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Chapter: Basic & Clinical Pharmacology : Pancreatic Hormones & Antidiabetic Drugs

Characteristics of Available Insulin Preparations

Commercial insulin preparations differ in a number of ways, such as differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and duration of their biologic action.

Characteristics of Available Insulin Preparations

Commercial insulin preparations differ in a number of ways, such as differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and duration of their biologic action.

A. Principal Types and Duration of Action of Insulin Preparations

Four principal types of injected insulins are available: (1) rapid-acting, with very fast onset and short duration; (2) short-acting, with rapid onset of action; (3) intermediate-acting; and (4) long-acting, with slow onset of action (Figure 41–5, Table 41–4). Injected rapid-acting and short-acting insulins are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. Injected intermediate-acting NPH insulins have been modified to provide prolonged action and are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin). Insulin glargine and insulin detemir are clear, soluble long-acting insulins.

The goal of subcutaneous insulin therapy is to replicate normal physiologic insulin secretion and replace the background or basal (overnight, fasting, and between-meal) as well as bolus or prandial (mealtime) insulin. An exact reproduction of the normal glycemic profile is not technically possible because of the limitations inher-ent in subcutaneous administration of insulin. Current regimens generally use insulin analogs because of their more predictable action. Intensive therapy (“tight control”) attempts to restore near-normal glucose patterns throughout the day while minimizing the risk of hypoglycemia.

Intensive regimens involving multiple daily injections (MDI) use long-acting insulin analogs to provide basal or background coverage, and rapid-acting insulin analogs to meet the mealtime requirements. The latter insulins are given as supplemental doses to correct transient hyperglycemia. The most sophisticated insulin regimen delivers rapid-acting insulin analogs through a continu-ous subcutaneous insulin infusion device. Conventional therapy consists of split-dose injections of mixtures of rapid- or short-acting and intermediate-acting insulins.

1. Rapid-acting insulin—Three injected rapid-acting insulinanalogs—insulin lispro, insulin aspart, and insulin glulisine— are commercially available. The rapid-acting insulins permit more physiologic prandial insulin replacement because their rapid onset

and early peak action more closely mimic normal endogenous prandial insulin secretion than does regular insulin, and they have the additional benefit of allowing insulin to be taken immediately before the meal without sacrificing glucose control. Their dura-tion of action is rarely more than 4–5 hours, which decreases the risk of late postmeal hypoglycemia. The injected rapid-acting insulins have the lowest variability of absorption (approximately 5%) of all available commercial insulins (compared with 25% for regular insulin and 25% to over 50% for long-acting analog for-mulations and intermediate insulin, respectively). They are the preferred insulins for use in continuous subcutaneous insulin infu-sion devices.

Insulin lispro, the first monomeric insulin analog to be mar-keted, is produced by recombinant technology wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29, and lysine at position B29 has been moved to B28 (Figure 41–1). Reversing these two amino acids does not interfere in any way with insulin lispro’s binding to the insulin receptor, its circulating half-life, or its immunogenicity, which are similar to those of human regular insulin. However, the advantage of this analog is its very low propensity—in contrast to human insulin—to self-associate in antiparallel fashion and form dimers. To enhance the shelf life of insulin in vials, insulin lispro is stabilized into hexa-mers by a cresol preservative. When injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5–15 minutes and peak activity as early as 1 hour. The time to peak action is relatively constant, regardless of the dose.

Insulin aspart is created by the substitution of the B28 proline with a negatively charged aspartic acid (Figure 41–1). This modifica-tion reduces the normal ProB28 and GlyB23 monomer-monomer interaction, thereby inhibiting insulin self-aggregation. Its absorption and activity profile are similar to those of insulin lispro, and it is more reproducible than regular insulin, but it has binding properties, activity, and mitogenicity characteristics similar to those of regular insulin in addition to equivalent immunogenicity.

Insulin glulisine is formulated by substituting a lysine for asparagine at B3 and glutamic acid for lysine at B29. Its absorp-tion, action, and immunologic characteristics are similar to those of other injected rapid-acting insulins. After high-dose insulin glulisine interaction with the insulin receptor, there may be down-stream differences in IRS-2 pathway activation relative to human insulin. The clinical significance of such differences is unclear.

2. Short-acting insulin—Regular insulin is a short-acting sol-uble crystalline zinc insulin that is now made by recombinant DNA techniques to produce a molecule identical to that of human insulin. Its effect appears within 30 minutes, peaks between 2 and 3 hours after subcutaneous injection, and generally lasts 5–8 hours. In high concentrations, eg, in the vial, regular insulin molecules self-aggregate in antiparallel fashion to form dimers that stabilize around zinc ions to create insulin hexamers. The hexameric nature of regular insulin causes a delayed onset and prolongs the time to peak action. After subcutaneous injection, the insulin hexamersare too large and bulky to be transported across the vascular endothelium into the bloodstream. As the insulin depot is diluted by interstitial fluid and the concentration begins to fall, the hex-amers break down into dimers and finally monomers. This results in three rates of absorption of the injected insulin, with the final monomeric phase having the fastest uptake out of the injection site.


The clinical consequence is that when regular insulin is admin-istered at mealtime, the blood glucose rises faster than the insulin with resultant early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Therefore, regular insulin should be injected 30–45 or more minutes before the meal to minimize the mismatching. As with all older insulin formulations, the duration of action as well as the time of onset and the intensity of peak action increase with the size of the dose. Clinically, this is a critical issue because the pharmacokinetics and pharmacody-namics of small doses of regular and NPH insulins differ greatly from those of large doses. The delayed absorption, dose-dependent duration of action, and variability of absorption ( 25%) of regu-lar human insulin frequently results in a mismatching of insulin availability with need, and its use is declining.

However, short-acting, regular soluble insulin is the only type that should be administered intravenously because the dilution causes the hexameric insulin to immediately dissociate into mono-mers. It is particularly useful for intravenous therapy in the manage-ment of diabetic ketoacidosis and when the insulin requirement is changing rapidly, such as after surgery or during acute infections.

3. Intermediate-acting and long-acting insulins

a. NPH (neutral protamine Hagedorn, or isophane) insulin—-NPH insulin is an intermediate-acting insulin whose absorption and onset of action are delayed by combining appropriate amounts of insulin and protamine so that neither is present in an uncom-plexed form (“isophane”). After subcutaneous injection, prote-olytic tissue enzymes degrade the protamine to permit absorption of insulin. NPH insulin has an onset of approximately 2–5 hours and duration of 4–12 hours (Figure 41–5); it is usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement. The dose regulates the action profile; specifically, small doses have lower, earlier peaks and a short duration of action with the converse true for large doses. The action of NPH is highly unpredictable, and its vari-ability of absorption is over 50%. The clinical use of NPH is waning because of its adverse pharmacokinetics combined with the availability of long-acting insulin analogs that have a more predictable and physiologic action.

Insulin glargine—Insulin glargine is a soluble, “peakless” (ie,having a broad plasma concentration plateau), long-acting insulin analog. This product was designed to provide reproducible, con-venient, background insulin replacement. The attachment of two arginine molecules to the B-chain carboxyl terminal and substitu-tion of a glycine for asparagine at the A21 position created an analog that is soluble in an acidic solution but precipitates in the more neutral body pH after subcutaneous injection. Individual insulin molecules slowly dissolve away from the crystalline depot and provide a low, continuous level of circulating insulin. Insulin glargine has a slow onset of action (1–1.5 hours) and achieves a maximum effect after 4–6 hours. This maximum activity is main-tained for 11–24 hours or longer. Glargine is usually given once daily, although some very insulin-sensitive or insulin-resistant individuals benefit from split (twice a day) dosing. To maintain solubility, the formulation is unusually acidic (pH 4.0), and insulin glargine should not be mixed with other insulins. Separate syringes must be used to minimize the risk of contamination and subse-quent loss of efficacy. The absorption pattern of insulin glargine appears to be independent of the anatomic site of injection, and this drug is associated with less immunogenicity than human insu-lin in animal studies. Glargine’s interaction with the insulin recep-tor is similar to that of native insulin and shows no increase in mitogenic activity in vitro. It has sixfold to sevenfold greater bind-ing than native insulin to the insulin-like growth factor-1 (IGF-1) receptor, but the clinical significance of this is unclear.

c. Insulin detemir—This insulin is the most recently developedlong-acting insulin analog. The terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the terminal B29 lysine. These modifications pro-long the availability of the injected analog by increasing both self-aggregation in subcutaneous tissue and reversible albumin binding. Insulin detemir has the most reproducible effect of the intermediate- and long-acting insulins, and its use is associated with less hypoglycemia than NPH insulin. Insulin detemir has a dose-dependent onset of action of 1–2 hours and duration of action of more than 12 hours. It is given twice daily to obtain a smooth background insulin level.

4. Mixtures of insulins—Because intermediate-acting NPHinsulins require several hours to reach adequate therapeutic levels, their use in diabetic patients usually requires supplements of rapid- or short-acting insulin before meals. For convenience, these are often mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH insulin without affecting their rapid absorption. However, premixed preparations have thus far been unstable. To remedy this, intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed. These intermediate insulins have been designated as “NPL” (neutral protamine lispro) and “NPA” (neu-tral protamine aspart) and have the same duration of action as NPH insulin. They have the advantage of permitting formulation as premixed combinations of NPL and insulin lispro, and as NPA and insulin aspart, and they have been shown to be safe and effec-tive in clinical trials. The Food and Drug Administration (FDA) has approved 50%/50% and 75%/25% NPL/insulin lispro and 70%/30% NPA/insulin aspart premixed formulations. Additional ratios are available abroad. Insulin glargine and detemir must be given as separate injections. They are not miscible acutely or in a premixed preparation with any other insulin formulation.

Premixed formulations of 70%/30% NPH/regular continue to be available. These preparations have all the limitations of regular insulin, namely, highly dose dependent pharmacokinetic and pharmacodynamic profiles, and variability in absorption.

B. Insulin Production

Mass production of human insulin and insulin analogs by recom-binant DNA techniques is carried out by inserting the human or a modified human proinsulin gene into Escherichia coli or yeast and treating the extracted proinsulin to form the insulin or insulin analog molecules.

C. Concentration

All insulins in the USA and Canada are available in a concentra-tion of 100 U/mL (U100). A limited supply of U500 regular human insulin is available for use in rare cases of severe insulin resistance in which larger doses of insulin are required.

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