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n.

1. A polypeptide hormone secreted by the islets of Langerhans and functioning in the regulation of the metabolism of carbohydrates and fats, especially the conversion of glucose to glycogen, which lowers the blood glucose level.
2. Any of various pharmaceutical preparations containing this hormone that are derived from the pancreas of certain animals or produced through genetic engineering and are used in the medical treatment and management of diabetes mellitus (type I).

[New Latin īnsula, island (of Langerhans) (from Latin, island) + –IN.]

Sidebar: In 1891, Frederick Banting was born in Alliston, Ontario. He graduated in 1916 from the University of Toronto medical school. After Medical Corps service in World War I, Banting became interested in diabetes and studied the disease at the University of Western Ontario. In 1919, Moses Barron, a researcher at the University of Minnesota, showed blockage of the duct connecting the two major parts of the pancreas caused shriveling of a second cell type, the acinar. Banting believed that by tying off the pancreatic duct to destroy the acinar cells, he could preserve the hormone and extract it from islet cells. Banting proposed this to the head of the University of Toronto's Physiology Department, John Macleod. Macleod rejected Banting's proposal, but supplied laboratory space, 10 dogs, and a medical student, Charles Best Begining in May 1921, Banting and Best tied off pancreatic ducts in dogs so the acinar cells would atrophy, then removed the pancreases to extract fluid from islet cells. Meanwhile, they removed pancreases from other dogs to cause diabetes, then injected the islet cell fluid. In January 1922, 14 year-old Leonard Thompson became the first human to be successfully treat-ed for diabetes using insulin. Best received his medical degree in 1925. Banting insisted Best also be credited, and almost turned down his Nobel Prize because Best was not included. Best became head of the University of Toronto's physiology department in 1929 and director of the university's Banting and Best Department of Medical Research after Banting's death in 1941.

Background

Insulin is a hormone that regulates the amount of glucose (sugar) in the blood and is required for the body to function normally. Insulin is produced by cells in the pancreas, called the islets of Langerhans. These cells continuously release a small amount of insulin into the body, but they release surges of the hormone in response to a rise in the blood glucose level.

Certain cells in the body change the food ingested into energy, or blood glucose, that cells can use. Every time a person eats, the blood glucose rises. Raised blood glucose triggers the cells in the islets of Langerhans to release the necessary amount of insulin. Insulin allows the blood glucose to be transported from the blood into the cells. Cells have an outer wall, called a membrane, that controls what enters and exits the cell. Researchers do not yet know exactly how insulin works, but they do know insulin binds to receptors on the cell's membrane. This activates a set of transport molecules so that glucose and proteins can enter the cell. The cells can then use the glucose as energy to carry out its functions. Once transported into the cell, the blood glucose level is returned to normal within hours.

Without insulin, the blood glucose builds up in the blood and the cells are starved of their energy source. Some of the symptoms that may occur include fatigue, constant infections, blurred eye sight, numbness, tingling in the hands or legs, increased thirst, and slowed healing of bruises or cuts. The cells will begin to use fat, the energy source stored for emergencies. When this happens for too long a time the body produces ketones, chemicals produced by the liver. Ketones can poison and kill cells if they build up in the body over an extended period of time. This can lead to serious illness and coma.

People who do not produce the necessary amount of insulin have diabetes. There are two general types of diabetes. The most severe type, known as Type I or juvenile-onset diabetes, is when the body does not produce any insulin. Type I diabetics usually inject themselves with different types of insulin three to four times daily. Dosage is taken based on the person's blood glucose reading, taken from a glucose meter. Type II diabetics produce some insulin, but it is either not enough or their cells do not respond normally to insulin. This usually occurs in obese or middle aged and older people. Type II diabetics do not necessarily need to take insulin, but they may inject insulin once or twice a day.

There are four main types of insulin manufactured based upon how soon the insulin starts working, when it peaks, and how long it lasts in the body. According to the American Diabetes Association, rapid-acting insulin reaches the blood within 15 minutes, peaks at 30-90 minutes, and may last five hours. Short-acting insulin reaches the blood within 30 minutes, it peaks about two to four hours later and stays in the blood for four to eight hours. Intermediate-acting insulin reaches the blood two to six hours after injection, peaks four to 14 hours later, and can last in the blood for 14-20 hours. And long-acting insulin takes six to 14 hours to start working, it has a small peak soon after, and stays in the blood for 20-24 hours. Diabetics each have different responses to and needs for insulin so there is no one type that works best for everyone. Some insulin is sold with two of the types mixed together in one bottle.

History

If the body does not produce any or enough insulin, people need to take a manufactured version of it. The major use of producing insulin is for diabetics who do not make enough or any insulin naturally.

Before researchers discovered how to produce insulin, people who suffered from Type I diabetes had no chance for a healthy life. Then in 1921, Canadian scientists Frederick G. Banting and Charles H. Best successfully purified insulin from a dog's pancreas. Over the years scientists made continual improvements in producing insulin. In 1936, researchers found a way to make insulin with a slower release in the blood. They added a protein found in fish sperm, protamine, which the body breaks down slowly. One injection lasted 36 hours. Another breakthrough came in 1950 when researchers produced a type of insulin that acted slightly faster and does not remain in the bloodstream as long. In the 1970s, researchers began to try and produce an insulin that more mimicked how the body's natural insulin worked: releasing a small amount of insulin all day with surges occurring at mealtimes.

Researchers continued to improve insulin but the basic production method remained the same for decades. Insulin was extracted from the pancreas of cattle and pigs and purified. The chemical structure of insulin in these animals is only slightly different than human insulin, which is why it functions so well in the human body. (Although some people had negative immune system or allergic reactions.) Then in the early 1980s biotechnology revolutionized insulin synthesis. Researchers had already decoded the chemical structure of insulin in the mid1950s. They soon determined the exact location of the insulin gene at the top of chromosome 11. By 1977, a research team had spliced a rat insulin gene into a bacterium that then produced insulin.

In the 1980s, researchers used genetic engineering to manufacture a human insulin. In 1982, the Eli Lilly Corporation produced a human insulin that became the first approved genetically engineered pharmaceutical product. Without needing to depend on animals, researchers could produce genetically engineered insulin in unlimited supplies. It also did not contain any of the animal contaminants. Using human insulin also took away any concerns about transferring any potential animal diseases into the insulin. While companies still sell a small amount of insulin produced from animals—mostly porcine—from the 1980s onwards, insulin users increasingly moved to a form of human insulin created through recombinant DNA technology. According to the Eli Lilly Corporation, in 2001 95% of insulin users in most parts of the world take some form of human insulin. Some companies have stopped producing animal insulin completely. Companies are focusing on synthesizing human insulin and insulin analogs, a modification of the insulin molecule in some way.

Raw Materials

Human insulin is grown in the lab inside common bacteria. Escherichia coli is by far the most widely used type of bacterium, but yeast is also used.

Researchers need the human protein that produces insulin. Manufacturers get this through an amino-acid sequencing machine that synthesizes the DNA. Manufacturers know the exact order of insulin's amino acids (the nitrogen-based molecules that line up to make up proteins). There are 20 common amino acids. Manufacturers input insulin's amino acids, and the sequencing machine connects the amino acids together. Also necessary to synthesize insulin are large tanks to grow the bacteria, and nutrients are needed for the bacteria to grow. Several instruments are necessary to separate and purify the DNA such as a centrifuge, along with various chromatography and x-ray crystallography instruments.

The Manufacturing
Process

Synthesizing human insulin is a multi-step biochemical process that depends on basic recombinant DNA techniques and an understanding of the insulin gene. DNA carries the instructions for how the body works and one small segment of the DNA, the insulin gene, codes for the protein insulin. Manufacturers manipulate the biological precursor to insulin so that it grows inside simple bacteria. While manufacturers each have their own variations, there are two basic methods to manufacture human insulin.

Working with human insulin

• The insulin gene is a protein consisting of two separate chains of amino acids, an A above a B chain, that are held together with bonds. Amino acids are the basic units that build all proteins. The insulin A chain consists of 21 amino acids and the B chain has 30.
• Before becoming an active insulin protein, insulin is first produced as preproinsulin. This is one single long protein chain with the A and B chains not yet separated, a section in the middle linking the chains together and a signal sequence at one end telling the protein when to start secreting outside the cell. After preproinsulin, the chain evolves into proinsulin, still a single chain but without the signaling sequence. Then comes the active protein insulin, the protein without the section linking the A and B chains. At each step, the protein needs specific enzymes (proteins that carry out chemical reactions) to produce the next form of insulin.

STARTING WITH A AND B

• One method of manufacturing insulin is to grow the two insulin chains separately. This will avoid manufacturing each of the specific enzymes needed. Manufacturers need the two mini-genes: one that produces the A chain and one for the B chain. Since the exact DNA sequence of each chain is known, they synthesize each mini-gene's DNA in an amino acid sequencing machine.
• These two DNA molecules are then inserted into plasmids, small circular pieces of DNA that are more readily taken up by the host's DNA.
• Manufacturers first insert the plasmids into a non-harmful type of the bacterium E. coli. They insert it next to the lacZ gene. LacZ encodes for 8-galactosidase, a gene widely used in recombinant DNA procedures because it is easy to find and cut, allowing the insulin to be readily removed so that it does not get lost in the bacterium's DNA. Next to this gene is the amino acid methionine, which starts the protein formation.
• The recombinant, newly formed, plasmids are mixed up with the bacterial cells. Plasmids enter the bacteria in a process called transfection. Manufacturers can add to the cells DNA ligase, an enzyme that acts like glue to help the plasmid stick to the bacterium's DNA.
• The bacteria synthesizing the insulin then undergo a fermentation process. They are grown at optimal temperatures in large tanks in manufacturing plants. The millions of bacteria replicate roughly every 20 minutes through cell mitosis, and each expresses the insulin gene.
• After multiplying, the cells are taken out of the tanks and broken open to extract the DNA. One common way this is done is by first adding a mixture of lysozome that digest the outer layer of the cell wall, then adding a detergent mixture that separates the fatty cell wall membrane. The bacterium's DNA is then treated with cyanogen bromide, a reagent that splits protein chains at the methionine residues. This separates the insulin chains from the rest of the DNA.
• The two chains are then mixed together and joined by disulfide bonds through the reduction-reoxidation reaction. An oxidizing agent (a material that causes oxidization or the transfer of an electron) is added. The batch is then placed in a centrifuge, a mechanical device that spins quickly to separate cell components by size and density.
• The DNA mixture is then purified so that only the insulin chains remain. Manufacturers can purify the mixture through several chromatography, or separation, techniques that exploit differences in the molecule's charge, size, and affinity to water. Procedures used include an ion-exchange column, reverse-phase high performance liquid chromatography, and a gel filtration chromatography column. Manufacturers can test insulin batches to ensure none of the bacteria's E. coli proteins are mixed in with the insulin. They use a marker protein that lets them detect E. coli DNA. They can then determine that the purification process removes the E. coli bacteria.

PROINSULIN PROCESS

• Starting in 1986, manufacturers began to use another method to synthesize human insulin. They started with the direct precursor to the insulin gene, proinsulin. Many of the steps are the same as when producing insulin with the A and B chains, except in this method the amino acid machine synthesizes the proinsulin gene.
• The sequence that codes for proinsulin is inserted into the non-pathogenic E. coli bacteria. The bacteria go through the fermentation process where it reproduces and produces proinsulin. Then the connecting sequence between the A and B chains is spliced away with an enzyme and the resulting insulin is purified.
• At the end of the manufacturing process ingredients are added to insulin to prevent bacteria and help maintain a neutral balance between acids and bases. Ingredients are also added to intermediate and long-acting insulin to produce the desired duration type of insulin. This is the traditional method of producing longer-acting insulin. Manufacturers add ingredients to the purified insulin that prolong their actions, such as zinc oxide. These additives delay absorption in the body. Additives vary among different brands of the same type of insulin.

Analog insulin

In the mid 1990s, researchers began to improve the way human insulin works in the body by changing its amino acid sequence and creating an analog, a chemical substance that mimics another substance well enough that it fools the cell. Analog insulin clumps less and disperses more readily into the blood, allowing the insulin to start working in the body minutes after an injection. There are several different analog insulin. Humulin insulin does not have strong bonds with other insulin and thus, is absorbed quickly. Another insulin analog, called Glargine, changes the chemical structure of the protein to make it have a relatively constant release over 24 hours with no pronounced peaks.

Instead of synthesizing the exact DNA sequence for insulin, manufacturers synthesize an insulin gene where the sequence is slightly altered. The change causes the resulting proteins to repel each other, which causes less clumping. Using this changed DNA sequence, the manufacturing process is similar to the recombinant DNA process described.

Quality Control

After synthesizing the human insulin, the structure and purity of the insulin batches are tested through several different methods. High performance liquid chromatography is used to determine if there are any impurities in the insulin. Other separation techniques, such as X-ray crystallography, gel filtration, and amino acid sequencing, are also performed. Manufacturers also test the vial's packaging to ensure it is sealed properly.

Manufacturing for human insulin must comply with National Institutes of Health procedures for large-scale operations. The United States Food and Drug Administration must approve all manufactured insulin.

The Future

The future of insulin holds many possibilities. Since insulin was first synthesized, diabetics needed to regularly inject the liquid insulin with a syringe directly into their bloodstream. This allows the insulin to enter the blood immediately. For many years it was the only way known to move the intact insulin protein into the body. In the 1990s, researchers began to make inroads in synthesizing various devices and forms of insulin that diabetics can use in an alternate drug delivery system.

Manufacturers are currently producing several relatively new drug delivery devices. Insulin pens look like a writing pen. A cartridge holds the insulin and the tip is the needle. The user set a dose, inserts the needle into the skin, and presses a button to inject the insulin. With pens there is no need to use a vial of insulin. However, pens require inserting separate tips before each injection. Another downside is that the pen does not allow users to mix insulin types, and not all insulin is available.

For people who hate needles an alternate to the pen is the jet-injector. Looking similar to the pens, jet injectors use pressure to propel a tiny stream of insulin through the skin. These devices are not as widely used as the pen, and they can cause bruising at the input point.

The insulin pump allows a controlled release in the body. This is a computerized pump, about the size of a beeper, that diabetics can wear on their belt or in their pocket. The pump has a small flexible tube that is inserted just under the surface of the diabetic's skin. The diabetic sets the pump to deliver a steady, measured dose of insulin throughout the day, increasing the amount right before eating. This mimics the body's normal release of insulin. Manufacturers have produced insulin pumps since the 1980s but advances in the late 1990s and early twenty-first century have made them increasingly easier to use and more popular. Researchers are exploring the possibility of implantable insulin pumps. Diabetics would control these devices through an external remote control.

Researchers are exploring other drug-delivery options. Ingesting insulin through pills is one possibility. The challenge with edible insulin is that the stomach's high acidic environment destroys the protein before it can move into the blood. Researchers are working on coating insulin with plastic the width of a few human hairs. The coverings would protect the drugs from the stomach's acid.

In 2001 promising tests are occurring on inhaled insulin devices and manufacturers could begin producing the products within the next few years. Since insulin is a relatively large protein, it does not permeate into the lungs. Researchers of inhaled insulin are working to create insulin particles that are small enough to reach the deep lung. The particles can then pass into the bloodstream. Researchers are testing several inhalation devices much like that of an asthma inhaler.

Another form of aerosol device undergoing tests will administer insulin to the inner cheek. Known as buccal (cheek) insulin, diabetics will spray the insulin onto the inside of their cheek. It is then absorbed through the inner cheek wall.

Insulin patches are another drug delivery system in development. Patches would release insulin continuously into the bloodstream. Users would pull a tab on the patch to release more insulin before meals. The challenge is finding a way to have insulin pass through the skin. Ultrasound is one method researchers are investigating. These low frequency sound waves could change the skin's permeability and allow insulin to pass.

Other research has the potential to discontinue the need for manufacturers to synthesize insulin. Researchers are working on creating the cells that produce insulin in the laboratory. The thought is that physicians can someday replace the non-working pancreas cells with insulin-producing cells. Another hope for diabetics is gene therapy. Scientists are working on correcting the insulin gene's mutation so that diabetics would be able to produce insulin on their own.

Where to Learn More

Books

Clark, David P, and Lonnie D. Russell. Molecular Biology Made Simple and Fun. 2nd ed. Vienna, IL: Cache River Press, 2000.

Considine, Douglas M., ed. Van Nostrand's Scientific Encyclopedia. 8th ed. New York: International Thomson Publishing Inc., 1995.

Periodicals

Dinsmoor, Robert S. "Insulin: A Never-ending Evolution." Countdown (Spring 2001).

Other

Diabetes Digest Web Page. 15 November 2001. <http://www.diabetesdigest.com>.

Discovery of Insulin Web Page. 16 November 2001. <http://web.idirect.com/~discover>.

Eli Lilly Corporation. Humulin and Humalog Development. CD-ROM, 2001.

Eli Lilly Diabetes Web Page. 16 November 2001. <http://www.lillydiabetes.com>.

Novo Nordisk Diabetes Web Page. 15 November 2001. <http://www.novonet.co.nz>.

[Article by: M. Rae Nelson]

Produced and secreted by the beta cells of the islets (insulae) of Langerhans of the pancreas, the hormone which regulates the use and storage of foodstuffs, especially the carbohydrates. Chemically insulin is a small, simple protein. Insulins from various species differ in the composition; these differences account for the fact that diabetics treated with animal insulins develop antibodies which may sometimes interfere with the action of the hormone. The structure has been verified by synthesis of insulin from pure amino acids in the laboratory. See also Carbohydrate metabolism; Immunology; Pancreas.

Insulin, being a polypeptide, can also be broken down by many proteolytic enzymes to its constituent amino acids. Because of these breakdown systems, the turnover of insulin in the body is rapid; its “half-life” has been estimated to be 10–30 min. The liver alone is capable of destroying about 50% of the insulin passing through it on its way from the pancreas to the bodily tissues.

The role played by insulin in the body is most clearly approached by considering the abnormalities resulting from removing insulin from an organism by surgical excision of the pancreas or by the chemical destruction of the insulin-producing cells: A state of severe diabetes is produced. Normally the blood glucose level is about 100 mg/100 ml. A carbohydrate meal raises the blood sugar to about 150 mg and the premeal value is reached again within 1.5 h. The normal organism manages to dispose of food by storage and oxidation within this period because insulin is present. When food (carbohydrate and protein) reaches the upper intestine, a substance is liberated which in turn stimulates the beta cells to secrete extra insulin. Insulin acts on most tissues to speed the uptake of glucose. In the cells the glucose is burned for energy, stored as glycogen, or transformed to and stored as fat. The human pancreas probably produces 1–2 mg of the hormone per day. This is sufficient to regulate the metabolism of more than 250 g of carbohydrate, 70 g of protein, and 75 g of fat, the usual composition of an ordinary 2000-calorie diet.

In diabetes the rate of glucose uptake is slowed, the level of circulating blood sugar rises, and sugar spills over into the excreted urine. Calories are wasted, more water is excreted, and there is muscular weakness and weight loss; hence urinary frequency, hunger, thirst, and fatigue. Whenever glucose metabolism is defective, stored fat is broken down to fatty acids because of the actions of adrenaline and the pituitary growth hormone. Insulin is able to reverse all these phenomena by favoring storage and swift intake of glucose into the tissues, by decreasing the breakdown of stored fat, and by promoting protein synthesis. See also Diabetes.

When insulin is secreted or given in excess, it may lower the blood sugar level much below its normal value, causing hypoglycemia. Hypoglycemia is dangerous because the metabolism in the brain cells depends primarily upon an adequate supply of glucose.

The precise molecular mechanisms of insulin action are still not known. The initial step is the binding of the hormone to a specific receptor on the cell membrane. This event somehow activates a set of transport molecules, so that glucose, potassium, and amino acids enter cells more freely. At the same time, fat breakdown is slowed and glycogen storage increased. All these actions depend upon the integrity of the outer cell membrane. See also Cell permeability.

Not all the cells of the body require or respond to insulin. The insulin-responsive tissues are the liver, skeletal muscle, the heart, and the adipose tissue. Sensitivity to insulin is affected by many conditions. Obesity, antibodies to the hormone or its receptor, oversecretion of growth hormone or adrenal steroids, ketosis, and unknown genetic factors all cause insulin resistance. Muscular exercise, correction of obesity, and a deficiency of pituitary or adrenal hormones are associated with an increased sensitivity to the hormone.

---

Glucose, dissolved in the blood (blood sugar), is one of the main sources of energy for the body. Different organs and tissues use other fuels to varying extents, but the brain uses glucose exclusively. To protect vital functions mammals have evolved a mechanism for keeping the concentration of glucose in the blood fairly constant — an example of homeostasis. This includes diverse hormonal responses that increase the blood glucose concentration. Yet, in what seems a remarkable oversight of nature, the body relies almost entirely upon just one hormone, the protein insulin, to bring about a decrease in blood glucose. Insulin facilitates the entry of glucose from the blood into the tissues of the body.

It has been known since 1899 that removal of the pancreas from dogs led to diabetes, with its characteristic persistent increase in blood glucose (hyperglycaemia) and presence of sugar in the urine (glycosuria). The fascinating saga of the eventual discovery of insulin by Banting and Best in 1921 is well known. They were able to show that injection of an extract from the pancreas of a healthy dog led consistently to a decrease in the amount of sugar in the blood and urine of diabetic dogs. They published their account, entitled ‘The Internal Secretion of the Pancreas’, in 1922. Their experiments, which were to prove life-saving, assured the insulin molecule a key place in medical history, and won a Nobel Prize for Banting and Macleod (in whose Canadian laboratory the work was done) as well as earning the grateful thanks of diabetic people in their millions around the world. It was some 30 years later that Frederick Sanger embarked on his painstaking but highly successful molecular dissection of insulin, which unravelled its precise amino acid sequence. This was a landmark achievement, representing as it did the first successful sequencing of any protein molecule, and it earned Sanger his first Nobel Prize. With subsequent establishment of its three-dimensional structure, insulin was revealed as a vital protein of classic polypeptide design. Despite 300 million years of divergent evolution, the molecular form and function of insulin has been remarkably well conserved across the entire zoological spectrum.

The dynamic glucose-insulin system on which the body's metabolism so critically depends is controlled and modulated by various factors impinging on the ‘b-cells’, which are found in the pancreas in cellular nodules, the Islets of Langerhans — named after the German pathologist who described them in 1869, long before their function was known. These ‘b-cells’ detect glucose in the blood and secrete insulin in appropriate amounts in response to the meal-induced tidal changes in blood glucose level.

Insulin is normally quite rapidly removed from the blood and survives in the circulation for only 5-15 min, thus placing a continuing demand on the b-cells for the release of more insulin in order to establish an effective feedback control of blood glucose concentration. This moment-by-moment process requires, in the b-cells, mechanisms for the manufacture, storage, and rapid release of insulin. To replenish its insulin supply, the genes of a pancreatic b-cell switch on their protein manufacturing machinery, producing a much larger single chain precursor molecule, called pro-insulin, which contains the amino acid sequence of insulin. Successive and controlled proteolysis (breakdown of this protein molecule) finally leaves the 51 amino acid sequence of insulin itself, and ensures its correct folding to create the three-dimensional shape of the molecule. Once formed in the b-cell, insulin is stored in granules as a symmetrical hexagonal array of 6 insulin molecules combined in a stable crystalline structure with 2 atoms of zinc. When released into the circulation at effective concentrations, insulin is transported as, and normally acts as, a single molecule.

To exert its effects on target cells — muscle, liver, or fat cells — the insulin molecule must first be recognized by specific insulin-receptor protein molecules in the cell membranes. Part of the insulin receptor spans the membrane, so that, when an insulin molecule binds to the external part of the receptor, a signal is transmitted across the membrane to other molecules, leading to a cascade of enzyme activity in the target cells.

Insulin resistance may occur when the blood glucose level is not well controlled, as in a type of diabetes which begins in adult life, where the pancreatic b-cells do not produce enough insulin. Not only does this lead to the appearance of the symptoms of diabetes, but the high level of glucose in the blood decreases the sensitivity of the target cell receptors for insulin and so makes the situation worse. It is possible to treat this type of diabetes by mouth with agents that boost the output of insulin from any viable b-cells that are present, or reduce the blood sugar by other means. If, on the other hand, pancreatic b-cells have all been destroyed, as in juvenile diabetes, then insulin must be injected daily as replacement therapy.

Unfortunately insulin cannot be given orally because it is a peptide and is therefore rapidly broken down by enzymes in the gut. Different preparations of insulin are available for injection, depending on the duration of action required. Insulin was originally extracted on a massive scale from the pancreas of animals (cows or pigs). It can now be obtained by genetic engineering of bacterial cells, causing them to express human insulin. It is noteworthy that insulin was the first protein to be commercially produced by such recombinant technology. Although this allows large scale production and isolation, pig pancreas remains the main source of insulin for human treatment: pig insulin differs from human insulin by only one amino acid.

Various insulin formulations may combine rapid-, medium-, or long-acting forms of crystalline insulin so that individual requirements for insulin can be matched to blood glucose levels following meals. Insulin has thus become firmly established in modern medicine as a remarkably effective therapeutic agent, but a whole life-time of constant injection is an unwelcome hazard for anyone suffering from juvenile diabetes. The design and production of a non-peptide, orally-active insulin analogue therefore remains a major goal of pharmaceutical research.

— E. K. Matthews

See endocrine. See also blood sugar; hormones; metabolism; pancreas.

Hormone secreted by the β-cells of the pancreas which controls carbohydrate metabolism. Diabetes mellitus is the result of an inadequate supply of insulin or failure of its function. Since insulin is a protein it would be digested if taken by mouth so must be injected. See also diabetes; diet, diabetic; glucose tolerance.

A hormone secreted by cells within the islets of Langerhans, in the pancreas. Insulin is released into the bloodstream in response to raised blood glucose levels. It stimulates the liver, muscles, and fat cells to remove glucose from the blood, and to store it as glycogen and fat in cells. It also promotes the conversion of glucose to fat and stimulates protein synthesis in muscles. Inhibition of insulin production (e.g. by adrenaline or exercise) results in increased blood glucose levels. Although insulin secretion is reduced during exercise, sensitivity to insulin increases in well-trained individuals. Lack of insulin or progressive loss of sensitivity to insulin, can result in diabetes mellitus.

Brand names: Exubera ®, Exubera®

Español:
• Insulina, Inhalada

Insulin inhalation powder

What is Insulin inhalation powder?

INSULIN INHALATION (Exubera®) is a human-made form of insulin. Insulin is a hormone produced naturally by the pancreas. Insulin lowers the amount of sugar in your blood. Keeping your blood sugar close to normal prevents or reduces long-term complications of diabetes including damage to the blood vessels, eyes, kidneys, or nerves. Insulin inhalation is a short-acting insulin that starts working faster than injected regular insulin. Because of the quicker onset of action, you should eat a meal within 10 minutes after inhaling your dose of insulin. This will help to reduce the risk of low blood sugar (hypoglycemia).The time-course of action of insulin may vary in different people and at different times in the same person. You need a prescription to buy inhaled insulin.

There are different types of insulin available. Each type has a different onset of action and a different duration of action in the body. You should learn which types you take and how you should administer them, and how each type acts in your body.

If you switch from injected insulin to inhaled insulin, your dose of insulin may change. Monitor your blood sugar more frequently. Take care to learn and recognize the symptoms of hypoglycemia (low blood sugar) and know how you should treat these reactions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• adrenal or pituitary gland problems
• asthma
• diarrhea
• fever or infection
• injury or trauma
• kidney disease
• liver disease
• lung diseases like COPD, chronic bronchitis, emphysema, or cystic fibrosis
• nausea, vomiting
• recent surgery
• thyroid disease
• currently smoke tobacco or quit smoking within the past 6 months
• an unusual reaction to Insulin, mannitol, medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should this medicine be used?

This medicine is for inhalation by mouth. Use exactly as directed. Do not use more than prescribed. Do not use more or less often than prescribed. It is important to follow the directions given to you by your prescriber or health care professional. You will be taught how to use the inhaler. If you are using more than one blister pack for a dose, inhale each blister pack separately. If you use the 3 mg blister pack, and it becomes unavailable, do not substitute three 1 mg blister packs. Contact your health care provider for instructions.

Your health care provider will tell you how long to wait after you inhale your dose of insulin before eating a meal. Most of the time, you will wait for 10 minutes or less. You will also be taught how to adjust doses for activities and illness.

Clean the chamber and mouthpiece of the inhaler once a week with a damp cloth and mild soap. Rinse with warm water. Make sure the inhaler is fully dry before using it. For the base of the inhaler, wipe the outside with a damp soft cloth. Do not use soap or any other cleanser. Do not clean the Release Unit. It should be replaced every 2 weeks. The inhaler should be replaced once a year.

What drug(s) may interact with Insulin Inhalation?

• other medicines for diabetes
• other medicines that are inhaled, especially those used for asthma like albuterol

Many medications may cause changes (increase or decrease) in blood sugar, these include:
• alcohol containing beverages
• angiotensin converting enzyme inhibitors (ACE inhibitors), often used for high blood pressure or heart problems (examples include captopril, enalapril, lisinopril)
• antiretroviral protease inhibitors (examples include indinavir, ritonavir, saquinavir)
• aspirin and aspirin-like drugs
• beta-blockers, often used for high blood pressure or heart problems (examples include atenolol, metoprolol, propranolol)
• certain medicines used for mental depression, emotional, or psychotic disturbances
• chromium
• cisapride
• clonidine
• cyclosporine
• danazol
• diazoxide
• disopyramide
• epinephrine
• female hormones, such as estrogens, progestins, or contraceptive pills
• fenofibrate
• gemfibrozil
• glucagon
• growth hormone (somatropin)
• guanethidine
• isoniazid
• lithium
• metoclopramide
• male hormones or anabolic steroids
• medications to suppress appetite or for weight loss
• medicines for allergies, asthma, cold, or cough
• niacin
• nicotine (including nicotine found in patches and gum)
• pentamidine
• pentoxifylline
• phenytoin
• propoxyphene
• quinolone antibiotics, medicines used for infections (examples include ciprofloxacin, levofloxacin, norfloxacin)
• some herbal dietary supplements
• steroid medicines such as prednisone or cortisone
• sulfonamides, medicines for infection ( examples include Azulfidine®, Bactrim®, Gantrisin® Septra®)
• tacrolimus
• thyroid hormones
• water pills (diuretics)

Some medications can hide the warning symptoms of low blood sugar (hypoglycemia). You may need to monitor your blood sugar more closely if you are taking one of these medications. These include:
• beta-blockers, often used for high blood pressure or heart problems (examples include atenolol, metoprolol, propranolol)
• clonidine
• guanethidine
• reserpine

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking Insulin Inhalation?

Visit your health care professional or prescriber for regular checks on your progress. To control your diabetes properly you must use insulin regularly and follow a regular diet and exercise schedule. Diabetes cannot be cured. Careful, daily control of blood sugar can postpone or prevent many of the long-term complications of diabetes.

Treatment with inhaled insulin has caused small declines in lung function. Because of this effect, your doctor will monitor your lung function before and during treatment with Exubera®.

Dangerously high or low blood sugar can occur when meals and insulin are not spaced properly. Checking and recording your blood glucose and urine ketone levels regularly is important. Sometimes it is hard to tell the difference between low and high blood sugar (see side effects). Use a glucometer (blood glucose or sugar measuring device), whenever possible, before you treat high or low blood sugar.

Always carry a quick-source of sugar with you in case you have symptoms of low blood sugar (hypoglycemia). Examples include hard sugar candy or glucose tablets.

Do not switch brands or types of insulin without consulting your health care professional or prescriber. Switching insulin brand or type can cause dangerously high or low blood sugar.

Always keep an extra supply of insulin on hand.

Wear a Medic Alert bracelet or necklace and/or carry an identification card with your name and address, condition, medication, and prescriber's name and address.

If you develop a cold, diarrhea, vomiting, or other infection or illness, you should contact your health care professional or prescriber. 'Sick-days' may require changes to your insulin dosage. Or your illness may need to be evaluated. Ask your health care professional or prescriber what you should do if you become ill. Do not stop taking your insulin; check with your health care professional or prescriber for advice.

Many nonprescription cough and cold products contain sugar or alcohol. These can affect diabetes control or can alter the results of tests used to monitor blood sugar. Avoid alcohol. Avoid products that contain alcohol or sugar.

If you are going to have surgery, make sure you tell the health care professionals that you take insulin.

What side effects may I notice from receiving Insulin Inhalation?

Learn how and when you should monitor your blood sugar, and what you should do if high or low blood sugar occurs. Side effects that you should report to your prescriber or health care professional as soon as possible:

Symptoms of hypoglycemia (low blood glucose):
• anxiety or nervousness, confusion, difficulty concentrating, hunger, pale skin, nausea, fatigue, sweating, headache, palpitations, numbness of the mouth, tingling in the fingers, tremors, muscle weakness, blurred vision, cold sensations, uncontrolled yawning, irritability, rapid heartbeat, shallow breathing, and loss of consciousness. You should learn to recognize your own symptoms of hypoglycemia. Your symptoms may be different than others. If you are uncertain about your symptoms of hypoglycemia, check your blood sugar often to help you learn to recognize the symptoms. Hypoglycemia may cause you to not be aware of your actions or surroundings if it is severe, so you should let others know what to do if you cannot help yourself in a severe reaction. Your prescriber or health care professional will teach you how to treat hypoglycemia. Always carry a quick source of sugar such as candies or glucose tablets with you.

Symptoms of high blood sugar (hyperglycemia):
• dizziness, dry mouth, flushed dry-skin, fruit-like breath odor, loss of appetite, nausea, stomach ache, unusual thirst, frequent passing of urine

Insulin also can cause rare but serious allergic reactions in some patients, including:
• severe skin rash and itching (hives)
• difficulty breathing

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• cough
• bitter taste

Where can I keep my medicine?

Store the inhaled insulin blister packs at room temperature (15—30 degrees C or 59—86 degrees F). Once the foil overwrap is opened, use the blister packs within 3 months. Do not refrigerate or freeze the blister packs; throw away the blister packs if they freeze. Keep unused blister packs in the foil overwrap. Protect the blister packs from moisture; keep out of humid places like the bathroom. Store the inhaler and the release unit at room temperature.

Keep out of the reach of children in a container that small children cannot open.

Last updated: 10/20/2005 2:13:00 PM

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

For more information on insulin, visit Britannica.com.

A hormone secreted by the beta cells of the Islets of Langerhans in the pancreas in response to elevated blood glucose levels. Insulin stimulates the liver, muscles, and fat cells to remove glucose from the blood for use or storage; it stimulates liver cells to convert glucose to glycogen; it promotes the conversion of glucose to fats; and promotes glycolysis. Reduced insulin production or a decrease in the insulin-sensitivity of target cells causes blood glucose levels to increase. Insulin secretion is reduced by adrenergic impulses in the sympathetic nervous system, and by epinephrine (adrenaline). Insulin production falls during acute bouts of exercise, but insulin sensitivity of target cells increases. In trained individuals, insulin does not fall as much during exercise as in the untrained. This allows more energy to be derived from free fatty acids. Exogenous sources of insulin are in the World Doping Agency's 2005 Prohibited List.

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(in-suh-lin, in-syuh-lin)

A hormone secreted by the pancreas that regulates the levels of sugar in the blood.

Persons suffering from diabetes mellitus may receive periodic or daily injections of insulin as a treatment for the disease.

A double-chain peptide hormone formed from proinsulin in the beta cells of the pancreatic islets of Langerhans. Insulin promotes the storage of glucose and the uptake of amino acids, increases protein and lipid synthesis, and inhibits lipolysis and gluconeogenesis.
The secretion of endogenous insulin is a response of the beta cells to a stimulus. The primary stimulus is glucose; others are amino acids, particularly leucine, and the ‘gut hormones’, such as secretin, pancreozymin and gastrin. These chemicals play an important role in maintaining normal blood glucose levels by triggering the release of insulin after ingestion of a meal.
Commercially prepared insulin is available in various types, which differ in the speed with which they act and in the duration of their effectiveness. There are three main groups: rapid acting (regular or semilente), intermediate acting (isophane suspension or NPH, zinc suspension or lente), and long acting (protamine zinc suspension or PZI, or ultralente). Mixtures are also marketed.

• i. deficiency — diabetes mellitus.
• i.-dextrose therapy — a combination used in emergencies to lower blood potassium levels in acute hypoadrenocorticism.
• i.:glucagon ratio — ratio of insulin to glucagon; thought to determine the predominance of the action of one hormone over the other.
• i.:glucose ratio — a comparison of simultaneously obtained blood levels of immunoreactive insulin and plasma glucose. An increased ratio suggests an insulin-secreting tumor of the pancreas. A modification is the amended insulin:glucose ratio, based on the calculation:
— $$\vskip13.5pt{\rm {serum\ insulin (\rmmu U/ml)\times100} \over {\rm plasma \ glucose (mg/dl) - 30}$$
• immunoreactive i. — radioimmunoassay methods are used in determining blood levels of insulin. Increased levels are found with hypoglycemia caused by functional islet cell tumors.
• i. pump — a device consisting of a syringe filled with a predetermined amount of short-acting insulin, a plastic cannula and a needle, and a pump that periodically delivers the desired amount of insulin. Sometimes used in humans, but of limited application in animals.
• i. sensitivity test, i. response test — used to differentiate diabetes mellitus from pituitary and adrenal diabetes. A test dose of exogenous insulin will produce a rapid and marked decrease in blood glucose if the pancreas is not secreting sufficient insulin. A much less dramatic response is produced if hyperglycemia is due to excessive secretion of either pituitary or adrenocortical hormones rather than insufficient insulin production.
• i. syringe — disposable syringe with a capacity of 1 ml or less and a fine gauge needle (27–29G) attached, and graduation markings corresponding to insulin units in standard preparations. Needles may also be treated to minimize pain on injection.