What are Incretins?
They are intestinal-derived factors produced by the intestinal mucosa in response to nutrient ingestion 1, and are capable of stimulating the release of insulin from the pancreas and thereby reduce blood glucose levels. The first incretin hormone to be identified was isolated from crude extracts of small intestine and initially was named gastric inhibitory polypeptide (GIP), based on its ability to inhibit gastric acid secretion in dogs 2. The second one, called hormone Glucagon Like Peptide 1 (GLP-1) is a tissue-specific posttranslational proteolytic product of the proglucagon gene that is released from intestinal L-cells in response to nutrient ingestion and enhances glucose-stimulated insulin secretion 3.
Mode of action:
Experimental evidence indicates that GLP-1 stimulates glucose-induced insulin secretion in islets of Langerhans in animals and humans. In humans, secretion of GLP-1 is correlated to the release of insulin. The effect of GLP-1 on insulin secretion is strictly glucose-dependent and there is no effect of GLP-1 on insulin secretion for glucose concentrations below 4.5 mmol/l 4. Additionally to its effects on insulin secretion, GLP-1 has been shown to stimulate insulin gene transcription and all steps of insulin biosynthesis in isolated beta cells, thereby providing continual supplies of insulin for secretion. GLP-1 is able to suppress glucagon secretion in pancreatic islet; the inhibitory effect is probably indirectly mediated via insulin release and via somatostatin secretion. However, a direct effect of GLP-1 is not completely excluded since GLP-1 receptors are expressed on pancreatic glucagon cells. The inhibitory effects of GLP-1 on glucagon secretion seem to represent an important mechanism for regulating elevated levels of blood glucose. In patients with type 1 diabetes, administration of GLP-1 decreased blood glucose levels while the secretion of glucagon was strongly inhibited, suggesting that GLP-1 suppressed the hepatic production of glucose induced by glucagon 5.
The effects on multiple organs:
GLP-1 exerts inhibitory effects on gastrointestinal secretion and motility, particularly on gastric emptying 6. Administration of GLP-1 at physiological doses in healthy volunteers results in a dose-dependent slowing of gastric emptying and of glucose absorption, which participate in a subsequent reduction of postprandial plasma glucose concentrations. The actions of GLP-1 on gastrointestinal motility and secretion probably involve neurally mediated mechanisms, including vago-vagal pathways. The physiological role of GLP-1 may be to adjust the absorptive capacity of the gut and to adjust the amount of chyme, by slowing gastrointestinal transit and decreasing secretion of digestive enzymes.
GLP-1 has been shown to reduce calorie intake and to enhance satiety, these effects being probably related to central mechanisms 7. In normal subjects, the intravenous administration of GLP-1 above physiological levels induced increased feelings of satiety as well as a reduction of food intake. Similar effects were observed in obese subjects, as well as in patients with type 2 diabetes. In type 2 diabetic patients treated with a subcutaneous infusion of GLP-1 for up to 6 weeks, the reduction in food intake was sustained and associated with a reduction in body weight
GLP-1 has been shown to exert positive effects on pancreatic beta cell mass 8. When given for prolonged periods to normal rodents or to animals with impaired glucose tolerance or diabetes, GLP-1 and its analogue exendin increased beta cell mass. Recent data indicate that the antiapoptotic effects were also observed in freshly isolated human islets cultures in vitro.
Treatment strategies:
DPP4 inhibitors are a new class of oral lowering agents for the treatment of type 2 diabetes 9. They act by blocking the dipeptidyl peptidase 4 enzyme which works to rapidly break down the GLP-1. As a result levels of GLP-1, which are low in patients with type 2 diabetes, become elevated. GLP-1 itself would need to be given by a continuous intravenous infusion for it to work therapeutically as it is so rapidly broken down by DPP4. So analogues of GLP-1 have been developed which are resistant to the effects of DPP4, but these have to be given by injection. The idea of increasing GLP-1 levels by inhibiting its breakdown was therefore developed. This can be achieved by using small molecules that can be taken orally. These agents lower blood glucose and reduce HbA1c when given orally to patients with type 2 diabetes. The overall experience to date with DPP4 inhibition is that they are orally active, safe, and highly tolerable agents with a minimal risk of producing hypoglycaemia. They show sustained robust and clinically significant improvements in glycaemia in monotherapy and in combination with metformin, sulphonylurea and TZD's.
