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A variety of insulin preparations are now available that differ in times of onset, peak effect, and duration of action, enabling the clinician to more appropriately satisfy their patients' requirements in a safe and effective manner (1,2). Insulin, which first became available for patients with diabetes mellitus in 1922 (3,4), was originally extracted from porcine and bovine pancreases and differed in structure from human insulin by one and three amino acids, respectively. The early preparations were dilute (1 unit/ml), of crude purity, and short-acting. Patients had to inject themselves four to six times a day with relatively large volumes, which made the injections painful. Local cutaneous reactions at injection sites (inflammation, lipoatrophy, and lipohypertrophy) were common due to contaminants. Moreover, because the preparations were antigenic, most patients developed insulin antibodies, which delayed the onset and prolonged the duration of insulin action. Development of antibodies sometimes caused severe immune insulin resistance that necessitated desensitization and the use of corticosteroids or specifically modified insulins (e.g., sulfated insulins).

As technology advanced, the preparations were standardized and became available in concentrations of 40 and 80 units/ml. Insulin in the United States is now uniformly 100 units/ml (U100). By the 1950s, longer-acting preparations were developed by adding chemicals to the buffer, which caused microcrystalliza-tion of the insulin, slowing absorption from the subcutaneous space into the blood (so-called "cloudy insulins"). Zinc was added to the Lente preparations (Lente and LTltralente), and protamine and a small amount of zinc to NPH (neutral protamine Hagedorn) (5). Combining these long-acting preparations with a fast-acting insulin such as Regular or Semilente permitted fewer injections and improved dosage individualization. Also, formulations of already-mixed short- and intermediate-acting insulins ("premixes") eventually came to market.

In the 1970s, advances in tissue chromatography led to preparations of higher purity, which markedly decreased antibody generation and immune insulin resistance, as well as local and systemic reactions. By the late 1980s, manufacture of human insulin using recombinant DNA technology became possible, so in most Westernized countries usage of animal insulin has mostly ceased. Human insulin has a slightly more rapid onset and shorter duration of action than the animal insulins, although the effect is of modest clinical significance. The one exception is Ultralente. Beef Ultralente, which is no longer available in the United States, was a peakless insulin that lasted over 24 hours, whereas human Ultralente has a peak and duration of action that resembles those of animal NPH (peak 810 hours, duration 15-20 hours).

With the development of the radioimmunoassay for insulin in I960, it became apparent that the normal secretion of insulin was mainly regulated by, and paralleled, changes in blood glucose levels. With meal ingestion, plasma insulin levels increase three- to fivefold to peak within 30-60 minutes, and return to premeal levels within 2-3 hours. Initially, twice-daily (before breakfast and supper) injections of mixtures of a fast-acting and intermediate-acting insulin were used in patients with type 1 diabetes, who have no endogenous insulin, in an attempt to simulate the physiological delivery of insulin. Later, this regimen was improved by using pre-meal injections of Regular or Semilente insulin with once-or twice-daily long-acting preparations such as Ultralente. An alternative to this "basal-bolus" approach came into use in the 1980s with insulin pumps—continuous subcutaneous insulin infusion (CSII)—that deliver a bolus of Regular insulin prior to meals superimposed on a basal rate and that can be preprogrammed to deliver an amount that varies according to the time of day. Regardless of whether the short-acting insulin was given by syringe, pen, or pump, the resultant plasma insulin levels and biological effect did not perfectly simulate the normal pattern, because the slow absorption of Regular or Semilente insulin required that it be taken 30-45 minutes prior to meals for optimal prevention of post-meal hyperglycemia (6). The required delay was inconvenient, and in practice

few patients actually waited that long. Moreover, the resultant plasma insulin levels did not generally peak until 60-120 minutes postprandially and remained elevated for up to 6 hours (7). Therefore, attempts to limit postprandial increases in plasma glucose by increasing insulin doses often resulted in hypoglycemia prior to the next meal. This was a serious limitation—it is now well recognized that hypoglycemia is the rate-limiting factor for achieving optimal glycemic control in patients with type 1 diabetes and in many patients with type 2 diabetes who take insulin.

Another problem was the variability in the day-to-day insulin profiles of the available insulins (8,9). The short-acting insulins (Regular and Semilente) have coefficients of variation in peak levels of 20-30%, whereas the longer-acting preparations (NPH, Lente, and Ultralente) have variations that are twice as great. Other factors affect the absorption characteristics (Table 1). The one of greatest clinical significance is variable absorption from different injection sites: insulin onset is quickest and its duration of action shortest from the abdomen, followed by the arms and then the buttocks and thighs (10).

The past decade has seen the development of insulins with amino acid substitutions that alter the absorption characteristics: "insulin analogs," or "designer insulins" ( I 1-15). There are now two preparations—lispro and aspart— that are absorbed faster and have a shorter duration of action than Regular human insulin, and another with a longer duration of action (>24 hours) than Ultralente that is essentially peakless—glargine (Table 2). These analogs have overcome many of the limitations of native human insulin: they have excellent day-to-day consistency in absorption characteristics, their absorption rates are minimally affected by the anatomical injection site, and the fast on-off effect of the rapid-acting preparations allows injecting at the time of eating and minimizes postprandial hypoglycemia. Thus, in many patients, the analogs have provided the first opportunity to design insulin programs that mimic normal patterns of physiological insulin delivery.

Insulin Action Chart
Table 2 Action Profiles of Various Insulin Preparations

Type of insulin

Onset

Peak

Duration

Human Regular

15-30 min

120 min

6-8 hr

Lispro insulin

15 min

60 min

3-4 hr

Aspart insulin

15 min

60 min

3-4 hr

Human NPH

2 h

5-7 hr

13-16 hr

Human Lente

Human Ultralente

1 hr

10 hr

20 hr

Insulin glargine

1.5 hr

Peakless

24 hr at least

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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