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Diabetes Drugs: Insulin

Mark Marino

August 7, 2009

Editor’s Note: This is the first post in our miniseries about diabetes drugs. Tune in on August 14 for the next installment.

insulinInsulin was the first medicine developed for the treatment of diabetes, and it remains the most effective therapy for treating hyperglycemia (high blood glucose).

The name insulin comes from the Latin insula which means island; it is so named because the beta cells, which produce insulin, are in a part of the pancreas called the islets of Langerhans. Insulin is a protein consisting of 51 amino acids. It is normally released into the blood in response to changes in blood glucose levels, but several hormones, nutrients, and drugs can also stimulate its release.

Insulin therapy is required for all people with Type 1 diabetes and for many people with Type 2 diabetes. While people with Type 1 diabetes lack insulin secretion due to the autoimmune destruction of the pancreatic beta cells (a process in which the immune system recognizes the beta cells as foreign to the body, and so attacks them), people with Type 2 diabetes have a mixture of insensitivity to insulin (called insulin resistance) and a decrease in insulin secretion (which may be due either to poorly functioning beta cells or to a decrease in the amount of beta cells).

Insulin reduces blood glucose levels by interacting with a protein on the surface of cells called the insulin receptor. There are two known types of insulin receptor that both serve the same purpose. The interaction between insulin and the insulin receptor triggers a complex series of reactions that are to date not fully understood, but that serve to increase the creation of protein, glycogen (a storage form of glucose), and most importantly, glucose transport proteins (proteins that bring glucose from the blood into the cell), thereby reducing blood glucose levels. Because of these actions, insulin is classified as an anabolic, or energy-storing, hormone.

Insulin receptors are most prominent on liver, muscle, and fat cells. These organs, which are the main target tissues for insulin, are termed insulin-sensitive organs, meaning that they require insulin to use glucose from the blood; organs that have fewer insulin receptors, such as the brain, do not depend on insulin for glucose transport into the cells.

Insulin that is secreted by the pancreas has a circulating half-life of approximately 6 minutes, which is to say that every 6 minutes, the amount of insulin in the blood declines by 50%. In fact, after it is released from the pancreas, insulin is no longer detectable in the bloodstream within 30 minutes. Insulin is removed from the body by enzymes in the kidney and the liver, as well as by its interaction with insulin receptors.

Insulin as a Treatment
Since insulin is a protein, it can only be given by injection into subcutaneous tissues (tissues just under the skin) or intravenous administration directly into the bloodstream. (Insulin is broken down by stomach acids if swallowed.) However, alternate forms of insulin are currently being developed that can be taken by mouth, inhaled, or sprayed into the nose or the mouth. (Inhaled insulin was available a few years ago, but the company that made it removed it from the market due to poor sales.)

When insulin first became available to people with diabetes, it was directly obtained from the pancreases of animals, and was therefore called pork or beef insulin, depending on the source. Insulin is now made in the laboratory in a variety of forms, generally classified as human or human analogs. These insulins have various ranges of times over which they are effective at lowering blood glucose, and are accordingly classified as rapid-acting, short-acting, intermediate-acting, and long-acting. The onset of action, peak action, and duration of action of various types of insulin are as follows:

    Human insulin:
    Regular:
    Onset of action: 30–60 minutes
    Peak effect: 2–4 hours
    Duration of action: 6–8 hours

    NPH
    Onset of action: 2–4 hours
    Peak effect: 4–6 hours
    Duration of action: 12–16 hours

    Analogs:
    Lispro (brand name Humalog):
    Onset of action: 5–15 minutes
    Peak effect: 60 minutes
    Duration of action: 4–5 hours

    Aspart (NovoLog):
    Onset of action: 5–15 minutes
    Peak effect: 60 minutes
    Duration of action: 4–5 hours

    Glulisine (Apidra):
    Onset of action: 5–15 minutes
    Peak effect: 60 minutes
    Duration of action: 4–5 hours

    Glargine (Lantus):
    Onset of action: 2 hours
    Peak effect: peakless
    Duration of action: approximately 24 hours

    Detemir (Levemir):
    Onset of action: 2 hours
    Peak effect: peakless
    Duration of action: approximately 14–16 hours

Human insulin is made by genetic engineering and is exactly the same protein as that produced by the human pancreas. Insulin analogs, on the other hand, have slight differences in the amino acid sequence from human insulin. They retain the ability to interact with the insulin receptor but have altered absorption rates, either being faster or much slower than human insulin.

The goal of insulin therapy has always been to reflect the typical blood glucose patterns seen in a person without diabetes: In this case, the pancreas not only puts out insulin in response to a meal or snack, but it also secretes insulin at a constant low level throughout the day. This constant stream of insulin is referred to as basal insulin, while the insulin that covers a rise in blood glucose from a meal or snack is known as a bolus.

Approaches to Insulin Therapy
Insulin therapy is necessary for people with Type 1 diabetes (as well as for some with Type 2 diabetes); often the best way to administer the insulin is with an insulin pump, which can give both basal insulin and bolus insulin doses. Another approach to insulin administration is known as “multiple daily insulin injection regimens,” in which long-acting insulin is given by injection once or twice a day, and as many injections of rapid-acting insulin as needed are given to cover meals and snacks.

The 2009 Consensus Statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) indicates that after using a regimen of healthful eating and physical activity along with the oral medicine metformin, the next treatment option for people with Type 2 diabetes is a regimen of basal insulin. This would aim to control HbA1c (an indicator of blood glucose control over the previous 2–3 months) and fasting blood glucose levels, and rapid-acting insulins could be added as necessary to provide coverage for meals.

Treatment with insulin can have some significant side effects, including a weight gain of between 4–8 pounds and hypoglycemia (low blood glucose). Clinical trials that aimed to get participants to an HbA1c of roughly 7% have indicated that approximately 1–3 out of 100 people using insulin will have one episode of low blood glucose requiring assistance per year. However, this also means that 97 out of 100 people will not have an episode of severe hypoglycemia in that same one-year period. Moreover, insulin therapy is very effective at reducing blood glucose and HbA1c levels, as well as at raising HDL (“good”) cholesterol and lowering triglycerides (a type of blood fat).

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