is a long acting analogue, soluble at neutral pH, which reversibly binds to albumin in plasma, prolonging its action. Its lower affinity for insulin receptors necessitates higher doses compared to human insulin. The reduction in body weight is an additional advantage of detemir. A major concern about all newer insulin analogues is their altered mitogenic properties and resultant risk of carcinogenicity on long term use. Albulin is a latest addition of insulin analogue which is under various in vitro and in vivo studies. Inhaled insulin in powder form (Exubera) is recently approved by FDA and appears promising.     

Production of insulin antibodies by mice rejecting insulin transfected cells

Antibodies to insulin appear prior to the development of Type I diabetes and their concentration may correlate with the rate of autoimmune beta cell destruction. In order to study potential mechanisms involved in the production of antibodies to insulin, we transplanted different strains of mice with histoincompatible non-islet cells (AtT20-Ins and NIH-3T3-Ins) synthesizing homologous insulin, in contrast to immunization with non-transfected cells and insulin in Freund's adjuvant. The pituitary cell line (AtT20) and the fibroblast cell line (NIH-3T3) were transfected with the rat insulin-II gene (which encodes an insulin molecule identical to that of mouse insulin-II). No antibodies to insulin were found after subcutaneous injection of AtT20-control cells (without the integrated rat insulin gene) or after injection of rat insulin complete Freund's adjuvant. After subcutaneous injections of living AtT20-Ins or NIH-3T3-Ins cells producing insulin (40 to 60 ng insulin/10(6) cells per injection) in two strains (BALB/cJ, C3H/HeJ) but not in a third (SJL/J), antibodies to insulin rapidly appeared. In addition, when AtT20-Ins cells were transplanted into Wistar-Furth rats, insulin antibodies appeared in three out of four animals. The level of antibodies induced was similar to the concentrations of insulin antibodies of prediabetic NOD mice. This finding suggests that during the immune destruction of a cell synthesizing insulin, humoral 'tolerance' to insulin can be rapidly abrogated. Genetic control of this response is suggested by the difference between response of BALB/cJ and C3H/He vs SJL/J.     

Improvement in severe insulin resistance with frequent injections of lispro insulin

Extreme insulin resistance is common in obese African Americans with type 2 diabetes. This case report describes an obese African-American woman who was treated with subcutaneous injections of lispro insulin every 2 hours with resultant decrease of mean daily blood glucose from 264.7 mg/dL to 111 mg/dL and in insulin requirement from 479 U/24 hours to 60 U/24 hours. This case demonstrates that extreme insulin resistance is reversible in the short term.     

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

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 = 1,503y/ (1,398 - 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.     

Identification of insulin autoantibodies of IgA isotype that preferentially target non-human insulin

Insulin autoantibodies (IAA) precede clinical type 1 diabetes in children. Immunization events leading to IAA are unknown. The aim of this study was to determine whether some IAA result from mucosal immunization. IgA-IAA and binding of IAA to non-human insulin were examined in selected high and low affinity IAA-positive samples and in first IAA-positive samples from children aged <2 years. High affinity IAA (>10(9)L/mol) bound strongly to human insulin and poorly to chicken insulin. In contrast, 12/13 lower affinity IAA were chicken insulin-reactive, binding equally to human and chicken insulin (n=4), or preferentially binding chicken insulin (n=8). IgA-IAA were found in association with chicken insulin-reactive IAA, and included cases where IgA-IAA predominated over IgG-IAA. Among 20 IAA-positive children aged <2 years, one had early IgA-chicken insulin-reactive IAA that were replaced by high affinity IgG-IAA. The findings suggest that some IAA can result from immunization against molecules other than human insulin at mucosal sites.     

The pharmacokinetics of two different concentrations of short-acting insulin,intermediate-acting insulin,and an insulin mixture following subcutaneous injection

Summary To compare the pharmacokinetics of two different concentrations, containing either 40 or 100 IU/ml of short-acting human insulin (Velasulin HM), intermediate-acting human insulin (Insulatard HM), or an insulin mixture (25% short-acting insulin, 75% intermediate-acting insulin; Mixtard HM), three randomized, single-blind, crossover trials were performed using the euglycemic clamp technique. Eighteen healthy volunteers received insulin of either formulation subcutaneously in each of the studies (15 IU Velasulin, 20 IU Insulatard, or Mixtard). The blood glucose levels were maintained constant by glucose infusions. In the trial using Velasulin, the two different insulin concentrations were equivalent regarding the total absorption [area under the curve (AUC) of serum insulin: 126 ± 28 and 123 ± 35 mU/1 x 12 h for U40 and U100 (x ± SD)], but not in regard to the rate of absorption (t max 1.3 ± 0.4 and 2.4 ± 1.0 h for U40 and U100). In the case of Insulatard, total absorption was not equivalent (AUC 153 ± 35 and 128 ± 37 ml/l x 24 h for U40 and U100), but the rate of absorption was equivalent (t max 4.8 ± 2.9 and 5.3 ± 4.6 h). In the Mixtard series, total absorption was equivalent (AUC 142 ± 32 and 128±22 mU/1 x 24 h), but the rate of absorption was not (t max 2.2 ± 0.9 and 3.2 ± 4.2 h for U40 and U100). The glucose requirement was not equivalent in each of the three series. It was higher for the U-100 formulation in the Velasulin trial (2363±578 ml/12 h for U40 and 2601 ± 820 mi/ 12h for U100) and lower in the Insulatard trial (2203 ± 1271 ml/24 h for U40 and 1864 ± 864 ml/ 24h for U100) and the Mixtard trial (2559 ± 914 ml/24h for U40 and 2067 ± 896 ml/24 h for U100). When switching insulin from U40 to U100 formulations, more frequent blood glucose monitoring in the early phase following the insulin injection is recommended.Abbreviations AUC area under curve - c max maximal concentration - t max time when c max is reached - RIA radioimmunoassay - U40 insulin concentration 40 IU/ml - U100 insulin concentration 100 IU/ml