Intermediate-acting Insulin Preparations: NPH and ... - Diabetes Care

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INTERMEDIATE-ACTING INSULIN: NPH AND LENTE/TORSTEN DECKERT (a) (b) FIG. I. Photomicrograph of (a) NPH suspension and (b) lente insulin suspension at room temperature. 1.0 cm =20 /u,m. hagen, Denmark). The species specificity seems to play a role in the immunogenicity of insulin, since insulin preparations containing beef insulin have been shown to induce insulin antibodies more easily than insulin preparations containing only porcine insulin. 11 The purity of the insulin component varies over a wide range. During the last years there has been a development toward insulin preparations of higher purity, since it has been shown that several side effects (for example, lipoatrophy, insulin resistance, insulin allergy, and the development of several humoral antibodies) depend largely on the purity of the insulin preparation. 4 * 5 The purity of NPH as well as lente insulin preparations is expressed in suffix as single peak, single component, monocomponent (MC), or rare immunogenic (RI). Single peak means that insulin has been isolated by gel filtration, which separates molecules according to their size (i.e., insulin, arginine insulin, desamidoinsulin, ethylester insulin, and small amounts of other polypeptides). Single component, monocomponent, and rare immunogenum (RI) means that insulin has been further purified by chromatography, which also separates molecules of the same molecular size and therefore contains less impurities. As well, NPH made from porcine insulin as lente insulin of highly purified quality is available. However, for docu- 624 DIABETES CARE, VOL. 3 NO. 5, SEPTEMBER-OCTOBER 1980
INTERMEDIATE-ACTING INSULIN: NPH AND LENTE/TORSTEN DECKERT TABLE 1 Content of protamine and zinc in NPH and lente insulins NPH Lente Protamine Physical state pH Zn (mg/100 U) (mg/100 U) Crystalline 70% crystalline 30% amorphous 7.3 7.3 0.02 0.20 0.3-0.4 0 menting purity, techniques such as gel filtration and chromatography are insufficient. The purity of insulin should be further specified by radioimmunologic determination of the relevant contaminants [i.e., a-components, proinsulin, glucagon-like materials, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP), somatostatin] by well-documented techniques. Also, the purity of protamine, zinc, and other additives should be stated. Otherwise, the purity of NPH and lente insulins cannot be compared. ABSORPTION FROM SUBCUTANEOUS TISSUE bsorption studies with NPH and lente insulins have been done either by following the disappearance of radioactivity from subcutaneous tissue after the injection of labeled NPH or lente insulin or by following the plasma insulin concentration after subcutaneous injection of these preparations in patients with only minor or no endogenous insulin secretion. However, the same techniques have not been used and the results therefore are not strictly comparable. The most extensive studies with radioactive-labeled NPH insulin have been done by Ktflendorf et al. 6 and with labeled lente insulin by Binder et al. 7 ' 8 The differences between NPH and lente insulin, according to their results, are shown in Table 2. Twenty-four hours after injection in the femoral region, remarkably more radioactivity is found at the injection site after lente insulin compared with NPH insulin. The disappearance of radioactivity at the injection site after NPH insulin followed first-order kinetics, 6 whereas lente was absorbed in a biphasic curve, 7 probably because lente insulin is a mixture of amorphous and crystalline zinc insulin. The reproducibility of day-to-day absorption in the same patient, measured as the variation coefficient of the time until 40-50% of the maximal radioactivity disappeared, was 26% for NPH insulin 6 and about 35% for lente insulin. 7 Thus, the reproducibility of the resorption of both insulin TABLE 2 Differences in absorption between NPH and lente insulins Percent of injected insulin at injection site after: 10 h 24 h 36 h preparations seems to be in the same range. It must, however, be mentioned that the experiments with lente insulin were\done with non-highly purified insulins. After subcutaneous injection of NPH insulin in reasonable doses, plasma insulin concentration increases significantly after 2 h and is maximal after 5 h. 6 After lente insulin in comparable amounts, the time for significant initial increments to occur is not known. The maximal plasma insulin concentration seems to be reached 7 h after the injection of lente insulin. 9 Twenty-four hours after the injection of NPH insulin, the plasma insulin concentration is not higher than before the injection. Twenty-four hours after lente insulin, plasma insulin still seems to be elevated. 10 COURSE OF ACTION The time curve of the blood glucose lowering action of NPH and lente insulins (as given by Nordisk Insulinlaboratorium and the Novo Company in 1978) is shown in Table 3. However, randomized crossover experiments against placebo in fasting diabetic subjects have only been done by K^lendorf et al. with NPH insulin. 6 They found that the starting action began 120 min after the injection, and that the maximal action occurred 5.5 h after the injection, 30 min after the maximal plasma insulin concentration had been reached. From Rasmussen et al.'s experiments in nonfasting diabetic subjects, it seems that the maximal effect after lente was first achieved after 10 h. 9 The porcine lente-like preparation Monotard appears to have a shorter effect than lente insulin. Our crossover experiments on maturity-onset diabetic subjects using highly purified porcine NPH insulin and the highly purified porcine lente-like preparation Monotard did not indicate differences in the blood glucose lowering effects between these two preparations (Figure 2). Reproducibility of the blood glucose lowering effect of NPH insulin in maturity-onset diabetes was shown to be excellent. 6 It can be concluded from resorption studies, studies of plasma insulin concentration after subcutaneous injection, and studies of the blood glucose lowering effects of NPH and lente that lente has a more protracted action than NPH insulin. MIXABILITY Regular insulin can be mixed with NPH or lente insulin in the same syringe in every ratio. However, the course of effect will change with lente/regular mixtures depending on the TABLE 3 Time curve of action of NPH and lente insulins Onset Course of effect (h) Maximum End NPH Lente 40 70 10 40 0 25 NPH Lente 1*4 2Vi 4-12 24 24 Vi Data from K0lendorf et al. 6 and Binder. 7 Data from Nordisk Insulinlaboratorium and Novo Company, 1978. DIABETES CARE, VOL. 3 NO. 5, SEPTEMBER-OCTOBER 1980 625
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