Hello, my name is Jens Juul Holst, and I'm professor of medical physiology at the University of Copenhagen During the last couple of decades two new remarkably successful principles for diabetes therapy have appeared that have had remarkable success and are used World-wide today: I am talking about incretin based therapies and surgical therapy usually performed for obesity. We have grouped the topics together in this lecture, because they are – at least to some extent - linked together. First let us recapitulate the incretin concept: It is the amplification of insulin secretion that is seen when glucose is taken in orally as opposed to when it is given intravenously at a rate which results in exactly the same plasma glucose excursions as the oral administration. This can be done, if you carefully monitor the blood glucose concentrations during the infusion, say every 5 min, and then adjust the infusion rate accordingly. In healthy individuals one should be prepared to infuse about 20- 25 grams of glucose in order to copy the glucose excursions in response to an oral glucose tolerance test with 75 grams of glucose. This also tells you that the oral administration activates a powerful mechanism that removes 50 of the 75 grams of glucose from the circulation because it took only 25 grams to copy the concentration curve, when glucose was infused intravenously. The mechanism is the incretin effect, and it involves a stimulation of insulin secretion by these two gut hormones. They are produced in endocrine cells of the gut epithelium. Here we see a schematic representation of the wall of the small intestine . There are several layers. Counting from the outside we find the peritoneal lining and the muscles layer responsible for the gut motility. Approaching the lumen we find the connective tissue of submucosa and finally the mucosa with the villi and the crypts which are covered by epithelium. The epithelium has mainly 4 cell types namely the enterocytes, which are responsible for nutrient absorption, the goblet cells, which produce mucus, the Paneth cells in the bottom of the crypts which are important for the defense mechanisms of the gut and finally the endocrine cells. These cells are scattered across the epithelium and different cell types are mixed between each other. Therefore, it is generally not possible to remove one specific cell type by cutting out a certain segment of the gut and this has hampered the elucidation of the functions of the gut hormones. The gut endocrine cells are typically of the open type. They have a flask-like shape with an apical cytoplasmic process which reaches the gut lumen – this is why they are called open-type – and is equipped with microvilli which protrude into the lumen and express a number of molecular sensors, so that the cell can “sense” the nutrients and other molecules in the intestinal chyme, the fluid of the gut lumen. In the upper part of the small intestine, we have the majority of the so-called K-cells which produce GIP. The GLP-1 producing L-cells are more scattered but their density increases distally and is high even in the colon. GIP is formed from a precursor hormone, proGIP, from which the mature hormone, a peptide of 42 amino acids, is cleaved out by the enzyme prohormone convertase 1/3. GIP is released in response to nutrient ingestion, in particular glucose and lipids. The hormone binds to and activates a specific G-protein-coupled receptor, the GIP-receptor. The receptor is found in many tissues, which is interesting, but we know most about its actions in the pancreatic islets and in the white adipose tissue. In the islets, the beta cells, the alpha cells and the somatostatin-producing delta-cells respond to GIP, and all of them with a stimulated secretion. The mechanism involved is mainly activation of adenylate cyclase and intracellular accumulation of cAMP. GLP-1 is a product of the prohormone proglucagon. Phylogentically, in the evolution of specias,the L-cells of the gut are related to the pancreatic alpha cells. Both cells express the glucagon gene, which gives rise to the primary translation product proglucagon, but the resulting common prohormone is differentially processed. In the alpha cells proglucagon is cleaved by the enzyme prohormone convertase 2. The products are glucagon and the so-called major proglucagon fragment (MPF) which also contains 2 glucagon-like sequences, glucagon-like peptide 1 and 2. They are glucagon-like because they have approximately 50 % sequence homology, but they remain together in the major proglucagon fragment. The fragment is probably biologically inactive. In the gut, proglucagon is cleaved by another processing enzyme, prohormone convertase 1/3, and here the products are very different. The first is a large peptide of 69 amino acids in which the glucagon sequence is buried – it is called glicentin, and not much is known about its possible actions, but glicentin may be broken further down to a peptide of 37 amino acids, containing the full glucagon sequence plus a C-terminal octapeptide, and this peptide is highly bioactive. It is called oxyntomodulin, because it was thought to influence gastric acid secretion, but it turns out to be an agonist for both the glucagon and the GLP-1 receptor, and it is thought that it plays a role in appetite regulation. In the gut, as opposed to in the pancreas, the two glucagon-like sequences are cleaved out of the major proglucagon fragment and are released to the circulation. GLP-1 is a 30 amino acid peptide, which is often for historical reasons called GLP-1 (7-36)amide, while GLP-2 has 33 amino acids. GLP-2 is an extremely interesting hormone which has its own GLP-2 receptor, and plays an important role in the growth and adaptation of the gut. A slightly modified form has just been approved for treatment of certain forms of intestinal insufficiency because of the growth effects, but it has not been known to influence glucose metabolism or appetite, so, for the time being, no more about GLP-2.