Insulin therapy

Insulin treat almost all patients achrestic and many patients with an insulin diabetes mellitus. If necessary insulin can be entered i.v. and in oil, but for prolonged, lifelong treatment use mainly p / to an injection. P / to an injection of insulin don't recreate completely a picture of physiological secretion of this hormone. First, from a hypodermic fat insulin is soaked up gradually that doesn't reproduce physiological fast increase of concentration of hormone at meal with the subsequent recession of concentration. Secondly, from a hypodermic fat insulin gets not to portal system of a liver, and to a systemic blood stream. Therefore immediately insulin doesn't affect a hepatic metabolism. Nevertheless at accurate keeping of medical prescriptions treatment can be very successful.

Drugs of insulin have the different duration of action (short action, average duration of action and long action) and a different parentage (the human, bull, pork, admixed bull/pork). Now are available and human insulin’s which receive by methods of genetic engineering are widely used. Pork insulin differs from human in one amino acid (alanine instead of treonin in situation 30 V-chains, that is on its S-extremity). Bull differs from pork and human in two more amino acids (an alanine and valine instead of a treonin and isoleucinum in provisions 8 and 10 A-chains). To the middle of the 1970th drugs of insulin contained pro-insulin, glyuca like peptides, a pancreatic polypeptide, somatostatin and the VIP. Then in the market there were high cleaning pork insulin’s which were deprived of these impurity. In the late seventies all efforts concentrated on receiving recombinant human insulin.

In the last decade of the 20th century human insulin became choice drug in treatment of a diabetes mellitus.

Because of differences in the amino-acid sequence human, pork and bull insulin’s aren't identical on the physical and chemical properties. We will dissolve the human insulin received by methods of genetic engineering in water better, than pork as has additional hydroxyl group (as a part of treonin). Almost all drugs of human insulin have neutral pH and therefore are stable: they can be held till some days at the room temperature.

Units

Druggists measure doses and concentration of insulin by units (piece). This tradition went since those times when drugs of hormone were saturated with impurity and they needed to be standardized on biological activity. One unit of insulin are amount of hormone which at a hungry rabbit reduces concentration of a glucose in a blood to 45 mg of % (2.5 mmol/l). Now as the international standard serves the admixed bull/pork insulin with specific activity of 24 pieces/mg. Homogeneous drugs of human insulin have specific activity of 25 — 30 pieces/mg. Almost everything the drugs of insulin produced now represent solutions or suspensions with concentration of 100 pieces/ml (3,6 mg/ml, or 0,6 mmol/l). For patients with insulin resistance more strong solutions (500 pieces/ml) are issued.

Classification of insulin drugs

Insulin of short action are solutions crystalline Zincum-insulin, usually in the buffer with neutral pH. These drugs begin to work quicker than others, but have the smallest duration of action (tab. 61.3). They are usually entered ď / to in 30 — 45 min. prior to food (Dimitriadis and Gerich, 1983). Insulin of short action can also be entered i.v. and in oil. After i.v. jet introduction concentration of a glucose in a blood quickly falls, the maximum effect develops in 20 — 30 min. Drug quickly is removed from a blood, and hormones (a glucagon, catecholamins, a hydrocortisone and STG) in 2 — 3 h restore glucose level to initial. At secretion disturbances of hormones (for example, at the patients with a diabetes mellitus having vegetative neuropathy) concentration of a glucose in plasma remains low within many hours after jet administration of insulin in a dose of 0,15 pieces/kg as effect of insulin on cells continues after its excision from a blood for a long time. At a diabetic ketoacidosis, during resuscitation and an intensive care, and also in those situations when the need for insulin quickly changes (the periope-ratsionny period, labors), infusion of insulin of short action is expedient i.v.

At stable state insulin of short action is usually prescribed in a look ď / to injections in a combination with insulin of average duration of action or long action. Insulin of short action is the only drugs which suit for wearable batchers of insulin. Batchers load with buffering drugs that allows avoiding a crystallization of hormone in a hypodermic catheter during infusion which is carried out with very small rate (Loug-heed et al., 1980).

In the insulin of short action of a molecule of hormone produced nowadays are polymerized and represent hex measures. Hex measures of insulin are soaked up slowly, and that peak of concentration of hormone in a blood what is at the healthy person after food, with the help ď / to an injection it is impossible to frame. To overcome this disadvantage of an insulin therapy, began to develop semi-synthetic analogs of insulin which represent monomers or dimeasures. The set of bonds was experienced (Brange et al., 1990). From them two — lizpro-insulin and aspart-insulin — were clinically effective (Kang et al., 1991). Both drugs are soaked up from a hypodermic fat by 3 times quicker, than human insulin. Respectively, concentration of insulin in plasma is quicker enlarged and quicker sugar-lowering effect of drug begins. The injection of a semi-synthetic analog of insulin in 15 min. prior to food is interconvertible injections of human insulin in 30 min. prior to food. Lizpro-insulin — derivative human insulin, received by shift of the remains of a lysine and proline in provisions 28 and 29 of the V-chain was the first of such drugs (them sometimes call insulin of super short action) (quite so these remains are located in the molecule IFR-1 to which polymerization isn't inherent). Like human insulin, in the produced drugs lizpro-insulin is in a type of geksamer, however almost at once after introduction under a skin it breaks up to monomers. Therefore lizpro-insulin begins to work quicker, than insulin of short action, and works during smaller time. The review of Bolli et al is devoted to results of a clinical use of this drug. (1999). Lizpro-insulin has two advantages before insulin of short action. First, among the patients using lizpro-insulin the risk of a hypoglycemia decreased by 20 — 30%. Secondly, at them it is noticed small (for 0,3 — 0,5%), but statistically significant decrease of level of glikozilirovanny A1s hemoglobin what speaks about the best compensation of a diabetes mellitus. Aspart-insulin it is received by replacement of Pro28 of the V-chain by aspartic acid. Like lizpro-insulin, this drug after introduction under a skin quickly breaks up to monomers. Do not forget take Bronhalamin for better results.

Insulin of average duration of action it is worse than dissolve, are more slowly soaked up from a hypodermic fat and, therefore, insulin of short action have longer effect, than. Most widely use two drugs — NPH insulin and insulin to a tape. NPH insulin represents suspension of crystals Zincum-insulin and a protamine (in metric ratio) in phosphate buffer, insulin to a tape — the admixed suspension crystalline Zincum-insulin (insulin to ultra tape) and amorphous Zincum-insulin (insulin to a seven-tape) in the acetate buffer where solubility of insulin is minimum. The pharmacokinetics of human insulin of average duration of action slightly differs from pharmacokinetics of similar drugs of pork insulin. The difference can speak larger water repellency of human insulin, and also differences in interaction of pork and human insulin with protamine and Zincum. In this regard there is a problem of the choice of optimum time for an evening injection of insulin of average duration of action. The drugs of human insulin administered before a dinner not always provide normoglikemia next morning. Let's notice that differences in operation the combination of NPH insulin or insulin to a tape with insulin of short action in a regimen of double daily injections isn't revealed (Tunbridge et al., 1989). Insulins of average duration of action prescribe or 1 time a day before breakfast or 2 times a day. At patients with insulin diabetes mellitus the single injection of these drugs for the night quite often helps to avoid a hyperglycemia next morning (Riddle, 1985). When insulin to a tape is combined with insulin of short action, a part of the last in several hours can form complex bond with protamine and Zincum, and then the absorption of insulin of short action is slowed down (Colagiuri and Villalobos, 1986). NPH insulin doesn't influence absorption of insulin of short action at combined use; these drugs can be admixed independently or to use the ready combined drugs (see below; Davis et al., 1991a).

Insulin of long action is insulin to ultra tape (suspension crystalline Zincum-insulin) and protamine-Zincum-insulin (insulin suspension with Zincum and a protamine). Their action begins very slowly, but continues longly, without the expressed peak. They are intended for creation of low basal concentration of insulin in a blood for all day. Big T1/2 of insulin to ultra tape complicates definition of an optimum dose of drug: before achievement of steady state there pass several days. As well as in case of insulin of average duration of action, the admixed bull/pork insulin to ultra tape possesses longer action, than human. Insulin of long action prescribe 1 or 2 times a day and correct a dose according to glucose level in plasma on an empty stomach. The protamine-Zincum-insulin is used now seldom as it has very long and unpredictable effect. In the USA this medicine isn't sold any more.

At the vast majority of patients an insulin therapy includes use of insulin of average duration of action. The last 15 years go intensive searches of "ideal" drug. Human pro-insulin looks the promising candidate for this role. Experiments on animals with use of pork pro-insulin showed that this soluble substance works as insulin of average duration of action, more due to suppression of production of glucose a liver, in smaller — due to stimulation of utilization of a glucose periphery tissues. Such profile of activity is favorable for patients with a diabetes mellitus as the leading disturbance serves uncontrolled production of a glucose, and selective effect of drug on a liver leads to decrease of giperinsulinemia and, therefore, to depression of risk of a hypoglycemia. The first tests of human pro-insulin in clinic confirmed relative selectivity of drug concerning a liver and showed that on action duration it is similar to NPH insulin. However, according to preliminary results of clinical tests, human pro-insulin has no advantages before modern drugs of insulin of average duration of action. Moreover, because of high risk of a myocardial infarction at treatment by human pro-insulin its clinical tests were suspended.

Owing to the pharmacokinetics insulin to ultra tape possesses essential disadvantages therefore there is an urgent need in is long the operating analog of insulin which wouldn't have the expressed action peak. Many efforts were spent for creation of such drug. Glargin-insulin became the first such analog resolved for a clinical use in the USA. This drug is received by two modifications of a molecule of human insulin: attach two rests of an arginine to the S-extremity of the V-chain, and Asp21 of an A-chain replace with glycine (Rosskamp and Park, 1999). Glargin-insulin represents transparent solution with pH 4,0. Acidic pH stabilizes hexameasures of insulin and provides a long and predictable absorption of drug from a hypodermic fat. However because of acidic pH glargin-insulin can't be combined with the insulins of short action which are available today (including with lizpro-insulin) which have neutral pH. Clinical tests showed that glargin-insulin causes a hypoglycemia less often, is longly and evenly soaked up and in a regimen of single injections in days is more effective, than insulin to ultra tape.

Also other approaches to augmentation of duration of action of soluble analogs of insulin are used. One of them — accession of saturated fatty acid to a lysine s-amino group in situation 29 V-chains (Kurtzhals et al., 1997) therefore atsilirovanny insulin turns out. Now there are clinical tests of similar drugs.

Significant differences in an insulin pharmacokinetics at different patients and even at the same patient deserve a separate mention. Time of achievement of peak of concentration of insulin in a blood and the maximum sugar-lowering action can differ for 50%. Partly these fluctuations are bound to different rate of an absorption of drug from a hypodermic fat; it is considered that they are more expressed at insulin of average duration of action and insulin of long action. However recently it was shown that the same fluctuations are inherent to insulin of short action (Davis et al., 1991a). If to consider that these fluctuations are imposed on daily differences in a diet and an exercise stress, it is necessary only to be surprised how at such large number of patients it is possible to control successfully glucose level in a blood. It is the indications to an insulin therapy and its tasks. Ď / to an injection of insulin make a basis of treatment of all patients with achrestic diabetes mellitus sick with insulin diabetes mellitus at inefficiency of a dietetics and peroral sugar-lowering agents, and also pregnant women sick with Diabetum and the diabetes mellitus developing after pancreatectomy (American Diabetes Association, 1999). Besides, insulin is irreplaceable at treatment diabetic ketoatsido-for and plays an important role in treatment of a giperosmolyarny coma and maintaining patients both with achrestic, and with insulin diabetes mellitus. In all cases as the purpose of insulin therapy serves not only normalization of level of glucose in a blood, but also (elimination of other metabolic disturbances. It is difficult for last purpose to reach. The optimum result is achieved at an integrated approach to treatment: the diet, exercise stresses and injections of insulin have to be compounded among themselves. Below the principles of an insulin therapy are briefly described (in more detail — see LeRoith et al., 2000).

The daily need for insulin

At the healthy person with a normal weight daily production of insulin makes 18 — 40 pieces, or 0,2 — 0,5 pieces/kg (Polonsky and Rubenstein, 1986). About a half of this quantity is the share of basal secretion, other insulin co secretes in response to meal. Rate of basal secretion of insulin is peer to 0,5 — 1 pieces/h, after reception of a glucose inside it reaches 6 pieces/h (Waldhausl et al., 1979). At corpulent people with insulin resistance, but without diabetes mellitus secretion of insulin after food can be enlarged by 4 times and more. The co secreted insulin gets to portal system of a liver; its about a half is blasted by a liver, without reaching a systemic blood flow.

Patients with achrestic diabetes mellitus represent diverse group therefore the daily need for insulin at them fluctuates from 0,2 to 1 pieces/kg, averaging 0,6 — 0,7 pieces/kg. Corpulent patients because of insulin resistance of peripheric tissues usually need more insulin (about 2 pieces/kg/days). Patients with the daily need for insulin have less than 0,5 pieces/kg or residual secretion of insulin is kept, or they are more sensitive to effect of hormone owing to a good physical shape. As well as at healthy people, the need for insulin shares on basal. Basal requirement makes 40 — 60% of daily; this insulin is necessary for suppression of production of a glucose for cookies. Requirement usually becomes covered by insulin injections before meal; this insulin is necessary for digestion of nutrients. Many patients receive in days a single injection of insulin of average duration of action or the combined drug (insulin of average duration action/insulin of short action). It seldom happens enough for maintenance of normoglikemia. Meanwhile normalization of level of a glucose in a blood has paramount value: let's remember results of the research DCCT which showed that as the main reason for chronic complications serves the hyperglycemia. Apply more difficult schemes of an insulin therapy based on a combination of insulin of average duration or long action to insulin of short action to maintenance of normoglikemia.

The popular schemes of an insulin therapy consisting of two-three injections of different insulin are submitted in fig. 61.5

(LeRoith et al., 2000). Most often use the so-called fractional admixed scheme which comes down to two injections (before a breakfast and before a dinner) admixtures of insulin of average and short action (fig. 61.5, A). If the NPH insulin entered before a dinner or insulin doesn't provide to a tape normoglikemia for night, the evening dose can be shattered: before a dinner to enter insulin of short action and before going to bed — NPH insulin or insulin to a tape (fig. 61.5, B], And at healthy people, and at patients with a diabetes mellitus the need for insulin is especially high early in the morning; this phenomenon is known as a dawn hyperglycemia (Blackard et at, 1989). Therefore time of introduction of an evening dose of insulin and the choice of drug are extremely important for this injection.

Also the so-called regimen of repeated injections of insulin isn't less often used. At the same time the basal need for hormone is provided single (before a breakfast or for the night) or double injections of insulin of average duration or long action, and postprandialny - injections of insulin of short action before each meal (fig. 61.5, V). Approximately the same therapeutic effect is reached by means of a wearable batcher of insulin (fig. 61.5, D). Rate of infusion can be regulated, arranging it under daily needs (Kitabchi et al., 1983).

The dose of insulin is selected individually, being guided by glucose level in a blood. With the advent of glucose meters which patients can independently use and methods of measurement of concentration of A1s hemoglobin it became easier to select a dose of insulin. Special attention should be paid to patients with the accompanying pathology, a hormonal failure (for example, hypopituitarism, an adrenal failure), insulin resistance. 'j the Factors influencing an insulin absorption. Efficiency of an insulin therapy is influenced by factors which the absorption of insulin and its action, a diet, exercise stresses and others, so far unknown change, influences. Rate of an absorption of insulin from a hypodermic fat depends on the place of an injection, a type of drug, blood supply and muscular activity in the place of an injection, volume and concentration of the entered insulin and depth of an injection (at introduction in oil insulin begins to work quicker, than at ď / to introduction).

At ď / to introduction the latent period after which rate of absorption of insulin begins slowly, but steadily to increase is usually observed. In case of low concentration or small volume the preparatala-tentny period can be absent.

As the place ď / to insulin injections usually serve the forward abdominal wall, a breech, the forward surface of a hip or a dorsum of a forearm. Rate of an absorption decreases among a stomach is a forearm — a breech — a femur (Galloway et al., 1981). In order to avoid lipogi-pertrofia and lipoatrophia usually advise to change places ď / to injections. However these complications are improbable when using high cleaning drugs of insulin. If the patient prefers to do injections in a stomach, places of injections can be changed on it, without passing to other parts of a body. It will allow eliminating the major factor changing an insulin absorption. A stomach — the best place for morning injections: insulin is soaked up from here for 20 — 30% quicker, than from a forearm. If the patient refuses to do injections in a stomach, it is necessary to pick up the constant place for each component of an insulin therapy (for example, the morning dose is entered into a femur, evening into forearm).

Other factors are important too. The raised blood stream in a hypodermic fat, for example after massage, a hot bathtub, exercise stress enlarges rate of an absorption of insulin. In a standing position the blood stream in a hypodermic fat of legs considerably decreases whereas in a forward abdominal wall it almost doesn't change. The volume and concentration of the administered drug influence not only rate of an absorption, but also duration of effect of insulin. When mixing insulin of short action with insulin to a tape a part of a high-speed component is lost because of linkng with Zincum (Galloway et al., 1981). This effect is even more expressed when mixing insulin of short action with insulin to ultra tape. Therefore the drugs admixed in one syringe have to be administered at once, immediately. Mixing with NPH insulin almost doesn't influence absorption of insulin of short action. The combined drugs containing NPH insulin and insulin of short action in proportions 50:50,60:40, 70:30 and 80:20 are produced; in the USA from them only medicine with structure 70:30 and 50:50 is sold. Besides, in the USA there are combined drugs of NPH insulin and lizpro-insulin (tab. 61.4). At many patients with a diabetes mellitus won popularity the syringe handle, the filled insulin of short action, liz-pro-insulin, NPH insulin or the combined drugs (insulin of short action / insulin of NPH, the combined NPH lizpro-insulin). At a small number of patients insulin is blasted in a hypodermic fat; they need introduction of high doses of insulin (Schade and Duckworth, 1986).

There are injektor which allow to deliver insulin in a hypodermic fat "without nyxis". Injektor are expensive and bulky, but some patients prefer them. Dispersal of drug on a hypodermic fat theoretically has to accelerate an absorption of insulins of average duration and short action (Malone et al., 1986); however it is observed not always (Galloway et al., 1981).

Such injections lead to development of IgG-antibodies to insulin. This side effect was much stronger expressed at the old, badly purified drugs, than at modern high cleaning drugs of bull and pork insulin or recombinant human insulin. It isn't established whether prolonged treatment is followed by human insulin smaller production of antibodies in comparison with treatment of mono-comas ponent pork insulin. It is clear only that human insulin. However at the vast majority of patients of an antibody to insulin don't change pharmacokinetics of the administered drugs.

At some patients with a high antiserum capacity to insulin the pharmacokinetics of insulin of short action reminds pharmacokinetics of insulin of average duration of action, at the same time the last in itself renders longer effect too. It can lead to intensifying of a hyperglycemia after food (because of the slowed-down effect of insulin of short action) and hypoglycemia at night (because of the effect of insulin of average duration of action stretched in time).

IgG-antibodies to insulin get through a placenta and, obviously, are capable to cause a hyperglycemia in a fetus due to neutralization of the insulin co secreted by it. On the other hand, undesirable and unpredictable dissociation of complexes insulin an antibody can lead to giperinsulinemia and a hypoglycemia at a fetus or at the newborn. It is shown that transition from the admixed bull/pork insulin to monokompo-nent drugs is followed by depression of an antiserum capacity to insulin (Chertow et al., 1988). Therefore during pregnancy it is recommended to use only human insulin. On sale there are many models of a wearable batcher of the insulin intended for a continuous p / to infusion of this hormone (Kitabchi et al., 1983). This type of an insulin therapy suits not all as requires persistent attention, especially in an initiation of treatment. But for adherents of an intensive insulin therapy the wearable batcher serves as an excellent substitute of a regimen of repeated injections. Modern batchers provide infusion of insulin with constant rate which can be switched with day on night, for example to avoid a dawn hyperglycemia. Before food the installed program includes jet administration of insulin according to quantity and structure of a nutrition which should be eaten.

Insulin therapy by means of a wearable batcher of insulin has inherent only to it disadvantages. As in batchers insulin of short action which almost doesn't collect in a hypodermic fat is used only, the sudden termination of an insulin therapy is capable to result quickly in deficiency of insulin and a diabetic ketoacidosis with the hardest hyperpotassemia. Modern batchers are supplied with enunciators which react to change of pressure in infusional system, but nevertheless from a sudden stopping of the pump, shift of a needle, crystallization of insulin or an excess of a catheter nobody is insured. One more complication hypodermic abscesses and phlegmon. Success of treatment in many respects is defined by the correct selection of patients who most of all suit a wearable batcher of insulin. Disadvantages of this type of an insulin therapy are compensated by its one important advantage. During exercise stresses the wearable batcher of insulin is capable to frame the concentration of hormone in a blood coming to physiological (at the healthy person at this time secretion of insulin falls) and not to allow developing hypoglycemia. Injection of insulin can't provide it.

Side effects

Read separate article: Side effects of insulin

New forms of an insulin therapy

Experimental approaches to treatment of a diabetes mellitus include new drugs of insulin, new ways of introduction, batchers for intraperitoneal administration of insulin, the implanted insulin granules, an artificial pancreas, transplantation of insular cells, pancreas and gene therapy.

New ways of insulin delivery

Insulin was tried to be entered inside by inhalations and by means of the granules implanted under skin. Inhalations look the most perspective: for intensifying of an absorption of insulin through mucous respiratory tracts to drug are added by various substances, for example Mannitolum, glycine or sodium citrate (Skyleret al., 2001; Cefalu et al., 2001). The absorption occurs quickly, on pharmacokinetics inhalation drugs of insulin approach the insulin of short action entered ď / to. Now efforts are concentrated on development of convenient inhalers of the small size. The implanted granules are intended for slow release of insulin for days and weeks. The peroral way of administration of insulin, undoubtedly, would be convenient for patients and would provide rather high concentration of hormone in portal system of a liver, however attempts to strengthen an insulin absorption in an intestine weren't crowned with a little appreciable success yet. Methods consisted in the basic in embedding or including of insulin in liposomes. Batchers for intraperitoneal administration of insulin deliver hormone in portal system of a liver. They were approved in public within several months.

Transplantation and gene therapy

These two approaches represent seductive replacement to insulin. Transplantation of a segment of a pancreas with success is carried out already to several hundred patients (Sutherland et al., 1989). However operation is technically difficult and is usually carried out only by that patient who suffers from a diabetes mellitus and its complications long ago. Transplantation of the isolated islands of a pancreas is technically less difficult. She is worked on rodents with an experimental diabetes mellitus and recently approved on small group of patients with achrestic diabetes mellitus along with the new scheme of immune suppressive therapy without glucocorticoids (Shapiro et al., 2000). Introduction of a gene of insulin to fibroblasts or other cells which then return in the owner's organism is one more way of treatment of a diabetes mellitus fulfilled on rodents.