Experience has proved that in more than 50% of diabetic patients with Type 2 Diabetes Mellitus (DM), a mere diet is not sufficient to keep the glycemia within its normal levels. It is then necessary to begin with medication.
Since individual Type 2 DM medicaments have their own logic deriving from the nature of this disease, we will bring a short overview of the DM causes.
The underlying cause of diabetes mellitus is the so-called insulin resistance. The insulin resistance is a state in which tissues (especially muscular and fatly ones) are not sufficiently sensitive to insulin. Insulin in these tissues is responsible especially for glucose entry in the cells. It enables its burning to produce energy and, consequently, decreasing its concentrations in the bloodstream. This is, of course, a very simplified explanation, yet sufficient to understand the issue.
The term insulin resistance denotes reduced sensitivity of tissues to insulin. This means in practice that, to enable to move a certain amount of glucose into the cells, more insulin is needed in a patient with insulin resistance compared to a healthy one. Increased insulin resistance is found in patients with metabolic syndrome in a comparatively young age and, if the disease develops in the usual way, the insulin resistance gradually rises.
Each increase is accompanied in the body by greater insulin production . At a certain stage however, the capacity of insulin production in the pancreas reaches its upper limits and it cannot cope with further increase in insulin resistance by producing some more insulin.
This is the moment when blood glucose concentrations rise above the upper limits of the normal values range and diabetes can be detected. The glycemia levels may then be influenced by a decrease in the speed of digestion, either by influencing the absorption of saccharides in the intestine or the speed with which the stomach empties.
Based on the understanding of the disease’s principles, the following types of medicaments are developed:
- medicaments decreasing insulin resistance
- medicaments increasing insulin production in an organism
- medicaments slowing down the absorption of saccharides in the intestine
- medicaments slowing down emptying the stomach and increasing insulin production (a new group of medicaments which we believe to be shortly available).
The medicaments in the groups 1 and 2 are considered to be the basic ones, preparations in group 3 are considered to be supporting the treatment and group 4 is just about to come out.
Medicaments decreasing insulin resistance (Group 1)
The principle of their effect is in decreasing the insulin resistance. There are preparations of two types in this group:
- Metformin
- Glitazones.
A. Metformin ranks among the so-called biguanides. It is a diabetic medicament of the first choice (it is a medicament administered as first). Its effect consists in decreasing insulin resistance especially by influencing the metabolism of the liver. This is one of the reasons why patients using metmorfin should avoid alcohol. A doctor prescribing the medicine should also be careful to a certain degree when dealing with patients with a more developed ischeamic heart disease, chronic obstructive lung disease, kidney and liver damage. The medicament cannot be used in a number of these cases. Otherwise metmorfin is a well tolerated and very effective drug. According to the latest recommendations of the European and American scientific societies, it will most probably be necessary to administer this preparation to Type 2 DM patients much earlier than has so far been done and it will, therefore, be used in the treatment to a maximum extent. The oldest drug containing this preparation is Glucophage, but this substance is present in a number of medicaments used in the Czech Republic that would be very hard to enumerate all here. The medicament is used most often in two daily doses in twelve hours’ intervals. In some cases, the preparation is prescribed to be used three times a day before the main meals. Unfavourable effects do not often occur. If they occur, these are mostly gastrointestinal problems. Some situations can be solved by switching to modern metformin preparations.
B. Glitazones are the representatives of a relatively new medicament group. The final effect of these preparations is again the decreased insulin resistance. Their effect consists in influencing certain endocellular genes which consequently mediate their possitive effect. In the Czech Republic there are used two representatives from this group: rosiglitazone and pioglitazone (Avandia and Actos). The preparations are used in one daily dose and the effect of their onset may be observed after several weeks of their administration. These medicaments are not prescribed to patients with a more severe cardiac, liver or renal disease.
Medicaments increasing insulin production (Group 2)
A. Derivatives of sulphonylurea. This group consists of a number of preparations which affect beta pancreatic cells and force it to increase insulin synthesis. It results in lower glycemia levels and an improved glycemic profile. These preparations are mostly included in the treatment if metmorfin alone is not capable of controlling the glycemia. As opposed to the two former groups, these derivatives of sulphonylurea can bring about hypoglycemia. Every patient using them should strictly keep the diabetic regimen including the diet and should also be instructed by his doctor how to proceed when he is not able to accept food (eg. in cases of gastrointestinal illnesses) since the risk of hypoglycemia may be comparatively high. Modern representatives of this medicament group are used twice or once a day.
B. Glinides. The medicaments included in this group (nateglinides and repaglinides) speed insulin production. Compared to most sulphonylurea preparations the onset of their effect is quick, they very well influence postprandial glycemia (after meal sugar levels). They are used three times a day.
Medicaments inhibiting the absorption of saccharides (Group 3)
Acarbosis. It is the most frequently used medicament in this therapeutic group. Its effect results in blocking the glucosidases, the enzymes in the intestines which then results in a slower break down of saccharides in the intestine and, consequently, their slower absorption. The glycemia levels are lower and more stable in the postprandial period.
Medicaments inhibiting gastric emptying in the stomach and increasing insulin secretion (Group 4)
These preparations should be available to our patients in the course of the next year. Their effect depends on the GLP-1 (glucagon-like polypeptide1) released in the intestine which influences the organism in a number of ways. From the diabetes point of view, the most important are these two:
- influencing stomach motility (ability to move),
- increasing insulin secretion.
GLP-1 and the entero-insular axis (the connection between the intestine and the beta-cell)
GLP-1 is a hormone produced by the intestine. Its release is stimulated by food intake. A certain amount of the secernated hormone which reaches the system circulation and target structures in a biologically active form prior to its degradation influences above all insulin secretion – the exocytosis of the granules in the beta cells in the pancreas as much as the biosynthesis of insulin affecting trophically the pancreatic beta cells, influencing the motility of the gastrointestinal tract, decreasing the concentrations of plasmatic glucose and reducing glycemia deviations. It brings about the feeling of satiety thus being able to contribute to weight reduction. It has, therefore, an antidiabetic effect too.
GLP-1 inhibits intestine motility thus slowing down the passage through the intestine. It also inhibits gastric emptying in the stomach and the secretion of HCl. It inhibits glucagon secretion. It improves insulin sensitivity, and indicates the feeling of satinity in the central nervous system (CNS) thus resulting in the decrease of body weight by decreasing the food intake. It acts as the incretine hormone in the pancreas stimulating induced food by insulin secretion. GLP-1 stimulates exocytosis of the insulin granules from the pancreatic beta cells. It also stimulates gene transcription and other biosynthetic processes during insulin synthesis. It leads to beta cells multiplication in the pancreas. It is also possible that apoptosis (the disposal) of beta cells is reduced.
GLP-1 is very quickly degraded in an organism especially by the DPP IV enzyme, its halftime in an organism is approx. 1 – 2 minutes.
In Type 2 diabetics there is described a certain defect in the physiology of incretines: either decreased secretion or increased degradation of incretine hormones, or even both.
The possibilities of GLP-1 employment in the therapy of Type 2 Diabetes Mellitus
This hormone, due to its positive effect on glycemia values, has been investigated as to its possible employment in the diabetes mellitus treatment. Its short lifetime is regarded as a disadvantage which would enable its use only when administered by continuous infusion. This would be, however, not practical and quite impossible. Scientific teams have succeeded in eliminating this disadvantage by the development of two types of substances:
A. GLP-1 analogues
GLP-1 analogues are substances which have a very similar structure to the hormone itself. They differ, however,in the part of its molecule responsible for its lifetime. These preparations stay in the body for 12 hours now. They are administered twice a day, their slight disadvantage is that they are applied in the form of a subcutaneous injection, which is the same as in the case of insulin. Their positive property is body weight decrease during the period of application as proved by several scientific studies.
B. DPP-IV enzyme blockers
DDP-IV enzyme blockers are substances which restrict the effect of the degradation enzyme. Thus the increase in the GLP-1 concentration is achieved and, consequently, its effect is elevated. These preparations are administered orally. We may start using the preparation Januvia this year which got the prestigious Galieni prize in 2007, awarded to the most innovative pharmaceutical technologies. This medicament will be most probably followed by other preparations based on a similar principle.