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Wikipedia

Insulin (medication)

January 25, 2023

"Insulin therapy" and "Synthetic insulin" redirect here. For the psychiatric treatment, see Insulin shock therapy. For the naturally occurring protein, see Insulin.

As a medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose.[4] Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states.[4] Insulin is also used along with glucose to treat hyperkalemia (high blood potassium levels).[5] Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle.[4] There are various types of insulin, suitable for various time spans. The types are often all called insulin in the broad sense, although in a more precise sense, insulin is identical to the naturally occurring molecule whereas insulin analogues have slightly different molecules that allow for modified time of action. It is on the World Health Organization's List of Essential Medicines.[6][7] In 2020, regular human insulin was the 307th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[8][9]

Insulin
Vials of insulin
Clinical data
Trade namesHumulin, Novolin, Insuman, others
AHFS/Drugs.comMonograph
MedlinePlusa682611
License data
Routes of
administration		Subcutaneous, intravenous, intramuscular, inhalation
ATC code
Legal status
Legal status
Identifiers
CAS Number
  • 9004-10-8
PubChem CID
  • 70678557
DrugBank
  • DB00030
ChemSpider
  • 34999906
UNII
  • 438UC14NDQ
KEGG
  • D04477
Chemical and physical data
FormulaC257H383N65O77S6
Molar mass5807.63 g·mol−1
Density1.09 g/cm3 [2]
Melting point233 °C (451 °F) [3]

Insulin can be made from the pancreas of pigs or cows.[10] Human versions can be made either by modifying pig versions or recombinant technology.[10] It comes in three main types: short–acting (such as regular insulin), intermediate-acting (such as neutral protamine Hagedorn (NPH) insulin), and longer-acting (such as insulin glargine).[10]

History

Insulin was first used as a medication in Canada by Charles Best and Frederick Banting in 1922.[11][12]

This is a chronology of key milestones in the history of the medical use of insulin. For more details on the discovery, extraction, purification, clinical use, and synthesis of insulin, see Insulin

  • 1921 Research on the role of pancreas in the nutritive assimilation[13]
  • 1922 Frederick Banting, Charles Best and James Collip use bovine insulin extract in humans at Connaught Laboratories in Toronto, Canada.[11]
  • 1922 Leonard Thompson becomes the first human to be treated with insulin.
  • 1922 James D. Havens, son of former congressman James S. Havens, becomes the first American to be treated with insulin.[14][15]
  • 1922 Elizabeth Hughes Gossett, daughter of the U.S. Secretary of State, becomes the first American to be (officially) treated in Toronto.[16][17]
  • 1923 Eli Lilly produces commercial quantities of much purer bovine insulin than Banting et al. had used
  • 1923 Farbwerke Hoechst, one of the forerunners of today's Sanofi Aventis, produces commercial quantities of bovine insulin in Germany
  • 1923 Hans Christian Hagedorn founds the Nordisk Insulinlaboratorium in Denmark – forerunner of today's Novo Nordisk
  • 1923 Constance Collier returns to health after being successfully treated with insulin in Strasbourg[18]
  • 1926 Nordisk receives a Danish charter to produce insulin as a non-profit
  • 1936 Canadians David M. Scott and Albert M. Fisher formulate a zinc insulin mixture at Connaught Laboratories in Toronto and license it to Novo
  • 1936 Hagedorn discovers that adding protamine to insulin prolongs the duration of action of insulin
  • 1946 Nordisk formulates Isophane porcine insulin aka Neutral Protamine Hagedorn or NPH insulin
  • 1946 Nordisk crystallizes a protamine and insulin mixture
  • 1950 Nordisk markets NPH insulin
  • 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer lasting insulin
  • 1955 Frederick Sanger determines the amino acid sequence of insulin
  • 1965 Synthesized by total synthesis by Wang Yinglai, Chen-Lu Tsou, et al.
  • 1969 Dorothy Crowfoot Hodgkin solves the crystal structure of insulin by X-ray crystallography
  • 1973 Purified monocomponent (MC) insulin is introduced
  • 1973 The U.S. officially "standardized" insulin sold for human use in the U.S. to U-100 (100 units per milliliter). Prior to that, insulin was sold in different strengths, including U-80 (80 units per milliliter) and U-40 formulations (40 units per milliliter), so the effort to "standardize" the potency aimed to reduce dosage errors and ease doctors' job of prescribing insulin for people. Other countries also followed suit.
  • 1978 Genentech produces biosynthetic human insulin in Escherichia coli bacteria using recombinant DNA techniques, licenses to Eli Lilly
  • 1981 Novo Nordisk chemically and enzymatically converts porcine to human insulin
  • 1982 Genentech synthetic human insulin (above) approved
  • 1983 Eli Lilly and Company produces biosynthetic human insulin with recombinant DNA technology, Humulin
  • 1985 Axel Ullrich sequences a human cell membrane insulin receptor.
  • 1988 Novo Nordisk produces recombinant biosynthetic human insulin
  • 1996 Lilly Humalog "lispro" insulin analogue approved.
  • 2000 Sanofi Aventis Lantus insulin "glargine" analogue approved for clinical use in the US and Europe.
  • 2004 Sanofi Aventis Apidra insulin "glulisine" insulin analogue approved for clinical use in the US.
  • 2006 Novo Nordisk Levemir "detemir" insulin analogue approved for clinical use in the US.
  • 2008 Abott laboratories " FreeStyle Navigator CGM" gets approved.[19]
  • 2013 The U.S. Food and Drug Administration (FDA) requested more cardiac safety tests for Insulin Degludec.
  • 2015 Insulin degludec was approved by the FDA on September 25, 2015.

Medical uses

 
Giving insulin with an insulin pen.

Insulin is used to treat a number of diseases including diabetes and its acute complications such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. It is also used along with glucose to treat high blood potassium levels. Use during pregnancy is relatively safe for the baby.[4] Insulin was formerly used in a psychiatric treatment called insulin shock therapy.[20]

Side effects

Some side effects are hypoglycemia (low blood sugar), hypokalemia (low blood potassium), and allergic reactions.[4] Allergy to insulin affected about 2% of people, of which most reactions are not due to the insulin itself but to preservatives added to insulin such as zinc, protamine, and meta-cresol. Most reactions are Type I hypersensitivity reactions and rarely cause anaphylaxis. A suspected allergy to insulin can be confirmed by skin prick testing, patch testing and occasionally skin biopsy. First line therapy against insulin hypersensitivity reactions include symptomatic therapy with antihistamines. The affected persons are then switched to a preparation that does not contain the specific agent they are reacting to or undergo desensitization.[21]

Cutaneous adverse effects

Other side effects may include pain or skin changes at the sites of injection. Repeated subcutaneous injection without site rotation can lead to lipohypertrophy and amyloidomas, which manifest as firm palpable nodules under the skin.[22]

Effects of early routine use

Early initiation of insulin therapy for the long-term management of conditions such as type 2 diabetes would suggest that the use of insulin has unique benefits however it must be noted that with insulin therapy, there is a need to gradually raise the dose and the complexity of the regimen, as well as the likelihood of developing severe hypoglycemia which is why many people and their doctors are hesitant to begin insulin therapy in the early stage of disease management.[23] Many obstacles associated with health behaviors also prevent people with type 2 diabetes mellitus from starting or intensifying their insulin treatment, including lack of motivation, lack of familiarity with or experience with treatments, and time restraints causing people to have high glycemic loads for extended periods of time prior to starting insulin therapy. This is why managing the side effects associated with long-term early routine use of insulin for type 2 diabetes mellitus can prove to be a therapeutic and behavioral challenge.[24]

Principles

 
The idealised diagram shows the fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day containing three meals. In addition, the effect of a sugar-rich versus a starch-rich meal is highlighted.

Insulin is an endogenous hormone, which is produced by the pancreas.[27] The insulin protein has been highly conserved across evolutionary time, and is present in both mammals and invertebrates. The insulin/insulin-like growth factor signalling pathway (IIS) has been extensively studied in species including nematode worms (e.g.C. elegans), flies (Drosophila melanogaster) and mice (Mus musculus). Its mechanisms of action are highly similar across species.[28]

Both type 1 diabetes and type 2 diabetes are marked by a loss of pancreatic function, though to differing degrees.[27] People who are affected with diabetes are referred to as diabetics. Many diabetics require an exogenous source of insulin to keep their blood sugar levels within a safe target range.[29][30][31]

In 1916, Nicolae C. Paulescu (1869–1931) succeeded in developing an aqueous pancreatic extract that normalized a diabetic dog. In 1921, he published 4 papers in the Society of Biology in Paris centering on the successful effects of the pancreatic extract in diabetic dogs. Research on the Role of the Pancreas in Food Assimilation by Paulescu was published in August 1921 in the Archives Internationales de Physiologie, Liège, Belgium. Initially, the only way to obtain insulin for clinical use was to extract it from the pancreas of another creature. Animal glands were obtainable as a waste product of the meatpacking industry. Insulin was derived primarily from cows (Eli Lilly and Company) and pigs (Nordisk Insulinlaboratorium). The making of eight ounces of purified insulin could require as much as two tons of pig parts.[32][33][34] Insulin from these sources is effective in humans as it is highly similar to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine).[34] Initially, lower preparation purity resulted in allergic reactions to the presence of non-insulin substances. Purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods. Minor allergic reactions still occur occasionally, even to synthetic "human" insulin varieties.[34]

Beginning in 1982, biosynthetic "human" insulin has been manufactured for clinical use through genetic engineering techniques using recombinant DNA technology. Genentech developed the technique used to produce the first such insulin, Humulin, but did not commercially market the product themselves. Eli Lilly marketed Humulin in 1982.[35] Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce a synthetic version of human insulin. Manufacturers claim this reduces the presence of many impurities. However, the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects; an example is the absence of C-peptide which has in recent years been shown to have systemic effects itself. Novo Nordisk has also developed a genetically engineered insulin independently using a yeast process.[36][37]

According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries, approximately 70% of the insulin that is currently sold in the world is recombinant, biosynthetic 'human' insulin.[38] A majority of insulin used clinically today is produced this way, although clinical experience has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Adverse reactions have been reported; these include loss of warning signs that patients may slip into a coma through hypoglycemia, convulsions, memory lapse and loss of concentration.[39] However, the International Diabetes Federation's position statement from 2005 is very clear in stating that "there is NO overwhelming evidence to prefer one species of insulin over another" and "[modern, highly purified] animal insulins remain a perfectly acceptable alternative."[40]

Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic "human" insulins or their analogues. A special FDA importation process is required to obtain bovine or porcine derived insulin for use in the U.S., although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier, and porcine lente insulin is also sold and marketed under the brand name Vetsulin(SM) in the U.S. for veterinary usage in the treatment of companion animals with diabetes.[41]

Basal insulin

In type 1 diabetes, insulin production is extremely low, and as such the body requires exogenous insulin. Some people with type 2 diabetes, particularly those with very high hemoglobin A1c values, may also require a baseline rate of insulin, as their body is desensitized to the level of insulin being produced. Basal insulin regulates the body's blood glucose between mealtimes, as well as overnight. This basal rate of insulin action is generally achieved via the use of an intermediate-acting insulin (such as NPH) or a long-acting insulin analog. In type 1 diabetics, it may also be achieved via continuous infusion of rapid-acting insulin using an insulin pump. Approximately half of a person's daily insulin requirement is administered as a basal insulin, usually administered once per day at night.[42]

Prandial insulin

When a person eats food containing carbohydrates and glucose, insulin helps regulate the body's metabolism of the food. Prandial insulin, also called mealtime or bolus insulin, is designed as a bolus dose of insulin prior to a meal to regulate the spike in blood glucose that occurs following a meal. The dose of prandial insulin may be static, or may be calculated by the patient using either their current blood sugar, planned carbohydrate intake, or both. This calculation may also be performed by an insulin pump in patients using a pump. Insulin regiments that consist of doses calculated in this manner are considered intensive insulin regimens.[43] Prandial insulin is usually administered no more than 15–30 minutes prior to a meal using a rapid-acting insulin or a regular insulin. In some patients, a combination insulin may be used that contains both NPH (long acting) insulin and a rapid/regular insulin to provide both a basal insulin and prandial insulin.[42]

Challenges in treatment

There are several challenges involved in the use of insulin as a clinical treatment for diabetes:[44]

  • Mode of administration.
  • Selecting the 'right' dose and timing. The amount of carbohydrates one unit of insulin handles varies widely between persons and over the day but values between 7 and 20 grams per 1 IE is typical.
  • Selecting an appropriate insulin preparation (typically on 'speed of onset and duration of action' grounds).
  • Adjusting dosage and timing to fit food intake timing, amounts, and types.
  • Adjusting dosage and timing to fit exercise undertaken.
  • Adjusting dosage, type, and timing to fit other conditions, for instance the increased stress of illness.
  • Variability in absorption into the bloodstream via subcutaneous delivery
  • The dosage is non-physiological in that a subcutaneous bolus dose of insulin alone is administered instead of combination of insulin and C-peptide being released gradually and directly into the portal vein.
  • It is simply a nuisance for people to inject whenever they eat carbohydrate or have a high blood glucose reading.
  • It is dangerous in case of mistake (such as 'too much' insulin).

Types

Medical preparations of insulin are never just insulin in water (with nothing else). Clinical insulins are mixtures of insulin plus other substances including preservatives. These prevent the protein from spoiling or denaturing too rapidly, delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on.[45]

Slight variations of the human insulin molecule are called insulin analogues, (technically "insulin receptor ligands") so named because they are not technically insulin, rather they are analogues which retain the hormone's glucose management functionality. They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper. They are either absorbed rapidly in an attempt to mimic real beta cell insulin (as with insulin lispro, insulin aspart, and insulin glulisine), or steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (as with insulin detemir and insulin glargine), all while retaining insulin's glucose-lowering action in the human body. However, a number of meta-analyses, including those done by the Cochrane Collaboration in 2005,[46] Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] released in 2007,[47] and the Canadian Agency for Drugs and Technology in Health (CADTH)[48] also released in 2007 have shown no unequivocal advantages in clinical use of insulin analogues over more conventional insulin types.[47][48]

Choosing insulin type and dosage/timing should be done by an experienced medical professional working closely with people who are diabetic .[citation needed]

The commonly used types of insulin are as follows.[27]

Fast-acting (Rapid-acting)

See also: Insulin analog

Includes the insulin analogues aspart, lispro, and glulisine. These begin to work within 5 to 15 minutes and are active for 3 to 4 hours. Most insulins form hexamers, which delay entry into the blood in active form; these analog insulins do not but have normal insulin activity. Newer varieties are now pending regulatory approval in the U.S. which are designed to work rapidly, but retain the same genetic structure as regular human insulin.[49][50]

Short-acting

Includes regular insulin, which begins working within 30 minutes and is active about 5 to 8 hours.[51]

Intermediate-acting

Includes NPH insulin, which begins working in 1 to 3 hours and is active for 16 to 24 hours.[52]

Long-acting

Includes the analogues glargine U100 and detemir, each of which begins working within 1 to 2 hours and continues to be active, without major peaks or dips, for about 24 hours, although this varies in many individuals.[53][54]

Ultra-long acting

Includes the analogues insulin glargine U300 and degludec, which begin working within 30 to 90 minutes and continues to be active for greater than 24 hours.[26]

Combination insulin products

Includes a combination of either fast-acting or short-acting insulin with a longer acting insulin, typically an NPH insulin. The combination products begin to work with the shorter acting insulin (5–15 minutes for fast-acting, and 30 minutes for short acting), and remain active for 16 to 24 hours. There are several variations with different proportions of the mixed insulins (e.g. Novolog Mix 70/30 contains 70% aspart protamine [akin to NPH], and 30% aspart.)[55]

Methods of administration

 
Insulin delivery devices

Unlike many medicines, insulin cannot be taken orally at the present time. Like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments (single amino acid components), whereupon all activity is lost. There has been some research into ways to protect insulin from the digestive tract, so that it can be administered in a pill. So far this is entirely experimental.[56]

Subcutaneous

Insulin is usually taken as subcutaneous injections by single-use syringes with needles, an insulin pump, or by repeated-use insulin pens with needles. People who wish to reduce repeated skin puncture of insulin injections often use an injection port in conjunction with syringes.[57]

The use of subcutaneous injections of insulin is designed to mimic the natural physiological cycle of insulin secretion, while taking into account the various properties of the formulations used such as half-life, onset of action, and duration of action. In many people, both a rapid- or short-acting insulin product as well as an intermediate- or long-acting product are used to decrease the amount of injections per day. In some, insulin injections may be combined with other injection therapy such as GLP-1 agonists. Cleansing of the injection site and injection technique are required to ensure effective insulin therapy.[42]

Insulin pump

Main article: Insulin pump

Insulin pumps are a reasonable solution for some. Advantages to the person are better control over background or basal insulin dosage, bolus doses calculated to fractions of a unit, and calculators in the pump that may help with determining bolus infusion dosages. The limitations are cost, the potential for hypoglycemic and hyperglycemic episodes, catheter problems, and no "closed loop" means of controlling insulin delivery based on current blood glucose levels.[citation needed]

Insulin pumps may be like 'electrical injectors' attached to a temporarily implanted catheter or cannula. Some who cannot achieve adequate glucose control by conventional (or jet) injection are able to do so with the appropriate pump.[58]

Indwelling catheters pose the risk of infection and ulceration, and some peoples may also develop lipodystrophy due to the infusion sets. These risks can often be minimized by keeping infusion sites clean. Insulin pumps require care and effort to use correctly.[58]

Dosage and timing

See also: Intensive insulinotherapy and Conventional insulinotherapy

Dosage units

One international unit of insulin (1 IU) is defined as the "biological equivalent" of 34.7 μg pure crystalline insulin.

The first definition of a unit of insulin was the amount required to induce hypoglycemia in a rabbit. This was set by James Collip at the University of Toronto in 1922. Of course, this was dependent on the size and diet of the rabbits. The unit of insulin was set by the insulin committee at the University of Toronto.[59] The unit evolved eventually to the old USP insulin unit, where one unit (U) of insulin was set equal to the amount of insulin required to reduce the concentration of blood glucose in a fasting rabbit to 45 m g/d l (2.5 m mol/L). Once the chemical structure and mass of insulin was known, the unit of insulin was defined by the mass of pure crystalline insulin required to obtain the USP unit.

The unit of measurement used in insulin therapy is not part of the International System of Units (abbreviated SI) which is the modern form of the metric system. Instead the pharmacological international unit (IU) is defined by the WHO Expert Committee on Biological Standardization.[60]

Potential complications

 
Diagram explaining the basal-bolus insulin schedule. The long acting insulin is given once (usually glargine, Lantus) or twice (usually detemir, Levemir) daily to provide a base, or basal insulin level. Rapid acting (RA) insulin is given before meals and snacks. A similar profile can be provided using an insulin pump where rapid acting insulin is given as the basal and premeal bolus insulin.

The central problem for those requiring external insulin is picking the right dose of insulin and the right timing.

Physiological regulation of blood glucose, as in the non-diabetic, would be best. Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas. The increased insulin level causes glucose absorption and storage in cells, reduces glycogen to glucose conversion, reducing blood glucose levels, and so reducing insulin release. The result is that the blood glucose level rises somewhat after eating, and within an hour or so, returns to the normal 'fasting' level. Even the best diabetic treatment with synthetic human insulin or even insulin analogs, however administered, falls far short of normal glucose control in the non-diabetic.[61]

Complicating matters is that the composition of the food eaten (see glycemic index) affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. In addition, fats and proteins cause delays in absorption of glucose from carbohydrates eaten at the same time. As well, exercise reduces the need for insulin even when all other factors remain the same, since working muscle has some ability to take up glucose without the help of insulin.[62]

Because of the complex and interacting factors, it is, in principle, impossible to know for certain how much insulin (and which type) is needed to 'cover' a particular meal to achieve a reasonable blood glucose level within an hour or two after eating. Non-diabetics' beta cells routinely and automatically manage this by continual glucose level monitoring and insulin release. All such decisions by a diabetic must be based on experience and training (i.e., at the direction of a physician, PA, or in some places a specialist diabetic educator) and, further, specifically based on the individual experience of the person. But it is not straightforward and should never be done by habit or routine. With some care however, it can be done reasonably well in clinical practice. For example, some people with diabetes require more insulin after drinking skim milk than they do after taking an equivalent amount of fat, protein, carbohydrate, and fluid in some other form. Their particular reaction to skimmed milk is different from other people with diabetes, but the same amount of whole milk is likely to cause a still different reaction even in that person. Whole milk contains considerable fat while skimmed milk has much less. It is a continual balancing act for all people with diabetes, especially for those taking insulin.

People with insulin-dependent diabetes typically require some base level of insulin (basal insulin), as well as short-acting insulin to cover meals (bolus also known as mealtime or prandial insulin). Maintaining the basal rate and the bolus rate is a continuous balancing act that people with insulin-dependent diabetes must manage each day. This is normally achieved through regular blood tests, although continuous blood sugar testing equipment (Continuous Glucose Monitors or CGMs) are now becoming available which could help to refine this balancing act once widespread usage becomes common.

Strategies

A long-acting insulin is used to approximate the basal secretion of insulin by the pancreas, which varies in the course of the day.[63] NPH/isophane, lente, ultralente, glargine, and detemir may be used for this purpose. The advantage of NPH is its low cost, the fact that you can mix it with short-acting forms of insulin, thereby minimizing the number of injections that must be administered, and that the activity of NPH will peak 4–6 hours after administration, allowing a bedtime dose to balance the tendency of glucose to rise with the dawn, along with a smaller morning dose to balance the lower afternoon basal need and possibly an afternoon dose to cover evening need. A disadvantage of bedtime NPH is that if not taken late enough (near midnight) to place its peak shortly before dawn, it has the potential of causing hypoglycemia. One theoretical advantage of glargine and detemir is that they only need to be administered once a day, although in practice many people find that neither lasts a full 24 hours. They can be administered at any time during the day as well, provided that they are given at the same time every day. Another advantage of long-acting insulins is that the basal component of an insulin regimen (providing a minimum level of insulin throughout the day) can be decoupled from the prandial or bolus component (providing mealtime coverage via ultra-short-acting insulins), while regimens using NPH and regular insulin have the disadvantage that any dose adjustment affects both basal and prandial coverage. Glargine and detemir are significantly more expensive than NPH, lente and ultralente, and they cannot be mixed with other forms of insulin.[citation needed]

A short-acting insulin is used to simulate the endogenous insulin surge produced in anticipation of eating. Regular insulin, lispro, aspart and glulisine can be used for this purpose. Regular insulin should be given with about a 30-minute lead-time prior to the meal to be maximally effective and to minimize the possibility of hypoglycemia. Lispro, aspart and glulisine are approved for dosage with the first bite of the meal, and may even be effective if given after completing the meal. The short-acting insulin is also used to correct hyperglycemia.[64]

The usual schedule for checking fingerstick blood glucose and administering insulin is before all meals and sometimes also at bedtime. More recent guidelines also call for a check 2 hours after a meal to ensure the meal has been 'covered' effectively.[citation needed]

Sliding scales

First described in 1934,[65] what physicians typically refer to as sliding-scale insulin (SSI) is fast- or rapid-acting insulin only, given subcutaneously, typically at meal times and sometimes bedtime,[66] but only when blood glucose is above a threshold (e.g. 10 mmol/L, 180 mg/dL).[67] The so-called "sliding-scale" method is widely taught, although it has been heavily criticized.[68][69][70][71] Sliding scale insulin (SSI) is not an effective way of managing long-term diabetes in individuals residing in nursing homes.[66][72] Sliding scale insulin leads to greater discomfort and increased nursing time.[72]

Sample regimen using insulin NPH and regular insulin
before breakfast before lunch before dinner at bedtime
NPH dose 12 units 6 units
regular insulin dose if fingerstick
glucose is (mg/dL) [mmol/L]:
70–100       [3.9–5.5] 4 units 4 units
101–150     [5.6–8.3] 5 units 5 units
151–200     [8.4–11.1] 6 units 6 units
201–250     [11.2–13.9] 7 units 7 units
251–300     [14.0–16.7] 8 units 1 unit 8 units 1 unit
>300         [>16.7] 9 units 2 units 9 units 2 units

Sample regimen using insulin glargine and insulin lispro:

  • Insulin glargine: 20 units at bedtime
Insulin lispro to be given as follows:
if fingerstick glucose
is (mg/dL) [mmol/L]: 		before breakfast before lunch before dinner at bedtime
70–100       [3.9–5.5] 5 units 5 units 5 units
101–150     [5.6–8.3] 6 units 6 units 6 units
151–200     [8.4–11.1] 7 units 7 units 7 units
201–250     [11.2–13.9] 8 units 8 units 8 units 1 unit
251–300     [14.0–16.7] 9 units 9 units 9 units 2 units
>300         [>16.7] 10 units 10 units 10 units 3 units

Carb counting and DAFNE

A more complicated method that allows greater freedom with meal times and snacks is "carb counting." This approach is taught to people who are diabetic in the UK and elsewhere as "Dose Adjustment For Normal Eating" or .

In Europe, people who are not familiar with the DAFNE regime can take an where the basic starting insulin dose guideline is "for every 10 g of carbohydrates you eat, take 1 unit of insulin". DAFNE courses also cover topics that naturally work alongside this regime, such as blood glucose monitoring, exercise and carbohydrate estimation to help the person work out their personal control requirements.

People can also use their total daily dose (TDD) of insulin to estimate how many grams of carbohydrates will be "covered" by 1 unit of insulin, and using this result, estimate how many units of insulin should be administered depending on the carbohydrate content of their meal. For example, if the person determines that 1 unit of insulin will cover 15 grams of carbohydrates, then they must administer 5 units of insulin before consuming a meal that contains 75 grams of carbohydrates.

Some alternative methods also consider the protein content of the meal (since excess dietary protein can be converted to glucose via gluconeogenesis).

With DAFNE, most dosages involve a fair degree of guesswork, especially with non-labeled foods, and will only work fairly consistently from one dosage to the next if the person is aware of their body's requirements. For example, a person finds they can take 1 unit of insulin to 10 g of carbohydrates in the morning and the evening, but find that their body requires more insulin for a meal in the middle of the day so they have to adjust to 1 unit per 8.5g of carbohydrates.

Other less obvious factors that affect the body's use of insulin must also be taken into account. For example, some people may find that their bodies process insulin better on hot days so require less insulin. With this, the person again has to adjust their dose to the best of their understanding from their past experiences.

The DAFNE regime requires the person to learn about their body's needs through experience, which takes time and patience, but it can then become effective.

Closed-loop predictive modeling

People with fluctuating insulin requirements may benefit from a closed-loop predictive modeling approach. As an extension on "carb counting", in this closed-loop predictive modeling approach, the four daily insulin dosages needed to reach the target blood sugar levels for the "normal" daily carbohydrate consumption and amount of physical activity, are continuously adjusted based on the pre-meal and pre-night blood sugar level readings. Each new blood sugar reading provides the feedback to fine-tune and track the body's insulin requirements. Within this strategy, the key specific factors, which have to be determined experimentally, are the blood sugar correction factor and the carbohydrate ratio. The blood sugar correction factor sets both the "proportional gain" and "integral gain" factors for the four feedback loops. When taken too low, deviations from the target blood sugar level are not corrected for effectively, when taken too high, the blood sugar regulation will become unstable. Since in this approach, the carbohydrate ratio is only used to account for non-standard carbohydrate intakes, it is usually not required to work with meal specific ratios.

Dose calculation

Insulin dosage is given by the formula

 

based on the person's blood glucose and carbohydrate intake and these constants:

  • TR = target rate
  • CF = corrective factor
  • KF = carbohydrate factor

Blood glucose and target rate are expressed in mg/dL or mmol/L. Constants should be set by a physician or clinical pharmacist.

Insulin Medication in Pregnancy

Diabetes in pregnancy is associated with numerous risks to the woman and the developing fetus. See Diabetes and pregnancy . The best course of action for treating and managing pre existing diabetes or gestational diabetes is still under research as the insulin needs during pregnancy are prone to quick variation.

During pregnancy, spontaneous hyperglycemia can develop and lead to gestational diabetes mellitus (GDM), a frequent pregnancy complication . With a prevalence of 6-20% among pregnant women globally, gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance developing or initially recognized during pregnancy.[73] Neutral protamine Hagedorn (NPH) insulin has been the cornerstone of insulin therapy during pregnancy, administered two to four times per day. Women with GDM and pregnant women with type I diabetes mellitus who frequently check their blood glucose levels and utilize glucose monitoring equipment for doing so, use continuous insulin infusion of a rapid-acting insulin analogue, such as lispro and aspart. However, a number of considerations go into choosing a regimen for administering insulin to patients. When managing GDM in pregnant women, these guidelines are crucial and can vary depending on certain physiological and interestingly the sociocultural environment as well. The current perinatal guidelines recommend a low daily dose of insulin and take into account the woman's physiological features and the frequency of self-monitoring. The importance of using specialized insulin therapy planning based on parameters like those stated above rather than a broad approach is emphasized.[74]

Women with pre-existing diabetes have the highest levels of insulin sensitivity early in pregnancy. Close glucose monitoring is required to prevent hypoglycemia, which can potentially result in altered consciousness, seizures, and maternal damage.[75] Low birth weight newborns might also be the result of hypoglycemia, especially in patients with type 1 diabetes, because they are frequently more insulin sensitive than persons with type 2 diabetes and more likely to be unaware of their hypoglycemic state. Close glucose monitoring is essential because after 16 weeks of pregnancy, women with preexisting diabetes become more insulin resistant and their insulin demands may fluctuate weekly. The need for insulin may rise from one pregnancy to the next.  Therefore, it is realistic to expect higher needs for glucose control with subsequent pregnancies in multiparous women.[75]

Abuse

The abuse of exogenous insulin carries with it an attendant risk of hypoglycemic coma and death when the amount used is in excess of that required to handle ingested carbohydrate. Acute risks include brain damage, paralysis, and death. Symptoms may include dizziness, weakness, trembling, palpitations, seizures, confusion, headache, drowsiness, coma, diaphoresis and nausea. All persons with overdoses should be referred for medical assessment and treatment, which may last for hours or days.[76]

Data from the US National Poison Data System (2013) indicates that 89.3% of insulin cases reported to poison centers are unintentional, as a result of therapeutic error. Another 10% of cases are intentional, and may reflect attempted suicide, abuse, criminal intent, secondary gain or other unknown reasons.[76] Hypoglycemia that has been induced by exogenous insulin can be chemically detected by examining the ratio of insulin to C-peptide in peripheral circulation.[77] It has been suggested that this type of approach could be used to detect exogenous insulin abuse by athletes.[78]

The possibility of using insulin in an attempt to improve athletic performance was suggested as early as the 1998 Winter Olympics in Nagano, Japan, as reported by Peter Sönksen in the July 2001 issue of Journal of Endocrinology. The question of whether non-diabetic athletes could legally use insulin was raised by a Russian medical officer.[79][80] Whether insulin would actually improve athletic performance is unclear, but concerns about its use led the International Olympic Committee to ban use of the hormone by non-diabetic athletes in 1998.[81]

The book Game of Shadows (2001), by reporters Mark Fainaru-Wada and Lance Williams, included allegations that baseball player Barry Bonds used insulin (as well as other drugs) in the apparent belief that it would increase the effectiveness of the growth hormone he was alleged to be taking.[82] Bonds eventually testified in front of a federal grand jury as part of a government investigation of BALCO.[83]

Bodybuilders in particular are claimed to be using exogenous insulin and other drugs in the belief that they will increase muscle mass. Bodybuilders have been described as injecting up to 10 IU of regular synthetic insulin before eating sugary meals.[81] A 2008 report suggested that insulin is sometimes used in combination with anabolic steroids and growth hormone (GH), and that "Athletes are exposing themselves to potential harm by self‐administering large doses of GH, IGF‐I and insulin".[84][85] Insulin abuse has been mentioned as a possible factor in the deaths of bodybuilders Ghent Wakefield and Rich Piana.[86]

Insulin, human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1) are self-administered by those looking to increase muscle mass beyond the scope offered by anabolic steroids alone. Their rationale is that since insulin and HGH act synergistically to promote growth, and since IGF-1 is a primary mediator of musculoskeletal growth, the 'stacking' of insulin, HGH and IGF-1 should offer a synergistic growth effect on skeletal muscle. This theory has been supported in recent years by top-level bodybuilders whose competition weight is in excess of 50 lb (23 kg) of muscle, larger than that of competitors in the past, and with even lower levels of body fat.[citation needed]

Insulin effects on strength, and exercise performance

Exogenous insulin significantly boosts the rate of glucose metabolism in training athletes along with a substantial increases in the peak V-02.[87] Insulin is thought to enhance performance by increasing protein synthesis, reducing protein catabolism, and facilitating the transfer of certain amino acids in human skeletal muscle. Insulin-treated athletes are perceived to have lean body mass because physiological hyperinsulinemia in human skeletal muscle improves the activity of amino acid transport, which in turn promotes protein synthesis.[87] Insulin stimulates the transport of amino acids into cells and also controls glucose metabolism. It decreases lipolysis and increases lipogenesis which is why bodybuilders and athletes use rhGH in conjunction with it as to offset this negative effect while maximizing protein synthesis. The athletes extrapolated the physiology of the diabetic patient in the sporting arena because they are interested in the suppression of proteolysis. Insulin  administration is found to be protein anabolic in the insulin-resistant state of chronic renal failure.[88] It inhibits proteolysis and when administered along with amino acids, it enhances net protein synthesis. Exogenous insulin injection creates an in-vivo hyperinsulinemic clamp, boosting muscle glycogen before and during the recovery phases of intense exercise. Power, strength, and stamina are all expected to increase as a result, and it might also speed up the healing process after intense physical activity. Second, insulin is expected to increase muscle mass by preventing the breakdown of muscle protein when consumed along with high carb-protein diet. Although a limited number of studies do suggest that insulin medication can be abused as a pharmacological treatment to boost strength and performance in young, healthy people or athletes , a recent assessment of the research argues that this is only applicable to a small group of "drug-naïve" individuals.[87]

Detection in biological fluids

Insulin is often measured in serum, plasma or blood in order to monitor therapy in people who are diabetic, confirm a diagnosis of poisoning in hospitalized persons or assist in a medicolegal investigation of suspicious death. Interpretation of the resulting insulin concentrations is complex, given the numerous types of insulin available, various routes of administration, the presence of anti-insulin antibodies in insulin-dependent diabetics and the ex vivo instability of the drug. Other potential confounding factors include the wide-ranging cross-reactivity of commercial insulin immunoassays for the biosynthetic insulin analogs, the use of high-dose intravenous insulin as an antidote to antihypertensive drug over dosage and postmortem redistribution of insulin within the body. The use of a chromatographic technique for insulin assay may be preferable to immunoassay in some circumstances, to avoid the issue of cross-reactivity affecting the quantitative result and also to assist identifying the specific type of insulin in the specimen.[89]

Combination with other antidiabetic drugs

A combination therapy of insulin and other antidiabetic drugs appears to be most beneficial in people who are diabetic, who still have residual insulin secretory capacity.[90] A combination of insulin therapy and sulfonylurea is more effective than insulin alone in treating people with type 2 diabetes after secondary failure to oral drugs, leading to better glucose profiles and/or decreased insulin needs.[90]

Society and culture

Economics

In the United States the unit price of insulin has increased steadily from 1991 to 2019.[91][92] It rose threefold from 2002 to 2013.[93] Costs can be as high as US$900 per month.[93] Concerns were raised in 2016 of pharmaceutical companies working together to increase prices.[93] In January 2019, lawmakers from the United States House of Representatives sent letters to insulin manufacturers Eli Lilly and Co., Sanofi and Novo Nordisk asking for explanations for their rapidly raising insulin prices. The annual cost of insulin for people with type 1 diabetes in the U.S. almost doubled from $2,900 to $5,700 over the period from 2012 to 2016.[94]

People in the U.S. pay two to six times more than the rest of the world, including Canada, for brand name prescription medicine, according to the International Federation of Health Plans. Canada, like many other industrialized countries, has price controls on the cost of pharmaceuticals.[95]

California, in July 2022, approved a budget that allocates $100 million for the state to create its own insulin at a close-to-cost price.[96]

Insulin, and all other medications, are supplied free of charge to people with diabetes by the National Health Service in the countries of the United Kingdom.[97]

Regulatory status

In March 2020, the FDA changed the regulatory pathway for approval of new insulin products.[98] Insulin is regulated as a biologic rather than as a drug.[98] The changed status gives the FDA more flexibility for approval and labeling.[99] In July 2021, the FDA approved insulin glargine-yfgn (Semglee), a biosimilar product that contains the long acting analog insulin glargine.[100] Insulin glargine-yfgn is interchangeable and less expensive than the reference product, insulin glargine (Lantus), which had been approved in 2000.[101][102] The FDA requires that new insulin products are not inferior to existing insulin products with respect to reduction in hemoglobin A1c. See Misbin, RI (February 2022). Insulin – History from an FDA Insider. Politics and Prose Publishing, Washington DC. Text ISBN 978-I-62429-391-77

Research

See also: Artificial pancreas

Inhalation

Main article: Inhalable insulin

In 2006 the U.S. Food and Drug Administration (FDA) approved the use of Exubera, the first inhalable insulin.[103] It was withdrawn from the market by its maker as of third quarter 2007, due to lack of acceptance.

Inhaled insulin claimed to have similar efficacy to injected insulin, both in terms of controlling glucose levels and blood half-life. Currently, inhaled insulin is short acting and is typically taken before meals; an injection of long-acting insulin at night is often still required.[104] When people were switched from injected to inhaled insulin, no significant difference was observed in HbA1c levels over three months. Accurate dosing was a particular problem, although people showed no significant weight gain or pulmonary function decline over the length of the trial, when compared to the baseline.[105]

Following its commercial launch in 2005 in the United Kingdom, it was not (as of July 2006) recommended by National Institute for Health and Clinical Excellence for routine use, except in cases where there is "proven injection phobia diagnosed by a psychiatrist or psychologist".[104]

In January 2008, the world's largest insulin manufacturer, Novo Nordisk, also announced that the company was discontinuing all further development of the company's own version of inhalable insulin, known as the AERx iDMS inhaled insulin system.[106] Similarly, Eli Lilly and Company ended its efforts to develop its inhaled Air Insulin in March 2008.[107] Afrezza, developed by Mannkind, was authorized by the FDA in June 2014 for use in adults with Type I and Type II diabetes, with a label restriction limiting its use only to those who also have asthma, active lung cancer, or chronic obstructive pulmonary disease.[108] Rapid-acting inhaled insulin is a component of the drug-device combination solution that is used at the start of every meal. It employs technosphere technology, which appears to have a more practical delivery method and more dosing flexibility, and a new inhaled insulin formulation (2.5 m). A thumb-sized inhaler with improved dosage flexibility is used to deliver inhalable insulin. It includes powder-dissolved recombinant human insulin (fumaryl diketopiperazine). Technosphere insulin is quickly absorbed by the lung surface after inhalation. Within 12 hours of inhalation, both substances—insulin, and powder (fumaryl diketopiperazine)—are virtually eliminated from healthy people's lungs. In comparison to Exubera (8–9%), just 0.3% of inhaled insulin was still present in the lungs after 12 hours. However since serum antibody levels have been reported to increase without substantial clinical changes, acute bronchospasm in asthmatic and COPD patients along with a significant reduction in Diffusing Lung Capacity for Carbon Monoxide, in comparison to subcutaneous insulin, have been reported with its usage, Afrezza was given FDA approval with a warning (Risk Evaluation and Mitigation Strategy).[109][108]

Transdermal

There are several methods for transdermal delivery of insulin. Pulsatile insulin uses microjets to pulse insulin into the person, mimicking the physiological secretions of insulin by the pancreas.[110] Jet injection had different insulin delivery peaks and durations as compared to needle injection. Some diabetics may prefer jet injectors to hypodermic injection.[111] Both electricity using iontophoresis[112] and ultrasound have been found to make the skin temporarily porous. The insulin administration aspect remains experimental, but the blood glucose test aspect of "wrist appliances" is commercially available Researchers have produced a watch-like device that tests for blood glucose levels through the skin and administers corrective doses of insulin through pores in the skin. A similar device, but relying on skin-penetrating "microneedles", was in the animal testing stage in 2015.[113] In the last couple of years, the use of chemical enhancers, electrical devices, and microneedle devices has shown tremendous promise for improving the penetration of insulin compared to passive transport via the skin . Transdermal insulin delivery shows a more patient-friendly and minimally invasive approach to daily diabetes care than the conventional hypodermic injection however, it must be noted that additional research is necessary to address issues such as long-term use, delivery efficiency, and reliability, as well as side effects involving inflammation and irritation.[114]

Intranasal

Insulin can be delivered to the central nervous system via the intranasal (IN) route with little to no systemic uptake or associated peripheral side effects. It has been demonstrated that intranasally delivered insulin rapidly accumulates in CSF fluid, indicating effective transport to the brain. This accumulation is thought to occur along olfactory and nearby routes. Although numerous studies have published encouraging results, further study is still being conducted to comprehend its long-term impacts in order to begin the successful clinical application.[115]

By mouth

The basic appeal of hypoglycemic agents by mouth is that most people would prefer a pill or an oral liquid to an injection. However, insulin is a peptide hormone, which is digested in the stomach and gut and in order to be effective at controlling blood sugar, cannot be taken orally in its current form.

The potential market for an oral form of insulin is assumed to be enormous, thus many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar.[116]

A number of derivatization and formulation strategies are currently being pursued to in an attempt to develop an orally available insulin.[117] Many of these approaches employ nanoparticle delivery systems[118][119][120] and several are being tested in clinical trials.[121][122][123]

Pancreatic transplantation

Main article: Islet cell transplantation

Another improvement would be a transplantation of the pancreas or beta cell to avoid periodic insulin administration. This would result in a self-regulating insulin source. Transplantation of an entire pancreas (as an individual organ) is difficult and relatively uncommon. It is often performed in conjunction with liver or kidney transplant, although it can be done by itself. It is also possible to do a transplantation of only the pancreatic beta cells. However, islet transplants had been highly experimental for many years, but some researchers in Alberta, Canada, have developed techniques with a high initial success rate (about 90% in one group). Nearly half of those who got an islet cell transplant were insulin-free one year after the operation; by the end of the second year that number drops to about one in seven. However, researchers at the University of Illinois at Chicago (UIC) have slightly modified the Edmonton Protocol procedure for islet cell transplantation and achieved insulin independence in diabetic people, with fewer but better-functioning pancreatic islet cells.[124] Longer-term studies are needed to validate whether it improves the rate of insulin-independence.

Beta cell transplant may become practical in the near future. Additionally, some researchers have explored the possibility of transplanting genetically engineered non-beta cells to secrete insulin.[125] Clinically testable results are far from realization at this time. Several other non-transplant methods of automatic insulin delivery are being developed in research labs, but none is close to clinical approval.

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External links

  • "Insulin". Drug Information Portal. U.S. National Library of Medicine.
  • "Insulin regular". Drug Information Portal. U.S. National Library of Medicine.
  • "Insulin [Injection], biphasic". Drug Information Portal. U.S. National Library of Medicine.

January 25, 2023
insulin, medication, insulin, therapy, synthetic, insulin, redirect, here, psychiatric, treatment, insulin, shock, therapy, naturally, occurring, protein, insulin, medication, insulin, pharmaceutical, preparation, protein, hormone, insulin, that, used, treat, . Insulin therapy and Synthetic insulin redirect here For the psychiatric treatment see Insulin shock therapy For the naturally occurring protein see Insulin As a medication insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose 4 Such conditions include type 1 diabetes type 2 diabetes gestational diabetes and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states 4 Insulin is also used along with glucose to treat hyperkalemia high blood potassium levels 5 Typically it is given by injection under the skin but some forms may also be used by injection into a vein or muscle 4 There are various types of insulin suitable for various time spans The types are often all called insulin in the broad sense although in a more precise sense insulin is identical to the naturally occurring molecule whereas insulin analogues have slightly different molecules that allow for modified time of action It is on the World Health Organization s List of Essential Medicines 6 7 In 2020 regular human insulin was the 307th most commonly prescribed medication in the United States with more than 1 million prescriptions 8 9 InsulinVials of insulinClinical dataTrade namesHumulin Novolin Insuman othersAHFS Drugs comMonographMedlinePlusa682611License dataUS DailyMed HumulinRoutes ofadministrationSubcutaneous intravenous intramuscular inhalationATC codeA10AD01 WHO Legal statusLegal statusCA only UK POM Prescription only 1 US only OTC EU Rx onlyIdentifiersCAS Number9004 10 8PubChem CID70678557DrugBankDB00030ChemSpider34999906UNII438UC14NDQKEGGD04477Chemical and physical dataFormulaC 257H 383N 65O 77S 6Molar mass5807 63 g mol 1Density1 09 g cm3 2 Melting point233 C 451 F 3 Insulin can be made from the pancreas of pigs or cows 10 Human versions can be made either by modifying pig versions or recombinant technology 10 It comes in three main types short acting such as regular insulin intermediate acting such as neutral protamine Hagedorn NPH insulin and longer acting such as insulin glargine 10 Contents 1 History 2 Medical uses 3 Side effects 3 1 Effects of early routine use 4 Principles 4 1 Basal insulin 4 2 Prandial insulin 5 Challenges in treatment 6 Types 6 1 Fast acting Rapid acting 6 2 Short acting 6 3 Intermediate acting 6 4 Long acting 6 5 Ultra long acting 6 6 Combination insulin products 7 Methods of administration 7 1 Subcutaneous 7 2 Insulin pump 8 Dosage and timing 8 1 Dosage units 8 2 Potential complications 8 3 Strategies 8 3 1 Sliding scales 8 3 2 Carb counting and DAFNE 8 3 3 Closed loop predictive modeling 9 Dose calculation 10 Insulin Medication in Pregnancy 11 Abuse 11 1 Insulin effects on strength and exercise performance 12 Detection in biological fluids 13 Combination with other antidiabetic drugs 14 Society and culture 14 1 Economics 14 2 Regulatory status 15 Research 15 1 Inhalation 15 2 Transdermal 15 3 Intranasal 15 4 By mouth 15 5 Pancreatic transplantation 16 References 17 External linksHistory EditInsulin was first used as a medication in Canada by Charles Best and Frederick Banting in 1922 11 12 This is a chronology of key milestones in the history of the medical use of insulin For more details on the discovery extraction purification clinical use and synthesis of insulin see Insulin 1921 Research on the role of pancreas in the nutritive assimilation 13 1922 Frederick Banting Charles Best and James Collip use bovine insulin extract in humans at Connaught Laboratories in Toronto Canada 11 1922 Leonard Thompson becomes the first human to be treated with insulin 1922 James D Havens son of former congressman James S Havens becomes the first American to be treated with insulin 14 15 1922 Elizabeth Hughes Gossett daughter of the U S Secretary of State becomes the first American to be officially treated in Toronto 16 17 1923 Eli Lilly produces commercial quantities of much purer bovine insulin than Banting et al had used 1923 Farbwerke Hoechst one of the forerunners of today s Sanofi Aventis produces commercial quantities of bovine insulin in Germany 1923 Hans Christian Hagedorn founds the Nordisk Insulinlaboratorium in Denmark forerunner of today s Novo Nordisk 1923 Constance Collier returns to health after being successfully treated with insulin in Strasbourg 18 1926 Nordisk receives a Danish charter to produce insulin as a non profit 1936 Canadians David M Scott and Albert M Fisher formulate a zinc insulin mixture at Connaught Laboratories in Toronto and license it to Novo 1936 Hagedorn discovers that adding protamine to insulin prolongs the duration of action of insulin 1946 Nordisk formulates Isophane porcine insulin aka Neutral Protamine Hagedorn or NPH insulin 1946 Nordisk crystallizes a protamine and insulin mixture 1950 Nordisk markets NPH insulin 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer lasting insulin 1955 Frederick Sanger determines the amino acid sequence of insulin 1965 Synthesized by total synthesis by Wang Yinglai Chen Lu Tsou et al 1969 Dorothy Crowfoot Hodgkin solves the crystal structure of insulin by X ray crystallography 1973 Purified monocomponent MC insulin is introduced 1973 The U S officially standardized insulin sold for human use in the U S to U 100 100 units per milliliter Prior to that insulin was sold in different strengths including U 80 80 units per milliliter and U 40 formulations 40 units per milliliter so the effort to standardize the potency aimed to reduce dosage errors and ease doctors job of prescribing insulin for people Other countries also followed suit 1978 Genentech produces biosynthetic human insulin in Escherichia coli bacteria using recombinant DNA techniques licenses to Eli Lilly 1981 Novo Nordisk chemically and enzymatically converts porcine to human insulin 1982 Genentech synthetic human insulin above approved 1983 Eli Lilly and Company produces biosynthetic human insulin with recombinant DNA technology Humulin 1985 Axel Ullrich sequences a human cell membrane insulin receptor 1988 Novo Nordisk produces recombinant biosynthetic human insulin 1996 Lilly Humalog lispro insulin analogue approved 2000 Sanofi Aventis Lantus insulin glargine analogue approved for clinical use in the US and Europe 2004 Sanofi Aventis Apidra insulin glulisine insulin analogue approved for clinical use in the US 2006 Novo Nordisk Levemir detemir insulin analogue approved for clinical use in the US 2008 Abott laboratories FreeStyle Navigator CGM gets approved 19 2013 The U S Food and Drug Administration FDA requested more cardiac safety tests for Insulin Degludec 2015 Insulin degludec was approved by the FDA on September 25 2015 Medical uses Edit Giving insulin with an insulin pen Insulin is used to treat a number of diseases including diabetes and its acute complications such as diabetic ketoacidosis and hyperosmolar hyperglycemic states It is also used along with glucose to treat high blood potassium levels Use during pregnancy is relatively safe for the baby 4 Insulin was formerly used in a psychiatric treatment called insulin shock therapy 20 Side effects EditSome side effects are hypoglycemia low blood sugar hypokalemia low blood potassium and allergic reactions 4 Allergy to insulin affected about 2 of people of which most reactions are not due to the insulin itself but to preservatives added to insulin such as zinc protamine and meta cresol Most reactions are Type I hypersensitivity reactions and rarely cause anaphylaxis A suspected allergy to insulin can be confirmed by skin prick testing patch testing and occasionally skin biopsy First line therapy against insulin hypersensitivity reactions include symptomatic therapy with antihistamines The affected persons are then switched to a preparation that does not contain the specific agent they are reacting to or undergo desensitization 21 Cutaneous adverse effectsOther side effects may include pain or skin changes at the sites of injection Repeated subcutaneous injection without site rotation can lead to lipohypertrophy and amyloidomas which manifest as firm palpable nodules under the skin 22 Effects of early routine use Edit Early initiation of insulin therapy for the long term management of conditions such as type 2 diabetes would suggest that the use of insulin has unique benefits however it must be noted that with insulin therapy there is a need to gradually raise the dose and the complexity of the regimen as well as the likelihood of developing severe hypoglycemia which is why many people and their doctors are hesitant to begin insulin therapy in the early stage of disease management 23 Many obstacles associated with health behaviors also prevent people with type 2 diabetes mellitus from starting or intensifying their insulin treatment including lack of motivation lack of familiarity with or experience with treatments and time restraints causing people to have high glycemic loads for extended periods of time prior to starting insulin therapy This is why managing the side effects associated with long term early routine use of insulin for type 2 diabetes mellitus can prove to be a therapeutic and behavioral challenge 24 Principles Edit The idealised diagram shows the fluctuation of blood sugar red and the sugar lowering hormone insulin blue in humans during the course of a day containing three meals In addition the effect of a sugar rich versus a starch rich meal is highlighted Amino Acid Sequence of Insulin Preparations 25 26 Amino Acid Substitutions A Chain Position B Chain PositionSourceSpecies A 8 A 10 A 21 B 28 B 29 B 30 B 31B 32Bovine Ala Val Asn Pro Lys Ala N APorcine Thr Ile Asn Pro Lys Ala N AHuman Thr Ile Asn Pro Lys Thr N AAspart Novolog Thr Ile Asn Asp Lys Thr N ALispro Humalog Thr Ile Asn Lys Pro Thr N AGlulisine Apidra Thr Ile Asn Pro Glu Thr N AGlargine Lantus Thr Ilc Gly Pro Lys Thr ArgDetemir Levemir Thr Ile Asn Pro Lys N A Myristic acidDegludec Tresiba Thr Ile Asn Pro Lys N A Hexadecanedioic acidAla Alanine Val Valine Asn Asparagine Pro Proline Lys Lysine Thr Threonine Ile Isoleucine Glu Glutamine Gly GlycineInsulin is an endogenous hormone which is produced by the pancreas 27 The insulin protein has been highly conserved across evolutionary time and is present in both mammals and invertebrates The insulin insulin like growth factor signalling pathway IIS has been extensively studied in species including nematode worms e g C elegans flies Drosophila melanogaster and mice Mus musculus Its mechanisms of action are highly similar across species 28 Both type 1 diabetes and type 2 diabetes are marked by a loss of pancreatic function though to differing degrees 27 People who are affected with diabetes are referred to as diabetics Many diabetics require an exogenous source of insulin to keep their blood sugar levels within a safe target range 29 30 31 In 1916 Nicolae C Paulescu 1869 1931 succeeded in developing an aqueous pancreatic extract that normalized a diabetic dog In 1921 he published 4 papers in the Society of Biology in Paris centering on the successful effects of the pancreatic extract in diabetic dogs Research on the Role of the Pancreas in Food Assimilation by Paulescu was published in August 1921 in the Archives Internationales de Physiologie Liege Belgium Initially the only way to obtain insulin for clinical use was to extract it from the pancreas of another creature Animal glands were obtainable as a waste product of the meatpacking industry Insulin was derived primarily from cows Eli Lilly and Company and pigs Nordisk Insulinlaboratorium The making of eight ounces of purified insulin could require as much as two tons of pig parts 32 33 34 Insulin from these sources is effective in humans as it is highly similar to human insulin three amino acid difference in bovine insulin one amino acid difference in porcine 34 Initially lower preparation purity resulted in allergic reactions to the presence of non insulin substances Purity has improved steadily since the 1920s ultimately reaching purity of 99 by the mid 1970s thanks to high pressure liquid chromatography HPLC methods Minor allergic reactions still occur occasionally even to synthetic human insulin varieties 34 Beginning in 1982 biosynthetic human insulin has been manufactured for clinical use through genetic engineering techniques using recombinant DNA technology Genentech developed the technique used to produce the first such insulin Humulin but did not commercially market the product themselves Eli Lilly marketed Humulin in 1982 35 Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell E coli in this case The host cells are then allowed to grow and reproduce normally and due to the inserted human DNA they produce a synthetic version of human insulin Manufacturers claim this reduces the presence of many impurities However the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects an example is the absence of C peptide which has in recent years been shown to have systemic effects itself Novo Nordisk has also developed a genetically engineered insulin independently using a yeast process 36 37 According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries approximately 70 of the insulin that is currently sold in the world is recombinant biosynthetic human insulin 38 A majority of insulin used clinically today is produced this way although clinical experience has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction Adverse reactions have been reported these include loss of warning signs that patients may slip into a coma through hypoglycemia convulsions memory lapse and loss of concentration 39 However the International Diabetes Federation s position statement from 2005 is very clear in stating that there is NO overwhelming evidence to prefer one species of insulin over another and modern highly purified animal insulins remain a perfectly acceptable alternative 40 Since January 2006 all insulins distributed in the U S and some other countries are synthetic human insulins or their analogues A special FDA importation process is required to obtain bovine or porcine derived insulin for use in the U S although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier and porcine lente insulin is also sold and marketed under the brand name Vetsulin SM in the U S for veterinary usage in the treatment of companion animals with diabetes 41 Basal insulin Edit In type 1 diabetes insulin production is extremely low and as such the body requires exogenous insulin Some people with type 2 diabetes particularly those with very high hemoglobin A1c values may also require a baseline rate of insulin as their body is desensitized to the level of insulin being produced Basal insulin regulates the body s blood glucose between mealtimes as well as overnight This basal rate of insulin action is generally achieved via the use of an intermediate acting insulin such as NPH or a long acting insulin analog In type 1 diabetics it may also be achieved via continuous infusion of rapid acting insulin using an insulin pump Approximately half of a person s daily insulin requirement is administered as a basal insulin usually administered once per day at night 42 Prandial insulin Edit When a person eats food containing carbohydrates and glucose insulin helps regulate the body s metabolism of the food Prandial insulin also called mealtime or bolus insulin is designed as a bolus dose of insulin prior to a meal to regulate the spike in blood glucose that occurs following a meal The dose of prandial insulin may be static or may be calculated by the patient using either their current blood sugar planned carbohydrate intake or both This calculation may also be performed by an insulin pump in patients using a pump Insulin regiments that consist of doses calculated in this manner are considered intensive insulin regimens 43 Prandial insulin is usually administered no more than 15 30 minutes prior to a meal using a rapid acting insulin or a regular insulin In some patients a combination insulin may be used that contains both NPH long acting insulin and a rapid regular insulin to provide both a basal insulin and prandial insulin 42 Challenges in treatment EditThere are several challenges involved in the use of insulin as a clinical treatment for diabetes 44 Mode of administration Selecting the right dose and timing The amount of carbohydrates one unit of insulin handles varies widely between persons and over the day but values between 7 and 20 grams per 1 IE is typical Selecting an appropriate insulin preparation typically on speed of onset and duration of action grounds Adjusting dosage and timing to fit food intake timing amounts and types Adjusting dosage and timing to fit exercise undertaken Adjusting dosage type and timing to fit other conditions for instance the increased stress of illness Variability in absorption into the bloodstream via subcutaneous delivery The dosage is non physiological in that a subcutaneous bolus dose of insulin alone is administered instead of combination of insulin and C peptide being released gradually and directly into the portal vein It is simply a nuisance for people to inject whenever they eat carbohydrate or have a high blood glucose reading It is dangerous in case of mistake such as too much insulin Types EditMedical preparations of insulin are never just insulin in water with nothing else Clinical insulins are mixtures of insulin plus other substances including preservatives These prevent the protein from spoiling or denaturing too rapidly delay absorption of the insulin adjust the pH of the solution to reduce reactions at the injection site and so on 45 Slight variations of the human insulin molecule are called insulin analogues technically insulin receptor ligands so named because they are not technically insulin rather they are analogues which retain the hormone s glucose management functionality They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper They are either absorbed rapidly in an attempt to mimic real beta cell insulin as with insulin lispro insulin aspart and insulin glulisine or steadily absorbed after injection instead of having a peak followed by a more or less rapid decline in insulin action as with insulin detemir and insulin glargine all while retaining insulin s glucose lowering action in the human body However a number of meta analyses including those done by the Cochrane Collaboration in 2005 46 Germany s Institute for Quality and Cost Effectiveness in the Health Care Sector IQWiG released in 2007 47 and the Canadian Agency for Drugs and Technology in Health CADTH 48 also released in 2007 have shown no unequivocal advantages in clinical use of insulin analogues over more conventional insulin types 47 48 Choosing insulin type and dosage timing should be done by an experienced medical professional working closely with people who are diabetic citation needed The commonly used types of insulin are as follows 27 Fast acting Rapid acting Edit See also Insulin analog Includes the insulin analogues aspart lispro and glulisine These begin to work within 5 to 15 minutes and are active for 3 to 4 hours Most insulins form hexamers which delay entry into the blood in active form these analog insulins do not but have normal insulin activity Newer varieties are now pending regulatory approval in the U S which are designed to work rapidly but retain the same genetic structure as regular human insulin 49 50 Short acting Edit Includes regular insulin which begins working within 30 minutes and is active about 5 to 8 hours 51 Intermediate acting Edit Includes NPH insulin which begins working in 1 to 3 hours and is active for 16 to 24 hours 52 Long acting Edit Includes the analogues glargine U100 and detemir each of which begins working within 1 to 2 hours and continues to be active without major peaks or dips for about 24 hours although this varies in many individuals 53 54 Ultra long acting Edit Includes the analogues insulin glargine U300 and degludec which begin working within 30 to 90 minutes and continues to be active for greater than 24 hours 26 Combination insulin products Edit Includes a combination of either fast acting or short acting insulin with a longer acting insulin typically an NPH insulin The combination products begin to work with the shorter acting insulin 5 15 minutes for fast acting and 30 minutes for short acting and remain active for 16 to 24 hours There are several variations with different proportions of the mixed insulins e g Novolog Mix 70 30 contains 70 aspart protamine akin to NPH and 30 aspart 55 Methods of administration Edit Insulin delivery devices Unlike many medicines insulin cannot be taken orally at the present time Like nearly all other proteins introduced into the gastrointestinal tract it is reduced to fragments single amino acid components whereupon all activity is lost There has been some research into ways to protect insulin from the digestive tract so that it can be administered in a pill So far this is entirely experimental 56 Subcutaneous Edit Insulin is usually taken as subcutaneous injections by single use syringes with needles an insulin pump or by repeated use insulin pens with needles People who wish to reduce repeated skin puncture of insulin injections often use an injection port in conjunction with syringes 57 The use of subcutaneous injections of insulin is designed to mimic the natural physiological cycle of insulin secretion while taking into account the various properties of the formulations used such as half life onset of action and duration of action In many people both a rapid or short acting insulin product as well as an intermediate or long acting product are used to decrease the amount of injections per day In some insulin injections may be combined with other injection therapy such as GLP 1 agonists Cleansing of the injection site and injection technique are required to ensure effective insulin therapy 42 Insulin pump Edit Main article Insulin pump Insulin pumps are a reasonable solution for some Advantages to the person are better control over background or basal insulin dosage bolus doses calculated to fractions of a unit and calculators in the pump that may help with determining bolus infusion dosages The limitations are cost the potential for hypoglycemic and hyperglycemic episodes catheter problems and no closed loop means of controlling insulin delivery based on current blood glucose levels citation needed Insulin pumps may be like electrical injectors attached to a temporarily implanted catheter or cannula Some who cannot achieve adequate glucose control by conventional or jet injection are able to do so with the appropriate pump 58 Indwelling catheters pose the risk of infection and ulceration and some peoples may also develop lipodystrophy due to the infusion sets These risks can often be minimized by keeping infusion sites clean Insulin pumps require care and effort to use correctly 58 Dosage and timing EditSee also Intensive insulinotherapy and Conventional insulinotherapy Dosage units Edit One international unit of insulin 1 IU is defined as the biological equivalent of 34 7 mg pure crystalline insulin The first definition of a unit of insulin was the amount required to induce hypoglycemia in a rabbit This was set by James Collip at the University of Toronto in 1922 Of course this was dependent on the size and diet of the rabbits The unit of insulin was set by the insulin committee at the University of Toronto 59 The unit evolved eventually to the old USP insulin unit where one unit U of insulin was set equal to the amount of insulin required to reduce the concentration of blood glucose in a fasting rabbit to 45 m g d l 2 5 m mol L Once the chemical structure and mass of insulin was known the unit of insulin was defined by the mass of pure crystalline insulin required to obtain the USP unit The unit of measurement used in insulin therapy is not part of the International System of Units abbreviated SI which is the modern form of the metric system Instead the pharmacological international unit IU is defined by the WHO Expert Committee on Biological Standardization 60 Potential complications Edit Diagram explaining the basal bolus insulin schedule The long acting insulin is given once usually glargine Lantus or twice usually detemir Levemir daily to provide a base or basal insulin level Rapid acting RA insulin is given before meals and snacks A similar profile can be provided using an insulin pump where rapid acting insulin is given as the basal and premeal bolus insulin The central problem for those requiring external insulin is picking the right dose of insulin and the right timing Physiological regulation of blood glucose as in the non diabetic would be best Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas The increased insulin level causes glucose absorption and storage in cells reduces glycogen to glucose conversion reducing blood glucose levels and so reducing insulin release The result is that the blood glucose level rises somewhat after eating and within an hour or so returns to the normal fasting level Even the best diabetic treatment with synthetic human insulin or even insulin analogs however administered falls far short of normal glucose control in the non diabetic 61 Complicating matters is that the composition of the food eaten see glycemic index affects intestinal absorption rates Glucose from some foods is absorbed more or less rapidly than the same amount of glucose in other foods In addition fats and proteins cause delays in absorption of glucose from carbohydrates eaten at the same time As well exercise reduces the need for insulin even when all other factors remain the same since working muscle has some ability to take up glucose without the help of insulin 62 Because of the complex and interacting factors it is in principle impossible to know for certain how much insulin and which type is needed to cover a particular meal to achieve a reasonable blood glucose level within an hour or two after eating Non diabetics beta cells routinely and automatically manage this by continual glucose level monitoring and insulin release All such decisions by a diabetic must be based on experience and training i e at the direction of a physician PA or in some places a specialist diabetic educator and further specifically based on the individual experience of the person But it is not straightforward and should never be done by habit or routine With some care however it can be done reasonably well in clinical practice For example some people with diabetes require more insulin after drinking skim milk than they do after taking an equivalent amount of fat protein carbohydrate and fluid in some other form Their particular reaction to skimmed milk is different from other people with diabetes but the same amount of whole milk is likely to cause a still different reaction even in that person Whole milk contains considerable fat while skimmed milk has much less It is a continual balancing act for all people with diabetes especially for those taking insulin People with insulin dependent diabetes typically require some base level of insulin basal insulin as well as short acting insulin to cover meals bolus also known as mealtime or prandial insulin Maintaining the basal rate and the bolus rate is a continuous balancing act that people with insulin dependent diabetes must manage each day This is normally achieved through regular blood tests although continuous blood sugar testing equipment Continuous Glucose Monitors or CGMs are now becoming available which could help to refine this balancing act once widespread usage becomes common Strategies Edit A long acting insulin is used to approximate the basal secretion of insulin by the pancreas which varies in the course of the day 63 NPH isophane lente ultralente glargine and detemir may be used for this purpose The advantage of NPH is its low cost the fact that you can mix it with short acting forms of insulin thereby minimizing the number of injections that must be administered and that the activity of NPH will peak 4 6 hours after administration allowing a bedtime dose to balance the tendency of glucose to rise with the dawn along with a smaller morning dose to balance the lower afternoon basal need and possibly an afternoon dose to cover evening need A disadvantage of bedtime NPH is that if not taken late enough near midnight to place its peak shortly before dawn it has the potential of causing hypoglycemia One theoretical advantage of glargine and detemir is that they only need to be administered once a day although in practice many people find that neither lasts a full 24 hours They can be administered at any time during the day as well provided that they are given at the same time every day Another advantage of long acting insulins is that the basal component of an insulin regimen providing a minimum level of insulin throughout the day can be decoupled from the prandial or bolus component providing mealtime coverage via ultra short acting insulins while regimens using NPH and regular insulin have the disadvantage that any dose adjustment affects both basal and prandial coverage Glargine and detemir are significantly more expensive than NPH lente and ultralente and they cannot be mixed with other forms of insulin citation needed A short acting insulin is used to simulate the endogenous insulin surge produced in anticipation of eating Regular insulin lispro aspart and glulisine can be used for this purpose Regular insulin should be given with about a 30 minute lead time prior to the meal to be maximally effective and to minimize the possibility of hypoglycemia Lispro aspart and glulisine are approved for dosage with the first bite of the meal and may even be effective if given after completing the meal The short acting insulin is also used to correct hyperglycemia 64 The usual schedule for checking fingerstick blood glucose and administering insulin is before all meals and sometimes also at bedtime More recent guidelines also call for a check 2 hours after a meal to ensure the meal has been covered effectively citation needed Sliding scales Edit First described in 1934 65 what physicians typically refer to as sliding scale insulin SSI is fast or rapid acting insulin only given subcutaneously typically at meal times and sometimes bedtime 66 but only when blood glucose is above a threshold e g 10 mmol L 180 mg dL 67 The so called sliding scale method is widely taught although it has been heavily criticized 68 69 70 71 Sliding scale insulin SSI is not an effective way of managing long term diabetes in individuals residing in nursing homes 66 72 Sliding scale insulin leads to greater discomfort and increased nursing time 72 Sample regimen using insulin NPH and regular insulin before breakfast before lunch before dinner at bedtimeNPH dose 12 units 6 unitsregular insulin dose if fingerstick glucose is mg dL mmol L 70 100 3 9 5 5 4 units 4 units101 150 5 6 8 3 5 units 5 units151 200 8 4 11 1 6 units 6 units201 250 11 2 13 9 7 units 7 units251 300 14 0 16 7 8 units 1 unit 8 units 1 unit gt 300 gt 16 7 9 units 2 units 9 units 2 unitsSample regimen using insulin glargine and insulin lispro Insulin glargine 20 units at bedtimeInsulin lispro to be given as follows if fingerstick glucose is mg dL mmol L before breakfast before lunch before dinner at bedtime70 100 3 9 5 5 5 units 5 units 5 units101 150 5 6 8 3 6 units 6 units 6 units151 200 8 4 11 1 7 units 7 units 7 units201 250 11 2 13 9 8 units 8 units 8 units 1 unit251 300 14 0 16 7 9 units 9 units 9 units 2 units gt 300 gt 16 7 10 units 10 units 10 units 3 unitsCarb counting and DAFNE Edit A more complicated method that allows greater freedom with meal times and snacks is carb counting This approach is taught to people who are diabetic in the UK and elsewhere as Dose Adjustment For Normal Eating or DAFNE In Europe people who are not familiar with the DAFNE regime can take an educational course where the basic starting insulin dose guideline is for every 10 g of carbohydrates you eat take 1 unit of insulin DAFNE courses also cover topics that naturally work alongside this regime such as blood glucose monitoring exercise and carbohydrate estimation to help the person work out their personal control requirements People can also use their total daily dose TDD of insulin to estimate how many grams of carbohydrates will be covered by 1 unit of insulin and using this result estimate how many units of insulin should be administered depending on the carbohydrate content of their meal For example if the person determines that 1 unit of insulin will cover 15 grams of carbohydrates then they must administer 5 units of insulin before consuming a meal that contains 75 grams of carbohydrates Some alternative methods also consider the protein content of the meal since excess dietary protein can be converted to glucose via gluconeogenesis With DAFNE most dosages involve a fair degree of guesswork especially with non labeled foods and will only work fairly consistently from one dosage to the next if the person is aware of their body s requirements For example a person finds they can take 1 unit of insulin to 10 g of carbohydrates in the morning and the evening but find that their body requires more insulin for a meal in the middle of the day so they have to adjust to 1 unit per 8 5g of carbohydrates Other less obvious factors that affect the body s use of insulin must also be taken into account For example some people may find that their bodies process insulin better on hot days so require less insulin With this the person again has to adjust their dose to the best of their understanding from their past experiences The DAFNE regime requires the person to learn about their body s needs through experience which takes time and patience but it can then become effective Closed loop predictive modeling Edit People with fluctuating insulin requirements may benefit from a closed loop predictive modeling approach As an extension on carb counting in this closed loop predictive modeling approach the four daily insulin dosages needed to reach the target blood sugar levels for the normal daily carbohydrate consumption and amount of physical activity are continuously adjusted based on the pre meal and pre night blood sugar level readings Each new blood sugar reading provides the feedback to fine tune and track the body s insulin requirements Within this strategy the key specific factors which have to be determined experimentally are the blood sugar correction factor and the carbohydrate ratio The blood sugar correction factor sets both the proportional gain and integral gain factors for the four feedback loops When taken too low deviations from the target blood sugar level are not corrected for effectively when taken too high the blood sugar regulation will become unstable Since in this approach the carbohydrate ratio is only used to account for non standard carbohydrate intakes it is usually not required to work with meal specific ratios Dose calculation EditInsulin dosage is given by the formula i n s u l i n g l u c o s e T R C F c a r b o h y d r a t e s K F K F g l u c o s e T R C F c a r b o h y d r a t e s C F K F displaystyle mathrm insulin frac mathrm glucose mathit TR mathit CF frac mathrm carbohydrates mathit KF frac mathit KF times mathrm glucose mathit TR mathit CF times mathrm carbohydrates mathit CF times mathit KF based on the person s blood glucose and carbohydrate intake and these constants TR target rate CF corrective factor KF carbohydrate factorBlood glucose and target rate are expressed in mg dL or mmol L Constants should be set by a physician or clinical pharmacist Insulin Medication in Pregnancy EditDiabetes in pregnancy is associated with numerous risks to the woman and the developing fetus See Diabetes and pregnancy The best course of action for treating and managing pre existing diabetes or gestational diabetes is still under research as the insulin needs during pregnancy are prone to quick variation During pregnancy spontaneous hyperglycemia can develop and lead to gestational diabetes mellitus GDM a frequent pregnancy complication With a prevalence of 6 20 among pregnant women globally gestational diabetes mellitus GDM is defined as any degree of glucose intolerance developing or initially recognized during pregnancy 73 Neutral protamine Hagedorn NPH insulin has been the cornerstone of insulin therapy during pregnancy administered two to four times per day Women with GDM and pregnant women with type I diabetes mellitus who frequently check their blood glucose levels and utilize glucose monitoring equipment for doing so use continuous insulin infusion of a rapid acting insulin analogue such as lispro and aspart However a number of considerations go into choosing a regimen for administering insulin to patients When managing GDM in pregnant women these guidelines are crucial and can vary depending on certain physiological and interestingly the sociocultural environment as well The current perinatal guidelines recommend a low daily dose of insulin and take into account the woman s physiological features and the frequency of self monitoring The importance of using specialized insulin therapy planning based on parameters like those stated above rather than a broad approach is emphasized 74 Women with pre existing diabetes have the highest levels of insulin sensitivity early in pregnancy Close glucose monitoring is required to prevent hypoglycemia which can potentially result in altered consciousness seizures and maternal damage 75 Low birth weight newborns might also be the result of hypoglycemia especially in patients with type 1 diabetes because they are frequently more insulin sensitive than persons with type 2 diabetes and more likely to be unaware of their hypoglycemic state Close glucose monitoring is essential because after 16 weeks of pregnancy women with preexisting diabetes become more insulin resistant and their insulin demands may fluctuate weekly The need for insulin may rise from one pregnancy to the next Therefore it is realistic to expect higher needs for glucose control with subsequent pregnancies in multiparous women 75 Abuse EditThe abuse of exogenous insulin carries with it an attendant risk of hypoglycemic coma and death when the amount used is in excess of that required to handle ingested carbohydrate Acute risks include brain damage paralysis and death Symptoms may include dizziness weakness trembling palpitations seizures confusion headache drowsiness coma diaphoresis and nausea All persons with overdoses should be referred for medical assessment and treatment which may last for hours or days 76 Data from the US National Poison Data System 2013 indicates that 89 3 of insulin cases reported to poison centers are unintentional as a result of therapeutic error Another 10 of cases are intentional and may reflect attempted suicide abuse criminal intent secondary gain or other unknown reasons 76 Hypoglycemia that has been induced by exogenous insulin can be chemically detected by examining the ratio of insulin to C peptide in peripheral circulation 77 It has been suggested that this type of approach could be used to detect exogenous insulin abuse by athletes 78 The possibility of using insulin in an attempt to improve athletic performance was suggested as early as the 1998 Winter Olympics in Nagano Japan as reported by Peter Sonksen in the July 2001 issue of Journal of Endocrinology The question of whether non diabetic athletes could legally use insulin was raised by a Russian medical officer 79 80 Whether insulin would actually improve athletic performance is unclear but concerns about its use led the International Olympic Committee to ban use of the hormone by non diabetic athletes in 1998 81 The book Game of Shadows 2001 by reporters Mark Fainaru Wada and Lance Williams included allegations that baseball player Barry Bonds used insulin as well as other drugs in the apparent belief that it would increase the effectiveness of the growth hormone he was alleged to be taking 82 Bonds eventually testified in front of a federal grand jury as part of a government investigation of BALCO 83 Bodybuilders in particular are claimed to be using exogenous insulin and other drugs in the belief that they will increase muscle mass Bodybuilders have been described as injecting up to 10 IU of regular synthetic insulin before eating sugary meals 81 A 2008 report suggested that insulin is sometimes used in combination with anabolic steroids and growth hormone GH and that Athletes are exposing themselves to potential harm by self administering large doses of GH IGF I and insulin 84 85 Insulin abuse has been mentioned as a possible factor in the deaths of bodybuilders Ghent Wakefield and Rich Piana 86 Insulin human growth hormone HGH and insulin like growth factor 1 IGF 1 are self administered by those looking to increase muscle mass beyond the scope offered by anabolic steroids alone Their rationale is that since insulin and HGH act synergistically to promote growth and since IGF 1 is a primary mediator of musculoskeletal growth the stacking of insulin HGH and IGF 1 should offer a synergistic growth effect on skeletal muscle This theory has been supported in recent years by top level bodybuilders whose competition weight is in excess of 50 lb 23 kg of muscle larger than that of competitors in the past and with even lower levels of body fat citation needed Insulin effects on strength and exercise performance Edit Exogenous insulin significantly boosts the rate of glucose metabolism in training athletes along with a substantial increases in the peak V 02 87 Insulin is thought to enhance performance by increasing protein synthesis reducing protein catabolism and facilitating the transfer of certain amino acids in human skeletal muscle Insulin treated athletes are perceived to have lean body mass because physiological hyperinsulinemia in human skeletal muscle improves the activity of amino acid transport which in turn promotes protein synthesis 87 Insulin stimulates the transport of amino acids into cells and also controls glucose metabolism It decreases lipolysis and increases lipogenesis which is why bodybuilders and athletes use rhGH in conjunction with it as to offset this negative effect while maximizing protein synthesis The athletes extrapolated the physiology of the diabetic patient in the sporting arena because they are interested in the suppression of proteolysis Insulin administration is found to be protein anabolic in the insulin resistant state of chronic renal failure 88 It inhibits proteolysis and when administered along with amino acids it enhances net protein synthesis Exogenous insulin injection creates an in vivo hyperinsulinemic clamp boosting muscle glycogen before and during the recovery phases of intense exercise Power strength and stamina are all expected to increase as a result and it might also speed up the healing process after intense physical activity Second insulin is expected to increase muscle mass by preventing the breakdown of muscle protein when consumed along with high carb protein diet Although a limited number of studies do suggest that insulin medication can be abused as a pharmacological treatment to boost strength and performance in young healthy people or athletes a recent assessment of the research argues that this is only applicable to a small group of drug naive individuals 87 Detection in biological fluids EditInsulin is often measured in serum plasma or blood in order to monitor therapy in people who are diabetic confirm a diagnosis of poisoning in hospitalized persons or assist in a medicolegal investigation of suspicious death Interpretation of the resulting insulin concentrations is complex given the numerous types of insulin available various routes of administration the presence of anti insulin antibodies in insulin dependent diabetics and the ex vivo instability of the drug Other potential confounding factors include the wide ranging cross reactivity of commercial insulin immunoassays for the biosynthetic insulin analogs the use of high dose intravenous insulin as an antidote to antihypertensive drug over dosage and postmortem redistribution of insulin within the body The use of a chromatographic technique for insulin assay may be preferable to immunoassay in some circumstances to avoid the issue of cross reactivity affecting the quantitative result and also to assist identifying the specific type of insulin in the specimen 89 Combination with other antidiabetic drugs EditA combination therapy of insulin and other antidiabetic drugs appears to be most beneficial in people who are diabetic who still have residual insulin secretory capacity 90 A combination of insulin therapy and sulfonylurea is more effective than insulin alone in treating people with type 2 diabetes after secondary failure to oral drugs leading to better glucose profiles and or decreased insulin needs 90 Society and culture EditEconomics Edit In the United States the unit price of insulin has increased steadily from 1991 to 2019 91 92 It rose threefold from 2002 to 2013 93 Costs can be as high as US 900 per month 93 Concerns were raised in 2016 of pharmaceutical companies working together to increase prices 93 In January 2019 lawmakers from the United States House of Representatives sent letters to insulin manufacturers Eli Lilly and Co Sanofi and Novo Nordisk asking for explanations for their rapidly raising insulin prices The annual cost of insulin for people with type 1 diabetes in the U S almost doubled from 2 900 to 5 700 over the period from 2012 to 2016 94 People in the U S pay two to six times more than the rest of the world including Canada for brand name prescription medicine according to the International Federation of Health Plans Canada like many other industrialized countries has price controls on the cost of pharmaceuticals 95 California in July 2022 approved a budget that allocates 100 million for the state to create its own insulin at a close to cost price 96 Insulin and all other medications are supplied free of charge to people with diabetes by the National Health Service in the countries of the United Kingdom 97 Regulatory status Edit In March 2020 the FDA changed the regulatory pathway for approval of new insulin products 98 Insulin is regulated as a biologic rather than as a drug 98 The changed status gives the FDA more flexibility for approval and labeling 99 In July 2021 the FDA approved insulin glargine yfgn Semglee a biosimilar product that contains the long acting analog insulin glargine 100 Insulin glargine yfgn is interchangeable and less expensive than the reference product insulin glargine Lantus which had been approved in 2000 101 102 The FDA requires that new insulin products are not inferior to existing insulin products with respect to reduction in hemoglobin A1c See Misbin RI February 2022 Insulin History from an FDA Insider Politics and Prose Publishing Washington DC Text ISBN 978 I 62429 391 77Research EditSee also Artificial pancreas Inhalation Edit Main article Inhalable insulin In 2006 the U S Food and Drug Administration FDA approved the use of Exubera the first inhalable insulin 103 It was withdrawn from the market by its maker as of third quarter 2007 due to lack of acceptance Inhaled insulin claimed to have similar efficacy to injected insulin both in terms of controlling glucose levels and blood half life Currently inhaled insulin is short acting and is typically taken before meals an injection of long acting insulin at night is often still required 104 When people were switched from injected to inhaled insulin no significant difference was observed in HbA1c levels over three months Accurate dosing was a particular problem although people showed no significant weight gain or pulmonary function decline over the length of the trial when compared to the baseline 105 Following its commercial launch in 2005 in the United Kingdom it was not as of July 2006 recommended by National Institute for Health and Clinical Excellence for routine use except in cases where there is proven injection phobia diagnosed by a psychiatrist or psychologist 104 In January 2008 the world s largest insulin manufacturer Novo Nordisk also announced that the company was discontinuing all further development of the company s own version of inhalable insulin known as the AERx iDMS inhaled insulin system 106 Similarly Eli Lilly and Company ended its efforts to develop its inhaled Air Insulin in March 2008 107 Afrezza developed by Mannkind was authorized by the FDA in June 2014 for use in adults with Type I and Type II diabetes with a label restriction limiting its use only to those who also have asthma active lung cancer or chronic obstructive pulmonary disease 108 Rapid acting inhaled insulin is a component of the drug device combination solution that is used at the start of every meal It employs technosphere technology which appears to have a more practical delivery method and more dosing flexibility and a new inhaled insulin formulation 2 5 m A thumb sized inhaler with improved dosage flexibility is used to deliver inhalable insulin It includes powder dissolved recombinant human insulin fumaryl diketopiperazine Technosphere insulin is quickly absorbed by the lung surface after inhalation Within 12 hours of inhalation both substances insulin and powder fumaryl diketopiperazine are virtually eliminated from healthy people s lungs In comparison to Exubera 8 9 just 0 3 of inhaled insulin was still present in the lungs after 12 hours However since serum antibody levels have been reported to increase without substantial clinical changes acute bronchospasm in asthmatic and COPD patients along with a significant reduction in Diffusing Lung Capacity for Carbon Monoxide in comparison to subcutaneous insulin have been reported with its usage Afrezza was given FDA approval with a warning Risk Evaluation and Mitigation Strategy 109 108 Transdermal Edit There are several methods for transdermal delivery of insulin Pulsatile insulin uses microjets to pulse insulin into the person mimicking the physiological secretions of insulin by the pancreas 110 Jet injection had different insulin delivery peaks and durations as compared to needle injection Some diabetics may prefer jet injectors to hypodermic injection 111 Both electricity using iontophoresis 112 and ultrasound have been found to make the skin temporarily porous The insulin administration aspect remains experimental but the blood glucose test aspect of wrist appliances is commercially available Researchers have produced a watch like device that tests for blood glucose levels through the skin and administers corrective doses of insulin through pores in the skin A similar device but relying on skin penetrating microneedles was in the animal testing stage in 2015 113 In the last couple of years the use of chemical enhancers electrical devices and microneedle devices has shown tremendous promise for improving the penetration of insulin compared to passive transport via the skin Transdermal insulin delivery shows a more patient friendly and minimally invasive approach to daily diabetes care than the conventional hypodermic injection however it must be noted that additional research is necessary to address issues such as long term use delivery efficiency and reliability as well as side effects involving inflammation and irritation 114 Intranasal Edit Insulin can be delivered to the central nervous system via the intranasal IN route with little to no systemic uptake or associated peripheral side effects It has been demonstrated that intranasally delivered insulin rapidly accumulates in CSF fluid indicating effective transport to the brain This accumulation is thought to occur along olfactory and nearby routes Although numerous studies have published encouraging results further study is still being conducted to comprehend its long term impacts in order to begin the successful clinical application 115 By mouth Edit The basic appeal of hypoglycemic agents by mouth is that most people would prefer a pill or an oral liquid to an injection However insulin is a peptide hormone which is digested in the stomach and gut and in order to be effective at controlling blood sugar cannot be taken orally in its current form The potential market for an oral form of insulin is assumed to be enormous thus many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar 116 A number of derivatization and formulation strategies are currently being pursued to in an attempt to develop an orally available insulin 117 Many of these approaches employ nanoparticle delivery systems 118 119 120 and several are being tested in clinical trials 121 122 123 Pancreatic transplantation Edit Main article Islet cell transplantation Another improvement would be a transplantation of the pancreas or beta cell to avoid periodic insulin administration This would result in a self regulating insulin source Transplantation of an entire pancreas as an individual organ is difficult and relatively uncommon It is often performed in conjunction with liver or kidney transplant although it can be done by itself It is also possible to do a transplantation of only the pancreatic beta cells However islet transplants had been highly experimental for many years but some researchers in Alberta Canada have developed techniques with a high initial success rate about 90 in one group Nearly half of those who got an islet cell transplant were insulin free one year after the operation by the end of the second year that number drops to about one in seven However researchers at the University of Illinois at Chicago UIC have slightly modified the Edmonton Protocol procedure for islet cell transplantation and achieved insulin independence in diabetic people with fewer but better functioning pancreatic islet cells 124 Longer term studies are needed to validate whether it improves the rate of insulin independence Beta cell transplant may become practical in the near future Additionally some researchers have explored the possibility of transplanting genetically engineered non beta cells to secrete insulin 125 Clinically testable results are far from realization at this time Several other non transplant methods of automatic insulin delivery are being developed in research labs but none is close to clinical approval References Edit Humulin S Soluble 100IU mL solution for injection in cartridge Summary of Product Characteristics SmPC emc Archived from the original on 5 August 2020 Retrieved 4 September 2020 Harding MM Hodgkin DC Kennedy AF O Conor A Weitzmann PD March 1966 The crystal structure of insulin II An investigation of rhombohedral zinc insulin crystals and a report of other crystalline forms Journal of Molecular Biology 16 1 212 26 doi 10 1016 S0022 2836 66 80274 7 PMID 5917731 Abel JJ February 1926 Crystalline Insulin Proceedings of the National Academy of Sciences of the United States of America 12 2 132 6 Bibcode 1926PNAS 12 132A doi 10 1073 pnas 12 2 132 PMC 1084434 PMID 16587069 a b c d e American Society of Health System Pharmacists Insulin Human www drugs 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en 2003 1512 PMID 15117881 External links Edit Insulin Drug Information Portal U S National Library of Medicine Insulin regular Drug Information Portal U S National Library of Medicine Insulin Injection biphasic Drug Information Portal U S National Library of Medicine Portal Medicine Retrieved from https en wikipedia org w index php title Insulin medication amp oldid 1135128284, wikipedia, wiki, book, books, library,

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