Insulin (medication)

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Insulin
Inzulin.jpg
Vials of insulin
Clinical data
Trade names Humulin, Novolin, Insuman, others
AHFS/Drugs.com Monograph
MedlinePlus a682611
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Routes of
administration 		Subcutaneous, intravenous, intramuscular, inhalation
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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 medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose. [6] Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. [6] Insulin is also used along with glucose to treat hyperkalemia (high blood potassium levels). [7] Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle. [6] 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. [8] [9] In 2020, regular human insulin was the 307th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [10] [11]

Contents

Insulin can be made from the pancreas of pigs or cows. [12] Human versions can be made either by modifying pig versions, or recombinant technology [12] using mainly E. coli or Saccharomycescerevisiae. [13] 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). [12]

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

Medical uses

The current standard insulin syringe. It's a disposable plastic one-piece syringe with an integral needle and an orange needle cap (introduced by Becton-Dickinson in 1970). It's also a low dead space syringe. Syringe with insulin for a cat.jpg
The current standard insulin syringe. It's a disposable plastic one-piece syringe with an integral needle and an orange needle cap (introduced by Becton-Dickinson in 1970). It's also a low dead space syringe.
Giving insulin with an insulin pen. Insulin Application.jpg
Giving insulin with an insulin pen.
Insulin pump in use. Insulin pump with infusion set.jpg
Insulin pump in use.

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. [6] Insulin was formerly used in a psychiatric treatment called insulin shock therapy. [23]

Side effects

Some side effects are hypoglycemia (low blood sugar), hypokalemia (low blood potassium), and allergic reactions. [6] 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. [24]

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

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. Suckale08 fig3 glucose insulin day.png
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. [30] 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. [31]

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 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. [35] [36] [37] 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). [37] 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. [37]

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. [38] 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. [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 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. [45]

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]

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 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, [49] Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] released in 2007, [50] and the Canadian Agency for Drugs and Technology in Health (CADTH) [51] also released in 2007 have shown no unequivocal advantages in clinical use of insulin analogues over more conventional insulin types. [50] [51]

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

Fast-acting (Rapid-acting)

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. [52] [53]

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 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. [56] [57]

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

Insulin delivery devices Insulin Delivery Devices.png
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. [59]

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. [60]

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 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. [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 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. [62] 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. [63]

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. Insulin basal bolus.png
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. [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 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. [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 breakfastbefore lunchbefore dinnerat bedtime
NPH dose12 units6 units
regular insulin dose if fingerstick
glucose is (mg/dL) [mmol/L]:
70–100       [3.9–5.5]4 units4 units
101–150     [5.6–8.3]5 units5 units
151–200     [8.4–11.1]6 units6 units
201–250     [11.2–13.9]7 units7 units
251–300     [14.0–16.7]8 units1 unit8 units1 unit
>300         [>16.7]9 units2 units9 units2 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 breakfastbefore lunchbefore dinnerat bedtime
70–100       [3.9–5.5]5 units5 units5 units
101–150     [5.6–8.3]6 units6 units6 units
151–200     [8.4–11.1]7 units7 units7 units
201–250     [11.2–13.9]8 units8 units8 units1 unit
251–300     [14.0–16.7]9 units9 units9 units2 units
>300         [>16.7]10 units10 units10 units3 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 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]

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. [89]

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 antidiabetic drugs appears to be most beneficial in people who are diabetic, who still have residual insulin secretory capacity. [93] 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. [93]

Society and culture

Economics: United States

In the United States the unit price of insulin has increased steadily from 1991 to 2019. [94] [95] It rose threefold from 2002 to 2013. [96] Costs can be as high as US$900 per month. [96] Concerns were raised in 2016 of pharmaceutical companies working together to increase prices. [96] 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. [97]

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. [101] Insulin is regulated as a biologic rather than as a drug. [101] The changed status gives the FDA more flexibility for approval and labeling. [102] In July 2021, the FDA approved insulin glargine-yfgn (Semglee), a biosimilar product that contains the long acting analog insulin glargine. [103] Insulin glargine-yfgn is interchangeable and less expensive than the reference product, insulin glargine (Lantus), which had been approved in 2000. [104] The FDA requires that new insulin products are not inferior to existing insulin products with respect to reduction in hemoglobin A1c. [105]

Research

Inhalation

In 2006 the U.S. Food and Drug Administration (FDA) approved the use of Exubera, the first inhalable insulin. [106] 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 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. [108]

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". [107]

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 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. [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 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. [127] 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. [128] 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.

Related Research Articles

Intensive insulin therapy or flexible insulin therapy is a therapeutic regimen for diabetes mellitus treatment. This newer approach contrasts with conventional insulin therapy. Rather than minimize the number of insulin injections per day, the intensive approach favors flexible meal times with variable carbohydrate as well as flexible physical activities. The trade-off is the increase from 2 or 3 injections per day to 4 or more injections per day, which was considered "intensive" relative to the older approach. In North America in 2004, many endocrinologists prefer the term "flexible insulin therapy" (FIT) to "intensive therapy" and use it to refer to any method of replacing insulin that attempts to mimic the pattern of small continuous basal insulin secretion of a working pancreas combined with larger insulin secretions at mealtimes. The semantic distinction reflects changing treatment.

Drugs used in diabetes treat diabetes mellitus by decreasing the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

Diabetes is a chronic disease in cats whereby either insufficient insulin response or insulin resistance leads to persistently high blood glucose concentrations. Diabetes affects up to 1 in 230 cats, and may be becoming increasingly common. Diabetes is less common in cats than in dogs. The condition is treatable, and if treated properly the cat can experience a normal life expectancy. In cats with type 2 diabetes, prompt effective treatment may lead to diabetic remission, in which the cat no longer needs injected insulin. Untreated, the condition leads to increasingly weak legs in cats and eventually to malnutrition, ketoacidosis and/or dehydration, and death.

<span class="mw-page-title-main">Insulin glargine</span> Long-acting insulin

Insulin glargine sold under the brand name Lantus among others is a long-acting modified form of medical insulin, used in the management of type I and type II diabetes. It is injected just under the skin. Effects generally begin an hour after use.

<span class="mw-page-title-main">Pramlintide</span> Diabetes medication

Pramlintide is an injectable amylin analogue drug for diabetes, developed by Amylin Pharmaceuticals. Pramlintide is sold as an acetate salt.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

An insulin analog is any of several types of medical insulin that are altered forms of the hormone insulin, different from any occurring in nature, but still available to the human body for performing the same action as human insulin in terms of controlling blood glucose levels in diabetes. Through genetic engineering of the underlying DNA, the amino acid sequence of insulin can be changed to alter its ADME characteristics. Officially, the U.S. Food and Drug Administration (FDA) refers to these agents as insulin receptor ligands, although they are usually just referred to as insulin analogs or even just insulin.

<span class="mw-page-title-main">NPH insulin</span> Intermediate acting insulin formulation

Neutral Protamine Hagedorn (NPH) insulin, also known as isophane insulin, is an intermediate-acting insulin given to help control blood sugar levels in people with diabetes. It is used by injection under the skin once to twice a day. Onset of effects is typically in 90 minutes and they last for 24 hours. Versions are available that come premixed with a short-acting insulin, such as regular insulin.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin twice daily or once weekly.

Inhalable insulin is a powdered form of insulin, delivered with an inhaler into the lungs where it is absorbed. In general inhaled insulins have been more rapidly absorbed than subcutaneous injected insulin, with faster peak concentration in serum and more rapid metabolism.

Insulin detemir, sold under the brand name Levemir among others, is a long-acting modified form of medical insulin used to treat both type 1 and type 2 diabetes. It is used by injection under the skin. It is effective for up to 24 hours.

<span class="mw-page-title-main">Insulin aspart</span> Rapid-acting man-made insulin

Insulin aspart, sold under the brand name NovoLog, among others, is a modified type of medical insulin used to treat type 1 and type 2 diabetes. It is generally used by injection under the skin but may also be used by injection into a vein. Maximum effect occurs after about 1–3 hours and lasts for 3–5 hours. Generally a longer-acting insulin like insulin NPH is also needed.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand names Victoza and Saxenda among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

<span class="mw-page-title-main">Minimed Paradigm</span> Insulin pumps

MiniMed Paradigm is a series of insulin pumps manufactured by Medtronic for patients with diabetes mellitus. The pump operates with a single AAA battery and uses a piston-plunger pump to infuse a programmed amount of insulin into the patient through a length of tubing. The Paradigm uses a one-way wireless radio frequency link to receive blood sugar measurements from select glucose meters. The Paradigm RT series adds the ability to receive data from a mated continuous blood-glucose monitor. Although the pump can use these measurements to assist in calculating a dose of insulin, no actual change in insulin delivery occurs without manual user-intervention.

<span class="mw-page-title-main">Lente insulin</span> Historical formulation of insulin as medication

Lente insulin was an intermediate duration insulin that is no longer used in humans. The onset of lente insulin is one to two hours after the dose is administered, and the peak effect is approximately 8 to 12 hours after administration, with some effects lasting over 24 hours.

<span class="mw-page-title-main">Insulin degludec</span> Ultralong-acting basal insulin analogue

Insulin degludec (INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. It is administered via subcutaneous injection once daily to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 42 hours, making it a once-daily basal insulin, that is one that provides a base insulin level, as opposed to the fast- and short-acting bolus insulins.

<span class="mw-page-title-main">Saroglitazar</span> Chemical compound

Saroglitazar is a drug for the treatment of type 2 diabetes mellitus and dyslipidemia. It is approved for use in India by the Drug Controller General of India. Saroglitazar is indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, saroglitazar has demonstrated reduction of triglycerides (TG), LDL cholesterol, VLDL cholesterol, non-HDL cholesterol and an increase in HDL cholesterol a characteristic hallmark of atherogenic diabetic dyslipidemia (ADD). It has also shown anti-diabetic medication properties by reducing the fasting plasma glucose and HBA1c in diabetes patients.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that inhibit sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

Insulin glargine/lixisenatide, sold under the brand name Soliqua 100/33 among others, is a fixed-dose combination medication that combines insulin glargine and lixisenatide and is used to treat diabetes.

References

  1. ↑ "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.
  2. ↑ "Inpremzia EPAR". European Medicines Agency. 23 February 2022. Retrieved 3 March 2023.
  3. ↑ "Inpremzia Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 3 4 5 American Society of Health-System Pharmacists. "Insulin Human". www.drugs.com. Archived from the original on 22 October 2016. Retrieved 1 January 2017.
  7. ↑ Mahoney BA, Smith WA, Lo DS, Tsoi K, Tonelli M, Clase CM (April 2005). "Emergency interventions for hyperkalaemia". The Cochrane Database of Systematic Reviews. 2005 (2): CD003235. doi:10.1002/14651858.CD003235.pub2. PMC   6457842 . PMID   15846652.
  8. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  10. ↑ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  11. ↑ "Insulin, Regular, Human – Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  12. 1 2 3 British national formulary: BNF 69 (69 ed.). British Medical Association. 2015. pp. 464–472. ISBN   978-0-85711-156-2.
  13. ↑ Baeshen NA, Baeshen MN, Sheikh A, Bora RS, Ahmed MM, Ramadan HA, et al. (October 2014). "Cell factories for insulin production". Microbial Cell Factories. 13 (1): 141. doi: 10.1186/s12934-014-0141-0 . PMC   4203937 . PMID   25270715.
  14. 1 2 "Frederick Banting, Charles Best, James Collip, and John Macleod". Science History Institute. June 2016. Archived from the original on 1 December 2018. Retrieved 22 August 2018.
  15. ↑ Fleishman JL, Kohler JS, Schindler S (2009). Casebook for The Foundation a Great American Secret. New York: PublicAffairs. p. 22. ISBN   978-0-7867-3425-2. Archived from the original on 18 January 2017.
  16. ↑ "Recherche sur le rôle du pancréas dans l'assimilation nutritive | The Discovery and Early Development of Insulin". insulin.library.utoronto.ca. Archived from the original on 1 August 2020. Retrieved 26 March 2020.
  17. ↑ Banting FG (17–29 May 1922). "Chart for James Havens". University of Toronto Libraries. Archived from the original on 1 August 2020. Retrieved 9 January 2019.
  18. ↑ Woodbury DO (February 1963). "Please save my son!". University of Toronto Libraries. Archived from the original on 29 May 2019. Retrieved 9 January 2019.
  19. ↑ Banting FG (16 August 1922). "Chart for Elizabeth Hughes". University of Toronto Libraries. Archived from the original on 10 January 2019. Retrieved 9 January 2019.
  20. ↑ Zuger A (4 October 2010). "Rediscovering the First Miracle Drug". New York Times . Archived from the original on 16 December 2014. Retrieved 6 October 2010.
  21. ↑ University of Toronto Libraries (1923). "Miss Collier's recovery". University of Toronto Libraries. Archived from the original on 10 January 2019. Retrieved 9 January 2019.
  22. ↑ Vecchio I, Tornali C, Bragazzi NL, Martini M (23 October 2018). "The Discovery of Insulin: An Important Milestone in the History of Medicine". Frontiers in Endocrinology. 9: 613. doi: 10.3389/fendo.2018.00613 . PMC   6205949 . PMID   30405529.
  23. ↑ Jones K (March 2000). "Insulin coma therapy in schizophrenia". Journal of the Royal Society of Medicine. 93 (3): 147–9. doi:10.1177/014107680009300313. PMC   1297956 . PMID   10741319.
  24. ↑ Ghazavi MK, Johnston GA (May–June 2011). "Insulin allergy". Clinics in Dermatology. 29 (3): 300–5. doi:10.1016/j.clindermatol.2010.11.009. PMID   21496738.
  25. ↑ Ip KH, Koch K, Lamont D (July 2021). "Cutaneous amyloidoma secondary to repeated insulin injections". Postgraduate Medical Journal. 97 (1149): 474. doi:10.1136/postgradmedj-2020-138428. PMID   32817579. S2CID   221221349.
  26. ↑ Hanefeld M (December 2014). "Use of insulin in type 2 diabetes: what we learned from recent clinical trials on the benefits of early insulin initiation". Diabetes & Metabolism. 40 (6): 391–399. doi: 10.1016/j.diabet.2014.08.006 . PMID   25451189.
  27. ↑ Owens DR (September 2013). "Clinical evidence for the earlier initiation of insulin therapy in type 2 diabetes". Diabetes Technology & Therapeutics. 15 (9): 776–785. doi:10.1089/dia.2013.0081. PMC   3757533 . PMID   23786228.
  28. ↑ Takiya L, Dougherty T. "Pharmacist's Guide to Insulin Preparations: A Comprehensive Review". Pharmacy Times. Archived from the original on 15 July 2011. Retrieved 2 August 2010.
  29. 1 2 Nasrallah SN, Reynolds LR (1 April 2012). "Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?". Clinical Medicine Insights. Endocrinology and Diabetes. 5: 31–7. doi:10.4137/CMED.S9494. PMC   3411522 . PMID   22879797.
  30. 1 2 3 Galdo JA, Thurston MM, Bourg CA (April 2014). "Clinical Considerations for Insulin Pharmacotherapy in Ambulatory Care, Part One: Introduction and Review of Current Products and Guidelines". Clinical Diabetes. 32 (2): 66–75. doi:10.2337/diaclin.32.2.66. PMC   4485243 . PMID   26130864.
  31. ↑ Papatheodorou I, Petrovs R, Thornton JM (November 2014). "Comparison of the mammalian insulin signalling pathway to invertebrates in the context of FOXO-mediated ageing". Bioinformatics. 30 (21): 2999–3003. doi:10.1093/bioinformatics/btu493. PMC   4201157 . PMID   25064569.
  32. ↑ "Insulin Basics". American Diabetes Association. Archived from the original on 14 February 2014. Retrieved 22 August 2018.
  33. ↑ McCall AL (March 2012). "Insulin therapy and hypoglycemia". Endocrinology and Metabolism Clinics of North America. 41 (1): 57–87. doi:10.1016/j.ecl.2012.03.001. PMC   4265808 . PMID   22575407.
  34. ↑ Davidson MB (July 2015). "Insulin Therapy: A Personal Approach". Clinical Diabetes. 33 (3): 123–35. doi:10.2337/diaclin.33.3.123. PMC   4503941 . PMID   26203205.
  35. ↑ Wendt D (1 November 2013). "Two tons of pig parts: Making insulin in the 1920s". National Museum of American History. Archived from the original on 27 October 2018. Retrieved 22 August 2018.
  36. ↑ Kehoe A (1989). "The story of biosynthetic human insulin". In Sikdar SK, Bier M, Todd PW (eds.). Frontiers in Bioprocesssing. Boca Raton, FL: CRC Press. ISBN   978-0-8493-5839-5. Archived from the original on 3 August 2020. Retrieved 22 August 2018.
  37. 1 2 3 Crasto W, Jarvis J, Davies M (9 September 2016). "Chapter 2 Existing insulin therapies". Handbook of Insulin Therapies. Springer. pp. 15–18. ISBN   978-3-319-10939-8. Archived from the original on 3 August 2020. Retrieved 22 August 2018.
  38. ↑ Altman LK (30 October 1982). "A New Insulin Given Approval For Use In U.S." The New York Times. Archived from the original on 23 August 2018. Retrieved 23 August 2018.
  39. ↑ Bowden ME (2018). "Old Brew, New Brew". Distillations. Science History Institute. 4 (2): 8–11. Archived from the original on 21 August 2018. Retrieved 21 August 2018.
  40. ↑ Novolog Patient Leaflet
  41. ↑ Diabetes Atlas (2nd ed.). Brussels: International Diabetes Federation. 2004. Archived from the original on 3 August 2012.
  42. ↑ Brown P (9 March 1999). "Diabetics not told of insulin risk". Guardian. Archived from the original on 4 February 2017.
  43. ↑ "Position Statement". Brussels: International Diabetes Federation. March 2005. Archived from the original on 4 May 2009.
  44. ↑ "Overview". Vetsulin-Veterinary. Archived from the original on 21 January 2010.
  45. 1 2 3 American Diabetes Association (20 December 2019). "Pharmacologic Approaches to Glycemic Treatment". Diabetes Care. 43 (Supplement 1): S98–S110. doi: 10.2337/dc20-S009 . PMID   31862752.
  46. ↑ American Diabetes Association (20 December 2019). "Diabetes Technology: Standards of Medical Care in Diabetes—2020". Diabetes Care. 43 (Supplement 1): S77–S88. doi: 10.2337/dc20-S007 . PMID   31862750.
  47. ↑ Sorli C (July 2014). "Identifying and meeting the challenges of insulin therapy in type 2 diabetes". Journal of Multidisciplinary Healthcare. 7: 267–82. doi: 10.2147/JMDH.S64084 . PMC   4086769 . PMID   25061317.
  48. ↑ Weiss M, Steiner DF, Philipson LH (1 February 2014). "Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships". In Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al. (eds.). Endotext. MDText.com, Inc. PMID   25905258.
  49. ↑ Richter B, Neises G (January 2005). "'Human' insulin versus animal insulin in people with diabetes mellitus". The Cochrane Database of Systematic Reviews. 2010 (1): CD003816. doi:10.1002/14651858.CD003816.pub2. PMC   8406912 . PMID   15674916.
  50. 1 2 IQwiG (German Institute for Quality and Efficiency in Health Care) (6 June 2007). "Rapid-acting insulin analogues in the treatment of diabetes mellitus type 1: Superiority Not Proven". Archived from the original on 19 July 2011. Retrieved 2 August 2010.
  51. 1 2 Banerjee S, Tran K, Li H, Cimon K, Daneman D, Simpson S, Campbell K (March 2007). "Short-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost effectiveness". Canadian Agency for Drugs and Technologies in Health. 87: 1–55. Archived from the original on 4 November 2019. Retrieved 4 November 2019.
  52. ↑ "Biodel Inc. Announces VIAject(TM) Data at Oral Presentation at the American Diabetes Association Meeting" (PDF). Archived from the original (PDF) on 31 October 2008.
  53. ↑ "FDA Accepts VIAject NDA for Review". Archived from the original on 6 August 2011.
  54. ↑ Krzymien J, Ladyzynski P (March 2019). "Insulin in Type 1 and Type 2 Diabetes-Should the Dose of Insulin Before a Meal be Based on Glycemia or Meal Content?". Nutrients. 11 (3): 607. doi: 10.3390/nu11030607 . PMC   6471836 . PMID   30871141.
  55. ↑ Saleem F, Sharma A (2022). "NPH Insulin". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   31751050 . Retrieved 4 January 2023.
  56. ↑ Cunningham AM, Freeman AM (2022). Glargine Insulin. Treasure Island (FL): StatPearls Publishing. PMID   32491688 . Retrieved 4 January 2023.{{cite book}}: |work= ignored (help)
  57. ↑ "Insulin detemir". PubChem. U.S. National Library of Medicine. Retrieved 4 January 2023.
  58. ↑ "DailyMed - NOVOLOG MIX 70/30- insulin aspart injection, suspension". dailymed.nlm.nih.gov. Retrieved 4 January 2023.
  59. ↑ Fonte P, Araújo F, Reis S, Sarmento B (March 2013). "Oral insulin delivery: how far are we?". Journal of Diabetes Science and Technology. 7 (2): 520–531. doi:10.1177/193229681300700228. PMC   3737653 . PMID   23567010.
  60. ↑ American Diabetes Association (January 2004). "Insulin administration". Diabetes Care. 27 (suppl_1): S106–S109. doi: 10.2337/diacare.27.2007.s106 . PMID   14693942.
  61. 1 2 Berget C, Messer LH, Forlenza GP (August 2019). "A Clinical Overview of Insulin Pump Therapy for the Management of Diabetes: Past, Present, and Future of Intensive Therapy". Diabetes Spectrum. 32 (3): 194–204. doi:10.2337/ds18-0091. PMC   6695255 . PMID   31462873.
  62. ↑ "Early definitions of a unit of insulin were based on a rabbit's physiological response. – Treating Diabetes". Treating Diabetes. Archived from the original on 8 September 2017. Retrieved 18 June 2017.
  63. ↑ "Mission statement". WHO Expert Committee on Biological Standardization. Archived from the original on 27 January 2012.
  64. ↑ Thota S, Akbar A (2022). "Insulin". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   32809523 . Retrieved 4 January 2023.
  65. ↑ Bird SR, Hawley JA (March 2017). "Update on the effects of physical activity on insulin sensitivity in humans". BMJ Open Sport & Exercise Medicine. 2 (1): e000143. doi:10.1136/bmjsem-2016-000143. PMC   5569266 . PMID   28879026.
  66. ↑ Scheiner G, Boyer BA (July 2005). "Characteristics of basal insulin requirements by age and gender in Type-1 diabetes patients using insulin pump therapy". Diabetes Research and Clinical Practice. 69 (1): 14–21. doi:10.1016/j.diabres.2004.11.005. PMID   15955383.
  67. ↑ Munguia C, Correa R (2022). Regular Insulin. Treasure Island (FL): StatPearls Publishing. PMID   31971734 . Retrieved 5 January 2023.{{cite book}}: |work= ignored (help)
  68. ↑ Joslin EP (1934). A Diabetic Manual for the Mutual Use of Doctor and Patient. Philadelphia, PA: Lea & Febiger. pp.  108.
  69. 1 2 Munshi MN, Florez H, Huang ES, Kalyani RR, Mupanomunda M, Pandya N, Swift CS, Taveira TH, Haas LB (February 2016). "Management of Diabetes in Long-term Care and Skilled Nursing Facilities: A Position Statement of the American Diabetes Association". Diabetes Care. 39 (2): 308–18. doi: 10.2337/dc15-2512 . PMC   5317234 . PMID   26798150.
  70. ↑ McDonnell ME, Umpierrez GE (March 2012). "Insulin therapy for the management of hyperglycemia in hospitalized patients". Endocrinology and Metabolism Clinics of North America. 41 (1): 175–201. doi:10.1016/j.ecl.2012.01.001. PMC   3738170 . PMID   22575413.
  71. ↑ Corsino L, Dhatariya K, Umpierrez G (2000). "Management of Diabetes and Hyperglycemia in Hospitalized Patients". In De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A (eds.). Endotext. South Dartmouth (MA): MDText.com, Inc. PMID   25905318. Archived from the original on 28 August 2021. Retrieved 23 August 2018.
  72. ↑ Zaman Huri H, Permalu V, Vethakkan SR (2 September 2014). "Sliding-scale versus basal-bolus insulin in the management of severe or acute hyperglycemia in type 2 diabetes patients: a retrospective study". PLOS ONE. 9 (9): e106505. Bibcode:2014PLoSO...9j6505Z. doi: 10.1371/journal.pone.0106505 . PMC   4152280 . PMID   25181406.
  73. ↑ Umpierrez GE, Palacio A, Smiley D (July 2007). "Sliding scale insulin use: myth or insanity?". The American Journal of Medicine. 120 (7): 563–7. doi:10.1016/j.amjmed.2006.05.070. PMID   17602924.
  74. ↑ Hirsch IB (January 2009). "Sliding scale insulin—time to stop sliding" (PDF). JAMA. 301 (2): 213–4. doi:10.1001/jama.2008.943. PMID   19141770. Archived (PDF) from the original on 3 November 2019. Retrieved 4 November 2019.
  75. 1 2 AMDA – The Society for Post-Acute and Long-Term Care Medicine (February 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation , AMDA – The Society for Post-Acute and Long-Term Care Medicine, archived from the original on 13 September 2014, retrieved 10 February 2013, which cites:
  76. ↑ Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH (October 2018). "The Pathophysiology of Gestational Diabetes Mellitus". International Journal of Molecular Sciences. 19 (11): 3342. doi: 10.3390/ijms19113342 . PMC   6274679 . PMID   30373146.
  77. ↑ Subiabre M, Silva L, Toledo F, Paublo M, López MA, Boric MP, Sobrevia L (September 2018). "Insulin therapy and its consequences for the mother, foetus, and newborn in gestational diabetes mellitus". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1864 (9 Pt B): 2949–2956. doi: 10.1016/j.bbadis.2018.06.005 . PMID   29890222. S2CID   48362789.
  78. 1 2 Alexopoulos AS, Blair R, Peters AL (May 2019). "Management of Preexisting Diabetes in Pregnancy: A Review". JAMA. 321 (18): 1811–1819. doi:10.1001/jama.2019.4981. PMC   6657017 . PMID   31087027.
  79. ↑ Dotinga R (24 August 2001). "Athletes Turn to Insulin to Boost Performance Experts warn of danger to non-diabetics". HealthDayNews. Archived from the original on 23 August 2018. Retrieved 22 August 2018.
  80. ↑ Sonksen PH (July 2001). "Insulin, growth hormone and sport". The Journal of Endocrinology. 170 (1): 13–25. doi: 10.1677/joe.0.1700013 . PMID   11431133.
  81. 1 2 Evans PJ, Lynch RM (August 2003). "Insulin as a drug of abuse in body building". British Journal of Sports Medicine. 37 (4): 356–357. doi: 10.1136/bjsm.37.4.356 . PMC   1724679 . PMID   12893725.
  82. ↑ Kakutani M (23 March 2006). "Barry Bonds and Baseball's Steroids Scandal". The New York Times. Archived from the original on 28 November 2018. Retrieved 22 August 2018.
  83. ↑ "Barry Bonds steroids timeline". ESPN.com. 7 December 2007. Archived from the original on 2 December 2018. Retrieved 22 August 2018.
  84. ↑ Holt RI, Sönksen PH (June 2008). "Growth hormone, IGF-I and insulin and their abuse in sport". British Journal of Pharmacology. 154 (3): 542–56. doi:10.1038/bjp.2008.99. PMC   2439509 . PMID   18376417.
  85. ↑ Reitman V (8 September 2003). "Bodybuilders and insulin Some weightlifters are using the hormone to gain muscle, a practice that poses serious risks, doctors warn". Los Angeles Times. Archived from the original on 27 November 2018. Retrieved 22 August 2018.
  86. ↑ Crosbie J (21 November 2017). "35-Year-Old Bodybuilder's Sudden Death Raises Questions About Insulin Use Ghent Wakefield was an aspiring WWE wrestler". Men's Health. Archived from the original on 23 August 2018. Retrieved 22 August 2018.
  87. 1 2 3 Graham MR, Evans P, Davies B, Baker JS (June 2008). "AAS, growth hormone, and insulin abuse: psychological and neuroendocrine effects". Therapeutics and Clinical Risk Management. 4 (3): 587–597. doi: 10.2147/tcrm.s2495 . PMC   2500251 . PMID   18827854.
  88. ↑ Lim VS, Yarasheski KE, Crowley JR, Fangman J, Flanigan M (September 2003). "Insulin is protein-anabolic in chronic renal failure patients". Journal of the American Society of Nephrology. 14 (9): 2297–2304. doi: 10.1097/01.ASN.0000085590.83005.A0 . PMID   12937306. S2CID   20467179.
  89. 1 2 Klein-Schwartz W, Stassinos GL, Isbister GK (March 2016). "Treatment of sulfonylurea and insulin overdose". British Journal of Clinical Pharmacology. 81 (3): 496–504. doi:10.1111/bcp.12822. PMC   4767194 . PMID   26551662.
  90. ↑ De León DD, Stanley CA (December 2013). "Determination of insulin for the diagnosis of hyperinsulinemic hypoglycemia". Best Practice & Research. Clinical Endocrinology & Metabolism. 27 (6): 763–9. doi:10.1016/j.beem.2013.06.005. PMC   4141553 . PMID   24275188.
  91. ↑ Thomas A, Thevis M, Delahaut P, Bosseloir A, Schänzer W (March 2007). "Mass spectrometric identification of degradation products of insulin and its long-acting analogues in human urine for doping control purposes". Analytical Chemistry. 79 (6): 2518–24. doi:10.1021/ac062037t. PMID   17300174.
  92. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 775–779.
  93. 1 2 Scheen AJ, Castillo MJ, Lefèbvre PJ (1993). "Combination of oral antidiabetic drugs and insulin in the treatment of non-insulin-dependent diabetes". Acta Clinica Belgica. 48 (4): 259–68. doi:10.1080/17843286.1993.11718317. PMID   8212978.
  94. ↑ Luo J, Avorn J, Kesselheim AS (October 2015). "Trends in Medicaid Reimbursements for Insulin From 1991 Through 2014". JAMA Internal Medicine . 175 (10): 1681–6. doi:10.1001/jamainternmed.2015.4338. PMID   26301721.
  95. ↑ Zargar AH, Kalra S, K M PK, Murthy S, Negalur V, Rajput R, et al. (June 2022). "Rising cost of insulin: A deterrent to compliance in patients with diabetes mellitus" . Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 16 (8): 102528. doi:10.1016/j.dsx.2022.102528. PMID   35863268. S2CID   249329716.
  96. 1 2 3 Thomas, Katie (30 January 2017). "Drug Makers Accused of Fixing Prices on Insulin" . The New York Times . Archived from the original on 8 September 2017. Retrieved 9 July 2023.
    full text available via archive link without subscription
  97. ↑ Abutaleb Y (30 January 2019). "U.S. lawmakers request info from insulin makers on rising prices". Reuters. Archived from the original on 31 January 2019. Retrieved 1 February 2019.
  98. ↑ "Here's Why Insulin and Other Drugs Are Cheaper in Canada". 28 July 2019. Archived from the original on 25 February 2021. Retrieved 13 January 2021.
  99. ↑ "California To Make Its Own Insulin In Fight Against Inflated Drug Prices". IFLScience. 8 July 2022. Archived from the original on 9 July 2022. Retrieved 11 July 2022.
  100. ↑ "Free prescriptions (England)". Diabetes UK. Retrieved 21 November 2022. If you use insulin or medicine to manage your diabetes, ... you don't pay for any item you're prescribed.
  101. 1 2 "Definition of the Term "Biological Product"". Federal Register. 21 February 2020. Archived from the original on 8 August 2022. Retrieved 8 August 2022.
  102. ↑ "Labeling Requirements for Human Prescription Drug and Biological Products – OMB 0910-0572". OMB. 31 January 2022. Archived from the original on 13 August 2022. Retrieved 8 August 2022.
  103. ↑ "Drug Approval Package: Semglee". U.S. Food and Drug Administration (FDA). 2 September 2021. Archived from the original on 27 May 2022. Retrieved 8 August 2022.
  104. ↑ "Drug Approval Package: Lantus (Insulin Glargine [rDNA Origin]) NDA #21-081". U.S. Food and Drug Administration (FDA). 20 November 2001. Archived from the original on 13 August 2022. Retrieved 8 August 2022.
  105. ↑ Misbin, RI (2022), Insulin – History from an FDA Insider, Washington, DC: Politics and Prose Publishing
  106. ↑ "FDA approval of Exubera inhaled insulin". U.S. Food and Drug Administration (FDA). Archived from the original on 26 December 2008.
  107. 1 2 NICE (21 June 2006). "Diabetes (type 1 and 2), Inhaled Insulin – Appraisal Consultation Document (second)". Archived from the original on 7 July 2006. Retrieved 26 July 2006.
  108. ↑ Cefalu WT, Skyler JS, Kourides IA, Landschulz WH, Balagtas CC, Cheng S, Gelfand RA (February 2001). "Inhaled human insulin treatment in patients with type 2 diabetes mellitus". Annals of Internal Medicine. 134 (3): 203–7. doi:10.7326/0003-4819-134-3-200102060-00011. PMID   11177333. S2CID   25294223.
  109. ↑ "Novo Nordisk refocuses its activities within inhaled insulin and discontinues the development of AERx". 14 January 2008. Archived from the original on 7 September 2012.
  110. ↑ "Lilly Ends Effort to Develop an Inhaled Insulin Product". The New York Times. 8 March 2008. Archived from the original on 12 September 2017. Retrieved 22 February 2017.
  111. 1 2 Mohanty RR, Das S (April 2017). "Inhaled Insulin - Current Direction of Insulin Research". Journal of Clinical and Diagnostic Research. 11 (4): OE01–OE02. doi:10.7860/JCDR/2017/23626.9732. PMC   5449846 . PMID   28571200.
  112. ↑ Klonoff DC (November 2014). "Afrezza inhaled insulin: the fastest-acting FDA-approved insulin on the market has favorable properties". Journal of Diabetes Science and Technology. 8 (6): 1071–1073. doi:10.1177/1932296814555820. PMC   4455463 . PMID   25355710.
  113. ↑ Arora A, Hakim I, Baxter J, Rathnasingham R, Srinivasan R, Fletcher DA, Mitragotri S (March 2007). "Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets". Proceedings of the National Academy of Sciences of the United States of America. 104 (11): 4255–60. Bibcode:2007PNAS..104.4255A. doi: 10.1073/pnas.0700182104 . PMC   1838589 . PMID   17360511.
  114. ↑ Guo L, Xiao X, Sun X, Qi C (January 2017). "Comparison of jet injector and insulin pen in controlling plasma glucose and insulin concentrations in type 2 diabetic patients". Medicine. 96 (1): e5482. doi:10.1097/MD.0000000000005482. PMC   5228650 . PMID   28072690.
  115. ↑ Dixit N, Bali V, Baboota S, Ahuja A, Ali J (January 2007). "Iontophoresis – an approach for controlled drug delivery: a review". Current Drug Delivery. 4 (1): 1–10. doi:10.2174/156720107779314802. PMID   17269912. Archived from the original on 28 August 2021. Retrieved 4 November 2019.
  116. ↑ Yu J, Zhang Y, Ye Y, DiSanto R, Sun W, Ranson D, Ligler FS, Buse JB, Gu Z (July 2015). "Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery". Proceedings of the National Academy of Sciences of the United States of America. 112 (27): 8260–5. Bibcode:2015PNAS..112.8260Y. doi: 10.1073/pnas.1505405112 . PMC   4500284 . PMID   26100900.
  117. ↑ Zhang Y, Yu J, Kahkoska AR, Wang J, Buse JB, Gu Z (January 2019). "Advances in transdermal insulin delivery". Advanced Drug Delivery Reviews. 139: 51–70. doi:10.1016/j.addr.2018.12.006. PMC   6556146 . PMID   30528729.
  118. ↑ Hallschmid M (April 2021). "Intranasal insulin". Journal of Neuroendocrinology. 33 (4): e12934. doi: 10.1111/jne.12934 . PMID   33506526. S2CID   231770007.
  119. ↑ "Oral Insulin – Fact or Fiction? – Resonance – May 2003". Archived from the original on 9 September 2007. Retrieved 23 September 2007.
  120. ↑ Kalra S, Kalra B, Agrawal N (November 2010). "Oral insulin". Diabetology & Metabolic Syndrome. 2: 66. doi: 10.1186/1758-5996-2-66 . PMC   2987915 . PMID   21059246.
  121. ↑ Card JW, Magnuson BA (December 2011). "A review of the efficacy and safety of nanoparticle-based oral insulin delivery systems". American Journal of Physiology. Gastrointestinal and Liver Physiology. 301 (6): G956–G967. doi:10.1152/ajpgi.00107.2011. PMID   21921287.
  122. ↑ Chen MC, Sonaje K, Chen KJ, Sung HW (December 2011). "A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery". Biomaterials. 32 (36): 9826–38. doi:10.1016/j.biomaterials.2011.08.087. PMID   21925726.
  123. ↑ Fonte P, Araújo F, Reis S, Sarmento B (March 2013). "Oral insulin delivery: how far are we?". Journal of Diabetes Science and Technology. 7 (2): 520–31. doi:10.1177/193229681300700228. PMC   3737653 . PMID   23567010.
  124. ↑ Iyer H, Khedkar A, Verma M (March 2010). "Oral insulin – a review of current status". Diabetes, Obesity & Metabolism. 12 (3): 179–85. doi:10.1111/j.1463-1326.2009.01150.x. PMID   20151994. S2CID   24632760. Archived from the original on 12 July 2021. Retrieved 4 November 2019.
  125. ↑ Pozzilli P, Raskin P, Parkin CG (February 2010). "Review of clinical trials: update on oral insulin spray formulation". Diabetes, Obesity & Metabolism. 12 (2): 91–6. doi:10.1111/j.1463-1326.2009.01127.x. PMID   19889002. S2CID   36965357. Archived from the original on 28 August 2021. Retrieved 23 August 2018.
  126. ↑ "First Oral Insulin For Diabetics Takes Major Step Towards FDA Approval". Oramed.com. 16 May 2018. Archived from the original on 23 August 2018. Retrieved 23 August 2018.
  127. ↑ Gangemi A, Salehi P, Hatipoglu B, Martellotto J, Barbaro B, Kuechle JB, Qi M, Wang Y, Pallan P, Owens C, Bui J, West D, Kaplan B, Benedetti E, Oberholzer J (June 2008). "Islet transplantation for brittle type 1 diabetes: the UIC protocol". American Journal of Transplantation. 8 (6): 1250–61. doi: 10.1111/j.1600-6143.2008.02234.x . PMID   18444920.
  128. ↑ Zhu YL, Abdo A, Gesmonde JF, Zawalich KC, Zawalich W, Dannies PS (August 2004). "Aggregation and lack of secretion of most newly synthesized proinsulin in non-beta-cell lines". Endocrinology. 145 (8): 3840–9. doi: 10.1210/en.2003-1512 . PMID   15117881.
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