Insulin is a peptide hormone synthesized from amino acids in specialized cells (beta cells) within the pancreas of humans and other animals. It regulates the metabolism of carbohydrates and fats by prompting cells in muscle, liver, and fat tissue to take up glucose from the blood and store it as a complex sugar (polysaccharide) called glycogen. The name of the hormone is derived from insula, the Latin word for island, because it is produced by specialized areas of tissue within the pancreas known as islets of Langerhans, named for the German anatomist who first identified them in 1869.
Insulin that is produced within the body of a human or other animal is called endogenous insulin to distinguish it from exogenous insulin, which is insulin derived from an outside source and given as a medication to treat diabetes in humans or other animals.
Endogenous insulin serves a number of different purposes in human physiology. Insulin:
Exogenous insulin is used as a medication to treat diabetes mellitus in humans, cats, and dogs. All humans diagnosed with type 1 diabetes require treatment with exogenous insulin; about 40% of patients with type 2 diabetes require exogenous insulin as part of their therapy.
Endogenous human insulin is a hormone composed of a chain of 51 amino acids with a molecular weight of 5808 Da (dalton). It is formed from a precursor known as proinsulin, which is encoded by the INS gene and produced in the endoplasmic reticulum of the beta cells within the islets of Langerhans in the pancreas. Proinsulin contains 86 amino acids and is converted into mature insulin in a series of steps that involves the removal of 35 amino acids. Four amino acids are removed altogether; the remaining 31 are split off to form the C-peptide protein. The clinical significance of C-peptide is its use as a marker for testing endogenous insulin secretion.
The human pancreas contains between one and three million islets of Langerhans. The beta cells account for 65%–80% of all the cells within the islets. The beta cells store insulin as well as release it in response to a rise in blood glucose levels. If a person's blood glucose level rises rapidly, the beta cells can release stored insulin while producing more of the hormone at the same time. Type 1 diabetes results from the destruction or dysfunction of the beta cells by an autoimmune process that results partly from genetic susceptibility and partly from environmental triggers. In type 2 diabetes, however, the beta cells decline over a much longer period of time, and insulin resistance plays a much larger role in the emergence of the disease.
Insulin produced by several other animal species is close enough to endogenous human insulin to be clinically effective in treating diabetes. Porcine (pig) insulin differs from human insulin by only one amino acid, and bovine (cattle) insulin by only three. Even shark insulin is close enough to human insulin to have been used for many years in Japan to treat diabetes.
Diabetes mellitus has been recognized as a disease since 1500 BCE, when it was described in an ancient Egyptian medical text as an illness characterized by excessive urine production. Indian physicians of the same period observed that the urine of a diabetic patient was sweet enough to attract ants. It was not until the nineteenth century that the role of the pancreas in blood sugar regulation was identified and understood. Although in 1869 Paul Langerhans had identified the islets in pancreatic tissue that now bear his name, he did not analyze their function. In 1889, the German physician Oskar Minkowski (1858–1931) established the relationship between the loss of pancreatic function and the symptoms of diabetes through experiments on dogs, but it was not until 1901 that an American medical student, Eugene Opie (1873–1971), identified the islets of Langerhans as the specific portion of pancreatic tissue whose destruction causes diabetes.
The next stage in finding a treatment for diabetes was isolating the substance secreted by the islets. Several scientists in Europe and the United States experimented with various types of pancreatic extracts, but their work was interrupted by World War I (1914–18). In 1920, Frederick Banting (1891–1941), a Canadian physician, was studying one of Minkowski's papers and decided to try to extract the substance that was secreted by the islets of Langerhans. Working with Charles Best (1899–1978), Banting succeeded in isolating a substance that he called isletin, later known as insulin, from the pancreas of a dog, and tested it on another dog whose pancreas had been removed. When the second dog was able to survive on injections of the isletin, Banting and Best felt ready for a clinical trial in humans. Their first patient was Leonard Thompson, a 14-year-old Toronto boy who was dying of type 1 diabetes. Thompson was successfully treated with Banting and Best's extract in January 1922. By November 1922, research had progressed to the point that the drug firm of Eli Lilly and Company was able to produce large quantities of highly purified animal insulin for general distribution in Canada and the United States. Banting and Best shared the Nobel Prize in Physiology or Medicine in 1923.
All exogenous insulin that was used to treat people with diabetes was derived from animal sources from 1922 through the early 1960s. Although the amino acid sequence of human insulin was identified in the 1950s, the first synthetic insulins were not produced in laboratories until the 1960s. Humulin, the first commercially available biosynthetic human insulin, was not approved for use until 1982. As of 2012, the vast majority (70% worldwide) of people with diabetes were treated with synthetic insulins.
Exogenous insulin used in the treatment of diabetes is either animal-derived or manufactured in a laboratory using recombinant DNA technology.
ANIMAL. Porcine and bovine insulins for human usage are no longer produced in the United States. A brand of porcine insulin called Vetsulin is still produced by Schering-Plough Animal Health for treating diabetes in dogs and cats, and is approved by the FDA for this purpose. The FDA also permits the importation of animal-derived insulin from the United Kingdom for the small minority of humans whose diabetes is better controlled by animal insulin than by one of the biosynthetic forms.
SYNTHETIC. Synthetic insulins can be classified in several ways, most commonly by their activity in the body or by their method of production. The doctor considers three important measurements in prescribing an insulin: onset (the time required for the insulin to enter the bloodstream and start to lower the patient's blood sugar level), peak (the period when the insulin is most effective), and duration (the total length of time the insulin continues to lower blood sugar). The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) classifies insulins according to activity in the body as follows:
Synthetic insulins are manufactured using recombinant DNA technology. The first such insulin, Humulin, was first marketed in 1982 by Eli Lilly, and was made by inserting human DNA into cells of Escherichia coli and allowing the cells to grow and reproduce normally. Novo Nordisk, a Danish company, uses a similar process to produce an insulin called NovoLog from yeast.
A newer category of synthetic insulin is called an insulin analogue; it is different from any insulin that occurs in nature, but it can still be used by the human body to control blood sugar levels. Insulin analogues are technically called insulin receptor ligands by the FDA. They have had their amino acid sequences altered by genetic engineering to alter their speed of onset and duration. The two major types of insulin analogues are 1) rapid-acting, intended to supply the bolus level of insulin required after a meal, and 2) longacting, intended to be released slowly in the blood-stream and supply the basal level of insulin for a full day. Rapid-acting insulin analogues include insulin aspart, insulin glulisine, and insulin lispro. Long-acting analogues include insulin detemir and insulin glargine.
Most insulins used to treat diabetes in humans must be injected subcutaneously (under the skin). An inhalable insulin called Exubera was developed and approved by the FDA in 2006, but it was withdrawn from the market in 2007 due to lack of acceptance. The second intranasal inhaled insulin, Afrezza (Mannkind Corporation) was approved by the U.S. Food and Drug Administration in June 2014 for use by patients with type 1 and type 2 diabetes. Afrezza is formulated as a powder in cartridges inserted into a specially designed inhaler. Patients with type 1 diabetes must use Afrezza with a long-acting insulin. Afrezza is used at mealtimes by patients with type 2 diabetes who are not getting enough glucose control with oral medications. It is not recommended for diabetic ketoacidosis. Afrezza is inhaled before each meal, or just after starting to eat. It is a rapid-acting insulin that is absorbed more quickly directly into the blood from lung cells. Afrezza peaks in the blood within 15 to 20 minutes and is cleared from the body in two to three hours; in comparison, injected rapid-acting insulin peaks in an hour and clears in 4 hours. Afrezza became available in U.S. pharmacies in February 2015. As of April 2018, Afrezza was still being marketed, though sales were not as vigorous as projected. As with other types of powder-based inhalers for other medical conditions, throat irritation and coughing may occur. Afrezza is not recommended for patients who smoke.
There has long been considerable interest in developing a form of insulin that could be taken by mouth, as many people with diabetes would prefer an oral insulin to repeated injections. The difficulty in formulating an oral insulin is that insulin itself is a protein that is broken down in the stomach during the digestive process. Several companies have been investigating and developing oral insulin formulations, but, as of April 2018, none have been found to be commercially viable due to drug delivery issues. New drug delivery techniques are in development that may make oral insulin a reality in the future.
People with diabetes requiring insulin therapy have three options for administering the drug by subcutaneous injection: syringes with needles, repeat-use injection pens with needles, or insulin pumps. Insulin injection pens come in two types: some use cartridges that must be inserted into the pen, while others are prefilled with insulin and discarded when all the insulin has been used. To use the pen, the patient dials the correct amount of insulin to be delivered, and the pen injects the insulin into the skin through a needle in a manner similar to a syringe.
LABORATORY. There are several laboratory tests that are used to evaluate people for the presence of diabetes or the effectiveness of insulin therapy, including:
HOMEGLUCOSE TESTING. In addition to laboratory tests that measure endogenous insulin secretion and blood glucose control, patients with diabetes should monitor their blood glucose levels at home. The traditional method of home monitoring involves the use of a glucometer, a small handheld battery-operated device that measures the level of blood glucose in a tiny amount of blood drawn from a fingerstick and placed on the end of a test strip inserted in the meter. Newer glucometers can calculate blood sugar averages over a two-week period, store information that can be uploaded onto a computer, or interpret blood sugar levels in blood drawn from sites other than the fingertip. People who take multiple injections of insulin each day or use an insulin pump are usually advised to check their blood sugar three times per day.
An alternative to the use of a glucometer is a continuous glucose monitoring (CGM) system. A typical system consists of a sensor worn under the skin that is replaced every few days, a link from the sensor to a (non-implanted) receiver that communicates with a receiver, and the receiver itself, which is worn like a pager. Traditional fingersticks are required from time to time to calibrate the CGM. In addition, CGM system readings lag about five minutes behind actual changes in blood glucose levels. For this reason, patients using a CGM system are advised to use a fingerstick blood glucose measurement to confirm an abnormal blood glucose CGM reading before taking corrective action.
The strength of insulin is measured by the number of units (U) per milliliter (mL). One unit equals 45.5 micrograms of pure crystalline insulin. Prior to 1973, insulins came in strengths ranging from 40 units/mL (U-40) to 100 units/mL (U-100). In 1973 the FDA standardized insulins sold in the United States to U100 to reduce prescription and dosage errors. Most other countries adopted the U-100 standard, although some still dispense U-40 insulin.
There are numerous precautions that patients must observe regarding insulin administration, storage, timing, and monitoring.
All currently available insulins require careful storage. They are complex preparations that contain preservatives and other chemicals to adjust the acidity of the insulin (to prevent reactions at the injection site) as well as the actual drug. Insulin can be stored in the refrigerator but can also be kept for as long as a month at room temperature to minimize the discomfort caused by injecting cold insulin. Insulin should never be kept in a freezer, exposed to direct sunlight or extreme heat or cold, or stored in the glove compartment of a car.
Insulin should never be used past the expiration date on the vial. In addition, vials of insulin should never be shaken but rubbed gently between the hands to make sure the insulin ingredients are mixed. Patients using regular or NPH insulin should examine the vial before each use to make sure that no clumps, crystals, or “frosting” are visible inside the vial. If any of these are found, the insulin should not be used.
With the exception of the long-acting insulins, which are designed to be injected only once a day, insulin injections are timed with respect to the patient's meals. To keep blood glucose at an acceptable level, an injection of regular insulin is given about 30 minutes before a meal, whereas a rapid-acting insulin is given at the beginning of the meal. Type 1 diabetes usually requires three or four injections of different types of insulin each day. People with type 2 diabetes may need only a single injection of insulin per day, usually given at supper or bedtime; others may need three or four injections per day to keep their blood sugar level under control.
Insulin is absorbed into the bloodstream at different speeds, depending on the site on the body used for the injection. The abdomen is the most commonly used site because it allows the insulin to be absorbed rapidly. Other sites include the upper arms, where absorption is slower, and the thighs or buttocks, where absorption is very slow. Patients are advised to use the same general body area for each injection so that each dose of insulin is absorbed at the same speed, but they should avoid using the exact same spot each time. The reason for moving the injection site from one dose to the next is to prevent the formation of lumps, pits, or fatty deposits beneath the skin; these deposits affect the body's absorption of insulin, and some patients may find them unsightly.
Some patients may develop allergies to the additives and preservatives used in the manufacture of synthetic insulins, particularly the intermediate- and long-acting formulations.
Insulin aspart and insulin glargine should not be used during pregnancy or lactation because they have not been studied in pregnant women. NPH and regular insulins are preferred for use during pregnancy. Because insulin is secreted in breast milk, blood glucose levels should be monitored in both mother and child during lactation.
Patients should inform their doctor of all prescription and over-the-counter medications that they are using before starting insulin injections. A large number of drugs can interact with insulins, including:
Glucose control is essential to diabetes treatment. Abnormal levels can result in a wide range of complications.
The most common complication of insulin use is hypoglycemia, or abnormally low blood sugar. It is a recurrent risk for diabetic patients receiving insulin therapy, particularly those with type 1 diabetes. Hypoglycemia can result from injecting too much insulin (measuring the dose incorrectly or misunderstanding the doctor's instruction), not eating enough food to raise blood sugar levels, lowering blood sugar levels through overexercise, or taking other medications that interact with insulin by increasing its effectiveness. In rare cases, hypoglycemia can result from an insulinoma, or a tumor in the pancreas that secretes excessive amounts of insulin.
The symptoms of hypoglycemia range from mild feelings of unease or irritability to yawning, mental confusion, nausea, hunger, tiredness, perspiration, headache, heart palpitations, numbness around the mouth, tremors, muscle weakness, and blurred vision. Severe hypoglycemia may include seizures, coma, and eventually permanent brain damage or death. It has been estimated that 2%–4% of deaths in people with type 1 diabetes result from hypoglycemia.
Mild hypoglycemia is treated by raising the blood sugar level through eating or drinking something sweet or sugary, often a piece of candy, a cookie, or orange juice. People with diabetes are typically advised to carry candy or a similar sweet or high-carbohydrate food with them at all times in case they experience the symptoms of hypoglycemia or their glucometer registers an abnormally low blood sugar level during home glucose testing. Severe diabetic hypoglycemia, sometimes called insulin shock, requires emergency hospital treatment. It is treated by intravenous administration of dextrose, a simple sugar, or glucagon, a peptide hormone that raises blood sugar levels.
Lipoatrophy is the medical term for the formation of a pit, small dent, or lump beneath the skin caused by repeated injections of insulin into the same location. One of the potentially serious consequences of lipoatrophy is that the injured tissue may reject the insulin or slow down its absorption, thereby complicating blood glucose measurement and accurate assessment of the patient's current insulin dosage. Lipoatrophy can usually be prevented by rotating the site of insulin injections.
Because insulins must be injected subcutaneously, infections can result from failure to cleanse the skin before injection or from nonsterile needles. Patients are instructed to cleanse the injection site before each injection by swabbing the skin with a cotton ball moistened with rubbing alcohol, and to avoid reusing insulin syringes. Although the American Diabetes Association notes that syringes can be safely reused by some patients to save costs, those with weakened immune systems, chronic illnesses, or open wounds on the hands should not risk the dangers of infection from reused syringes.
Although such cases are fortunately rare, instances of murder (or suicide) have been documented worldwide that involved the administration of large amounts of insulin to produce insulin shock, coma, and eventual death in the victim. It is possible to kill people who do not have diabetes with high doses of insulin (as well as those with diabetes), although the lethal dose varies somewhat from person to person.
Children diagnosed with either type 1 or type 2 diabetes need instruction on the care and proper injection of their insulin as well as help from other family members in coping with the emotional impact of diabetes. It is also important to have ongoing support from a dietitian to ensure the child maintains a proper diet. Parents may need to monitor their child's compliance with insulin injections as well as home glucose testing. The Nemours Foundation Diabetes Center ( http://kidshealth.org/parent/centers/diabetes_center.html#cat20724 ) is an excellent resource for diabetes- and insulin-related issues in children.
See also Adolescent nutrition ; AIDS/HIV diet and nutrition ; American Diabetes Association ; Atkins diet ; Bernstein diet ; Bodybuilding diet ; Carbohydrate addict's diet ; Children's diets ; Chromium ; Diabetes mellitus ; Diabetic diet ; Diet apps ; Ergogenic aids ; Gestational diabetes ; Ginseng ; Glucosamine ; Glycemic index diets ; High-fat, low-carb diets ; Low-sugar diet ; Mediterranean diet ; Metabolic syndrome ; Nutrigenomics ; Obesity ; Senior nutrition ; SlimFast ; South Beach diet ; Sugar ; TLC diet ; Veganism ; Whole grains .
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Food and Drug Administration (FDA), 10903 New Hampshire Ave., Silver Spring, MD, 20993, (888) INFO-FDA (463-6332), http://www.fda.gov/default.htm .
National Institute of Diabetes and Digestive and Kidney Diseases, 9000 Rockville Pk., Bethesda, MD, 20892, (800) 860-8747, TTY: (866) 569-1162, email@example.com, http://www.digestive.niddk.nih.gov .
Rebecca J. Frey, PhD
Revised by Jennifer E. Van Pelt, MA