Insulin (medication)

Insulin

Vials of insulin
Clinical data
Trade names	Humulin, Novolin, Insuman, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682611
License data	US DailyMed: Humulin
inhalation
ATC code	A10AD01 (WHO)
Legal status
Legal status	CA: OTC UK: POM (Prescription only)[1] US: ℞-only / OTC EU: Rx-only[2][3]
Identifiers
CAS Number	9004-10-8
PubChem CID	70678557
DrugBank	DB00030
ChemSpider	34999906
UNII	438UC14NDQ
KEGG	D04477
Chemical and physical data
Formula	C257H383N65O77S6
Molar mass	5807.63 g·mol−1
Density	1.09 g/cm3 [4]
Melting point	233 °C (451 °F) [5]

As a

Insulin can be made from the

History

Insulin was first used as a medication in Canada by Charles Best and Frederick Banting in 1922.^[14][15]

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^[16]
• 1922 Frederick Banting, Charles Best and James Collip use bovine insulin extract in humans at Connaught Laboratories in Toronto, Canada.^[14]
• 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.^[17][18]
• 1922 Elizabeth Hughes Gossett, daughter of the U.S. Secretary of State, becomes the first American to be (officially) treated in Toronto.^[19][20]
• 1923 Eli Lilly produces commercial quantities of much purer bovine insulin than Banting et al. had used
• 1923 Farbwerke
  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^[21]
• 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
  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 the EU.
• 2004
  Sanofi Aventis
  Apidra insulin "glulisine" insulin analogue approved for clinical use in the US.
• 2006
  Levemir
  "detemir" insulin analogue approved for clinical use in the US.
• 2008 Abott laboratories " FreeStyle Navigator CGM" gets approved.^[22]
• 2013 The US Food and Drug Administration (FDA) requested more cardiac safety tests for Insulin degludec.
• 2015 Insulin degludec was approved by the FDA in September 2015.

Medical uses

insulin pen

.

Insulin is used to treat a number of diseases including

Side effects

Some side effects are

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.^[25]

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, 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.^[26] 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.^[27]

Principles

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[28][29]
Amino Acid Substitutions
	A-Chain Position			B-Chain Position
Source Species	A-8	A-10	A-21	B-28	B-29	B-30	B-31 B-32
Bovine	Ala	Val	Asn	Pro	Lys	Ala	N/A
Porcine	Thr	Ile	Asn	Pro	Lys	Ala	N/A
Human	Thr	Ile	Asn	Pro	Lys	Thr	N/A
Aspart (Novolog)	Thr	Ile	Asn	Asp	Lys	Thr	N/A
Lispro (Humalog)	Thr	Ile	Asn	Lys	Pro	Thr	N/A
Glulisine (Apidra)	Thr	Ile	Asn	Pro	Glu	Thr	N/A
Glargine (Lantus)	Thr	Ilc	Gly	Pro	Lys	Thr	Arg
Detemir (Levemir)	Thr	Ile	Asn	Pro	Lys	N/A	Myristic acid
Degludec(Tresiba)	Thr	Ile	Asn	Pro	Lys	N/A	Hexadecanedioic acid
Ala=Alanine Val=Valine Asn=Asparagine Pro=Proline Lys=Lysine Thr=Threonine Ile=Isoleucine Glu=Glutamine Gly=Glycine

Insulin is an endogenous hormone, which is produced by the pancreas.^[30] The insulin

Both type 1 diabetes and type 2 diabetes are marked by a loss of pancreatic function, though to differing degrees.^[30] 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.^[32][33][34]

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

Beginning in 1982, biosynthetic "human" insulin has been manufactured for clinical use through genetic engineering techniques using

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.^[39][40]

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.^[41] 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.^[42] 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."^[43]

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.^[44]

Basal insulin

In type 1 diabetes, insulin production is extremely low, and as such the body requires

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.^[46] 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.^[45]

Challenges in treatment

There are several challenges involved in the use of insulin as a clinical treatment for diabetes:^[47]

• 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.^[48]

Slight variations of the human insulin molecule are called

The commonly used types of insulin are as follows.[30]

Fast-acting (Rapid-acting)

Includes the insulin analogues

Short-acting

Includes regular insulin, which begins working within 30 minutes and is active about 5 to 8 hours.^[54]

Intermediate-acting

Includes NPH insulin, which begins working in 1 to 3 hours and is active for 16 to 24 hours.^[55]

Long-acting

Includes the analogues

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.^[29]

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 16–24 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.)^[58]

Methods of administration

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.^[59]

Subcutaneous

Insulin is usually taken as

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 receptor agonists. Cleansing of the injection site and injection technique are required to ensure effective insulin therapy.^[45]

Insulin pump

]

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.^[61]

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.^[61]

Dosage and timing

Dosage units

One

pure crystalline insulin.

The first definition of a unit of insulin was the amount required to induce

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

Potential complications

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.[64]

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.^[65]

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

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

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.^[66] 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.^[67]

Sliding scales

First described in 1934,^[68] 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,^[69] but only when blood glucose is above a threshold (e.g. 10 mmol/L, 180 mg/dL).^[70] The so-called "sliding-scale" method is widely taught, although it has been heavily criticized.^{[71][72][73][74]} Sliding scale insulin (SSI) is not an effective way of managing long-term diabetes in individuals residing in nursing homes.^[69][75] Sliding scale insulin leads to greater discomfort and increased nursing time.^[75]

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

Insulin Medication in Pregnancy

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.^[76] 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.^[77]

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.^[78] 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.^[78]

As a performance-enhancing drug

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

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

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]

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

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.[89] Hypoglycemia that has been induced by exogenous insulin can be chemically detected by examining the ratio of insulin to C-peptide in peripheral circulation.^[90] It has been suggested that this type of approach could be used to detect exogenous insulin abuse by athletes.^[91]

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.^[92]

Combination with other antidiabetic drugs

A combination therapy of insulin and other

Society and culture

Economics: United States

In the United States the unit price of insulin has increased steadily from 1991 to 2019.

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.[98]

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.^[99]

Insulin, and all other medications, are supplied free of charge to people who use it to manage their diabetes by the National Health Services of the countries of the United Kingdom.^[100]

Regulatory status: United States

In March 2020, the FDA changed the regulatory pathway for approval of new insulin products.

Research

See also:

Artificial pancreas

Inhalation

In 2006 the U.S.

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.[107] When people were switched from injected to inhaled insulin, no significant difference was observed in Hb_A1c 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.^[108]

Following its commercial launch in 2005 in the United Kingdom, it was not (as of July 2006) recommended by

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.^[109] Similarly, Eli Lilly and Company ended its efforts to develop its inhaled Air Insulin in March 2008.^[110] 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.^[111] 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).^[112][111]

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.^[113] Jet injection had different insulin delivery peaks and durations as compared to needle injection. Some diabetics may prefer jet injectors to hypodermic injection.^[114] Both electricity using iontophoresis^[115] 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.^[116] 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, 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.^[117]

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.^[118]

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

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.^[119]

A number of derivatization and formulation strategies are currently being pursued to in an attempt to develop an orally available insulin.^[120] Many of these approaches employ nanoparticle delivery systems^{[121][122][123]} and several are being tested in clinical trials.^{[124][125][126]}

Pancreatic transplantation

Another improvement would be a

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

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