Insulin therapy

]Insulin therapy, refers to treatment of diabetes by administration ofexogenous insulin.

Insulin is used medically to treat some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with Type 2 diabetes mellitus are insulin resistant, have relatively low insulin production, or both; some patients with Type 2 diabetes may eventually require insulin when other medications fail to control blood glucose levels adequately.[

Insulin is required for all animal life (excluding certain insects). Its mechanism of action is almost identical in nematode worms (e.g.C. elegans), fish, and mammals, and it is a protein that has been highly conserved across evolutionary time. Insulin must be administered to patients who experience such a deprivation. Clinically, this condition is called diabetes mellitus type 1.

The initial sources of insulin for clinical use in humans were cow, horse, pig or fish pancreases. Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Differences in suitability of beef-, pork-, or fish-derived insulin for individual patients have historically been due to lower preparation purity resulting in allergic reactions to the presence of non-insulin substances. Though purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods, but minor allergic reactions still occur occasionally, although the same types of allergic reactions have also been known to occur in response to synthetic "human" insulin varieties. Insulin production from animal pancreases was widespread for decades, but very few patients today rely on insulin from animal sources, largely because few pharmaceutical companies sell it anymore.

Synthetic "human" insulin is now manufactured for widespread clinical use using genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities. Eli Lilly marketed the first such insulin, Humulin, in 1982. 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. 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.

Genentech developed the technique Lilly used to produce Humulin, although the company never commercially marketed the product themselves.Novo Nordisk has also developed a genetically engineered insulin independently. 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.[1] A majority of insulin used clinically today is produced this way, although the clinical evidence has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Also, the International Diabetes Federation's position statement 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."[2]

Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic "human" insulins or their analogs. 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.

There are several problems with insulin as a clinical treatment for diabetes:

Mode of administration.
Selecting the 'right' dose and timing.
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 patients to inject whenever they eat carbohydrate or have a high blood glucose reading.
It is dangerous in case of mistake (most especially 'too much' insulin).

In late 2003, Wockhardt commenced manufacture of a yeast-based insulin costing $3.25 in India claiming it eliminates the risk of contracting diseases such as BSE and CJD associated with insulin derived from pigs and cattle.[7] However, the company continues to manufacture insulin derived from pigs in the United Kingdom

Unlike many medicines, insulin cannot be taken orally. Like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments (even single amino acid components), whereupon all 'insulin 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.

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. Patients who wish to reduce repeated skin puncture of insulin injections often use an injection port in conjunction with syringes.

Administration schedules often attempt to mimic the physiologic secretion of insulin by the pancreas. Hence, both a long-acting insulin and a short-acting insulin are typically used.


[edit] Insulin pump
Main article: Insulin pump
Insulin pumps are a reasonable solution for some. Advantages to the patient 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.

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.

As with injections, if too much insulin is delivered or the patient eats less than he or she dosed for, there will be hypoglycemia. On the other hand, if too little insulin is delivered, there will be hyperglycemia. Both can be life-threatening. In addition, indwelling catheters pose the risk of infection and ulceration, and some patients 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. However, some patients with diabetes are capable of keeping their glucose in reasonable control only with an insulin pump.


[edit] Inhalation
Main article: Inhalable insulin
In 2006 the U.S. Food and Drug Administration approved the use of Exubera, the first inhalable insulin.[8] It has been withdrawn from the market by its maker as of 3Q 2007, due to lack of acceptance.

Inhaled insulin has 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.[9] When patients were switched from injected to inhaled insulin, no significant difference was found in HbA1c levels over three months. Accurate dosing is still a problem, although patients showed no significant weight gain or pulmonary function decline over the length of the trial, when compared to the baseline.[10] Following its commercial launch in 2005 in the UK, 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".[9]

In January 2008, the world's largest insulin manufacturer, Novo Nordisk A/S, 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.[11] Similarly, Eli Lilly and Company ended its efforts to develop its Air inhaled insulin in March 2008.[12] MannKind Corp. (whose majority owner, Alfred E. Mann, remained optimistic about the concept.[13]


[edit] Transdermal
There are several methods for transdermal delivery of insulin. Pulsatile insulin uses microjets to pulse insulin into the patient, mimicking the physiological secretions of insulin by the pancreas.[14] Jet injection had different insulin delivery peaks and durations as compared to needle injection. Some diabetics find control possible with jet injectors, but not with hypodermic injection.

Both electricity using iontophoresis[15] 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.

[edit] Oral insulin
The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. However, insulin is a protein, which is digested in the stomach and gut and in order to be effective at controlling blood sugar, can not be taken orally.

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. As of 2004, no products appear to be successful enough yet to bring to market.[17]

A Connecticut-based biopharmaceutical company called Biodel, Inc. is developing what it calls VIAtab, an oral formulation of insulin designed to be administered sublingually. This therapy is a tablet that dissolves in minutes when placed under the tongue. In a Phase I study, VIAtab delivered insulin to the blood stream quickly and resembled the first-phase insulin release spike found in healthy individuals. The company claims that an oral insulin therapy would be more convenient than currently available injectable or inhalable therapies, and they expect that convenience to result in increased insulin usage among the currently underserved early-stage patients with Type 2 diabetes, thus helping to create better long-term outcomes for that patient population.[18]

Oramed Pharmaceuticals, Inc., a biotechnology company based out of Jerusalem, Israel is currently conducting Phase 2B clinical trials of its oral insulin capsule, ORMD-0801 on 30 patients diagnosed with type 2 diabetes.[19]. An article published in the Journal of Diabetes Science and Technology indicates that Oramed's platform technology has two components: 1) A chemical make-up that protects Insulin during passage through the gastrointestinal tract, and 2) Absorption enhancers so that insulin could be absorbed by the intestine. Oramed Pharmaceuticals, Inc. through Phase 1 clinical trials, has demonstrated that its oral insulin is safe, well tolerated, and has consistently reduced glucose and c-peptide levels in patients.[20]

Australian biopharmaceutical company, Apollo Life Sciences, plans to enter the Phase I trial of its oral insulin tablet in mid-2008.[21]

Biocon, Asia's largest Biopharmaceutical company, based out of Bangalore, India is also developing an Oral Insulin Product. It has just completed Phase IIa trials.