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Mixtures of Insulin:
In our practice, we have found that it is now possible to mix and match insulins much more effectively than in the past. Although every person metabolizes insulin differently, and insulin absorption may be a bit different from one day to the next in the same person, a helpful combination can be found for most everyone.
This has led us to examine all insulins available for the best control. What we arrived at is the "insulin cocktail." Let's review the insulins we use.
The availability of Humalog insulin (insulin lispro) in 1996 provided a true "rapid-acting" insulin for the first time. The reversal of two amino acids, proline and lysine, near the end of the B-chain of insulin, resulted in a "hook," which prevents the usual six molecules of insulin from binding with each other. The result is a quicker-acting insulin (10 minutes) which hits peak activity in 30 to 90 minutes and has a duration of four hours.
Regular insulin was previously the most rapid-acting insulin available, with onset of activity in 30 minutes, a peak in two to four hours and duration of six to nine hours. The purpose of rapid-acting insulin is to cover food intake or lower high sugar levels. People had been advised to take Regular insulin 30 minutes before eating, but surveys showed that 90 percent of people did not do this. As a result, blood sugars initially rose to very high levels after meals, but hypoglycemia was common several hours after meals.
It is now recognized that the HbA1c test, the main way to tell who is in good sugar control, is influenced by both fasting sugar levels and by blood sugars after meals. Thus, any mixtures of insulin at meal times should include a rapid-acting insulin.
The absorption of NPH and Lente insulins varies between people, and even in the same person from one day to the next. This is a major reason for the increased use of insulin pumps, which remove the variability.
Lente insulin contains 30 percent semilente insulin (with actions similar to Regular insulin) and 70 percent Ultralente insulin (lasting approximately 15 hours). The Ultralente part of Lente is available alone and has a flatter curve of activity than NPH insulin. It is often effective when used to cover the nighttime without having to worry about an insulin peak in the middle of the night (as with NPH insulin). The NPH begins to peak in three to six hours in some people, but more commonly peaks in six to eight hours, and lasts approximately 13 hours. When given in the morning, its peak can be very effective in helping to cover the food eaten during the day.
The most common morning regimens used in the United States consist of either Humalog and NPH insulin, or of Humalog and Lente insulin (see figure A).
Most people now count carbohydrates to determine the dose of Humalog. An insulin dose of 1 unit per 10 grams carbohydrate is common at breakfast (though variable for different people). Many children who receive an early injection (e.g. 7 a.m.) and who are not users of NPH will have high blood sugars at lunch. It may then help to divide the short-acting insulin, with half to be given as Regular insulin and half as Humalog. We have used the term "insulin cocktail" for the mixing of three insulins in the same syringe. If exercise is planned in the first two hours after the shot, the Humalog can be reduced or omitted. If exercise is to occur between two to five hours after the shot, the Regular insulin can be reduced or omitted. Some families who have difficulty mixing insulins can use the premixed 70/30 NPH/Regular insulin. However, this mix does not contain Humalog to cover breakfast, and has too much Regular for most children, necessitating a morning snack. It also does not allow for using "thinking-scales" to raise or lower the dose of Regular insulin as might be needed on a given day.
There is also premixed Humalog-NPL insulin now available. The NPL stands for Neutral Protamine Lyspro. This Humalog Mix 75/25 con-sists of 75 percent NPL and 25 percent Humalog. This premixed insulin has higher activity two to four hours after the injection than NPH insulin, and lasts approximately 13 hours. Some patients are now trying injection of this insulin with Humalog prior to each meal, with half in the morning and one-quarter before lunch, dinner or bedtime.
For families that eat a late dinner, it may be useful to give part of the morning NPH insulin as Ultralente insulin. This may mean three insulins (a "cocktail") or four insulins (an "extreme cocktail") in the same syringe. If the mixtures are for a child, it is wise for the parent to draw up the insulin. The clear insulin (either Humalog and/or Regular) must always go into the syringe first.
If Ultralente insulin is used in the morning, a noon injection of Humalog is necessary to cover lunch (see figure B). The insulin pen helps make this injection easier. If a noon shot is not possible, adding Regular insulin to the morning Humalog and Ultralente may suffice. When the person is able to count carbohydrates, a ratio of 1 unit to 15 grams carbohydrate is most common (although this varies with individuals) at noon.
For teenagers planning a large afternoon snack (and not willing to take more Humalog at that time as is preferable), Regular insulin (or NPH insulin) is sometimes added in with the pre-lunch Humalog.
Mixtures of Humalog and Ultralente are often used at dinner (see figure C), as use of Humalog, rather than Regular insulin, reduces the nighttime lows. If counting carbohydrates, a ratio of 1 unit to 15 grams of carbohydrate is common. If blood sugars tend to run high at bedtime or if a large bedtime snack is to be eaten, a small amount of Regular (another "cocktail") is added to the mixture of Humalog and Ultralente.
The levels of growth hormone are high from approximately 4 a.m. and 9 a.m. in people after puberty, about 11 to 13 years of age. The growth hormone blocks insulin activity and results in higher blood sugars between 4 a.m. to 9 a.m. (the "Dawn phenomenon"). Adding some NPH to the Ultralente (an extreme-cocktail) may counteract the rise in sugar from the growth hormone.
Many people take Humalog, or Humalog and Regular, at dinner and then use NPH insulin at bedtime (see figure A). If the bedtime blood sugar is high, some people take a small amount of Humalog with the NPH. People who tend to run low during the night should use Ultralente (which has much flatter activity) at bedtime rather than the NPH insulin or Humalog.
There is now a new insulin, insulin-glargine (or Lantus insulin), which is a clear insulin having a duration of approximately 24 hours (see figure D). It is an acid insulin (all other insulins have a neutral pH) and must be taken alone or it will destroy the actions of the other insulins. It is best taken by pen at bedtime, to make sure no other insulins are mixed in. Humalog can then be taken, also by pen, whenever food is to be eaten.
The Keys to Success:
Mixing and matching the many insulins now available should allow for improved glucose control, as long as adequate numbers of blood sugars are maintained so that it is clear when more insulin activity is needed.
Working with a knowledgeable healthcare provider is important. It is also essential not to forget injections. Missed injections can alter the levels of the balancing hormones and throw off control for several days. Consistency remains a key.
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