Incretin

As an incretin effect, the central part of the 1960s described is called in medicine, that with the same blood glucose levels, the intravenous injection of glucose leads to a significantly lower secretion of the glucose-lowering hormone insulin as an oral glucose feeding. Therefore, the concentration of glucose in the blood does not explain alone the amount of insulin the pancreas. Mid-1980s, the amount of the incretin effect was estimated as a function of the amount of glucose to about 25 to 60 percent of the insulin response on the basis of experimental data.

Cause of the incretin effect

The cause of the incretin effect, the existence of hormones has been postulated to be formed by the intestines. Looking for these, referred to as incretins glucose -dependent hormones the first formed by the K- cells of the duodenal mucosa insulinotropic peptide ( GIP) has been found, its insulin- releasing activity was detected around 1970. However, since neutralization of the GIP reduces the incretin effect by only 20 to 50 percent, Searched for further Inkretinen. Mid-1980s, the glucagon-like peptide 1 was described (GLP -1), which is produced by the L- cells of the intestinal mucosa. The highest density of these cells can be found at the end of the small intestine called the ileum and the beginning of the large intestine called the cecum. It has been shown that GLP -1 has a significant share of the incretin effect and that its effect is additive to the effect of GIP. At present it is assumed that both of these hormones are responsible for the incretin effect throughout.

Clinical Application

Based on detailed analysis of GIP and GLP-1 has been trying to develop based on these hormones or their regulatory mechanisms medicines for the treatment of diabetes mellitus type 2.

For GIP showed that it at an elevated blood sugar has no stimulatory effect on insulin release. For GLP- 1, the effect is in diabetics, although lower than in metabolically healthy people, but enough for a blood sugar lowering effect. GLP-1 itself has been found, however, for a drug application because of degradation by the enzyme dipeptidyl peptidase- 4, and thus be too unstable to be too short time in its effect.

However, other substances have been found which are not subject to this enzymatic cleavage and show comparable with the effect of GLP -1 to its receptor due to structural similarities. These substances are known as incretin mimetics. Lead compound of this new class of drugs is the exenatide. It is the synthetic version of a hormone than exendin -4 in the saliva of the Gila Monster ( Heloderma suspectum ), an American lizard was found. Another class of active substances on the basis of the incretin effect, are the inhibitors of dipeptidyl peptidase- 4, the delay through the inhibition of dipeptidyl peptidase 4 shows the degradation of endogenous GLP-1.

For both classes of active showed that their effect is due to a stimulating the release of insulin and glucagon by inhibition of secretion and that their use reduces the blood sugar fasting and after food intake. For exenatide a reduction in body weight has been proven beyond. Moreover, evidence was found in other studies that long -term treatment with incretin mimetics and inhibitors of dipeptidyl peptidase- 4 may protect the insulin-producing beta cells and prevents their demise, or at least delayed. The effect of both drug classes also depends on the blood glucose levels, so that in contrast to the other approved anti-diabetic drugs is virtually no risk of a hypo.