Incretin effect

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In medicine, the incretin effect is the observation described in the mid-1960s that, with the same blood sugar level, the intravenous injection of glucose leads to a significantly lower release of the blood sugar-lowering hormone insulin than an oral glucose supply. The concentration of glucose in the blood does not only explain the amount of insulin released by the pancreas. In the mid-1980s, on the basis of experimental data, the extent of the incretin effect, depending on the amount of glucose, was estimated to be around 25 to 60 percent of the insulin response.

The cause of the incretin effect

The cause of the incretin effect was postulated to be the existence of hormones that are produced by the intestinal mucosa . In the search for these hormones, known as incretins, the glucose-dependent insulinotropic peptide (GIP) formed by the K cells of the duodenal mucosa was first found, the insulin-releasing effect of which was demonstrated around 1970. However, since neutralizing the GIP only reduces the incretin effect by 20 to 50 percent, further incretins were sought. In the mid-1980s, the glucagon-like peptide 1 (GLP-1) was described, which is produced by the L cells of the intestinal mucosa. The highest density of these cells is found at the end of the small intestine , the so-called ileum , and the beginning of the large intestine , known as the caecum . It could be shown that GLP-1 has a significant share in the incretin effect and that its effect is additive to the effect of GIP. It is currently believed that these two hormones are responsible for the overall incretin effect.

Clinical application

On the basis of detailed investigations of GIP and GLP-1, attempts were made to develop drugs based on these hormones or their regulatory mechanisms for the treatment of type 2 diabetes mellitus .

GIP was shown to have no stimulating effect on insulin release when the blood sugar level was increased. For GLP-1 the effect in diabetics is less than in metabolically healthy people, but sufficient for a blood sugar-lowering effect. However, GLP-1 itself turned out to be too unstable when used as a drug due to the degradation by the enzyme dipeptidyl peptidase 4 and therefore too short-term in its effect.

However, other substances were found which are not subject to this enzymatic cleavage and which, due to structural similarities, show an effect on its receptor that is comparable to that of GLP-1 . These substances are known as incretin mimetics. The main substance of this new class of active ingredients is exenatide : the synthetic version of a hormone found as exendin-4 in the saliva of the Gila crustacean ( Heloderma suspectum ), an American lizard species. Another class of active ingredients based on the incretin effect are the inhibitors of dipeptidyl peptidase 4, which delay the breakdown of the body's own GLP-1 by inhibiting dipeptidyl peptidase 4.

For both drug classes it was shown that their effect is based on a stimulation of the release of insulin and an inhibition of the glucagon secretion , and that their use lowers the blood sugar level on an empty stomach and after eating. Exenatide has also been shown to decrease body weight. In further studies, indications were found that longer-term treatment with incretin mimetics and inhibitors of dipeptidyl peptidase 4 might protect the insulin-producing beta cells and prevent or at least delay their demise. The effect of both drug classes is also dependent on the blood glucose level, so that in contrast to the other approved anti-diabetic drugs there is practically no risk of hypoglycaemia .

literature

  • DJ Drucker, MA Nauck: The Incretin System: Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl peptidase-4 Inhibitors in Type 2 Diabetes. In: The Lancet . 368/2006. Lancet Publishing Group, pp. 1696-1705, ISSN  0140-6736
  • T. Vilsboll, JJ Holst: Incretins, Insulin Secretion and Type 2 Diabetes Mellitus. In: Diabetologia . 47 (3) / 2004. Springer, pp. 357-366, ISSN  0012-186X