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Reaching the effects of gastric bypass on diabetes and obesity without surgery

Periodic Reporting for period 1 - BYPASSWITHOUTSURGERY (Reaching the effects of gastric bypass on diabetes and obesity without surgery)

Reporting period: 2017-01-01 to 2018-06-30

Gastric bypass surgery results in massive weight loss and diabetes remission. The effect is superior to intensive medical treatment, showing that there are mechanisms within the body that can cure diabetes and obesity. Revealing the nature of these mechanisms could lead to new, cost-efficient, similarly effective, non-invasive treatments of these conditions. The hypothesis is that hyper-secretion of a number of gut hormones mediates the effect of surgery, as indicated by a series of our recent studies, demonstrating that hypersecretion of GLP-1, a hormone discovered in my laboratory and basis for the antidiabetic medication of millions of patients, is essential for the improved insulin secretion and glucose tolerance. But what are the mechanisms behind the up to 30-fold elevations in secretion of these hormones following surgery? Constantly with a translational scope, all elements involved in these responses will be addressed in this project, from detailed analysis of food items responsible for hormone secretion, to identification of the responsible regions of the gut, and to the molecular mechanisms leading to hypersecretion. Novel approaches for studies of human gut hormone secreting cells, including specific expression analysis, are combined with our advanced and unique isolated perfused gut preparations, the only tool that can provide physiologically relevant results with a translational potential regarding regulation of hormone secretion in the gut. This will lead to further groundbreaking experimental attempts to mimic and engage the identified mechanisms, creating similar hypersecretion and obtaining similar improvements as the operations in patients with obesity and diabetes. Based on our profound knowledge of gut hormone biology accumulated through decades of intensive and successful research and our successful elucidation of the antidiabetic actions of gastric bypass surgery, we are in a unique position to reach this ambitious goal.
The main questions of this research project therefore are: What are the mechanisms behind the exaggerated responses after bypass operation, and is it possible to activate these mechanisms via nutritional or pharmaceutical means?
The first task of the project was to identify the factors which, after gastric bypass operations, cause the hypersecretion of the gut hormones, which in turn is responsible for the reduction in food intake and the increased insulin secretion that together explain the beneficial effects of the operations and the remission of diabetes, if present. Many factors have been proposed based on studies in mice, but our careful and comprehensive studies show that these do not apply to humans. After bypass, nutrients pass very rapidly to lower section of the gut where cells producing appetite-regulating hormones are denser. Here, the nutrients are digested and absorbed extremely rapidly and, it is this surprising process that leads to exaggerated secretion of the hormones. In model experiments in isolated perfused gut (from rats and mice), we can reproduce these events and map in detail the cellular processes that lead to secretion and demonstrate that, for instance, bile salts have to be specifically taken up by the cells and transported through the cells to interact from the outside with a specific receptor, which in turn via a now characterized signal system leads to secretion. So it is the exaggerated exposure of segments that are not normally exposed that is the primary reason for the hypersecretion, and this can be imitated for instance by intake certain carbohydrates (e.g. isomaltulose) which will result in a similar secretion even in unoperated individuals. We have also identified other mechanisms that regulate the secretion and which may be manipulated pharmacologically (e.g. the regulation by an inhibitory transmitter, somatostatin). Since the hormones that are secreted are responsible for the inhibition of food intake (and hence the majority of the effects of the operation), we also carry out experiments with administration of cocktails of these hormones, mimicking what happens after operation, and we have demonstrated strong inhibition of food intake, suggesting that this approach may be developed into future therapies.
As planned, we have mapped important aspects of nutrient stimulated secretion of gut hormones after gastric bypass operations, and the findings suggest that the hormones are differentially regulated. GLP-1 secretion which is our primary target because of its pronounced actions on food intake and insulin secretion, is clearly most stimulated by carbohydrates (meaning that it is the carbohydrate component of mixed meals that is responsible for the strongest stimulation of secretion) whereas for PYY stimuli are more complex, probably because secretion derives from more cells and more distal cells than GLP-1 secretion, but also include an important carbohydrate component. The nature of the carbohydrates is important; simple monosaccharides including glucose in particular are important (raising a problem: can you treat diabetes with intestinal glucose? Of course not, but which mechanisms are involved in the stimulation? And can those mechanisms form basis for pharmacological stimulation? This is indeed possible and that is what we are working on), but it is of interest that more complex carbohydrates (e.g. isomaltulose) and also combinations with glycosidase inhibitors in healthy subjects can mimic the profiles of the operated patients. The bile component, though important, is not grossly altered after bypass, but is together with lipids extremely important for secretion of the gut hormone, neurotensin. We are currently investigating the appetite/food intake inhibitory effect of neurotensin in humans, and this observation therefore is of considerable interest. The studies in vitro (isolated perfused gut) have resulted in numerous important pieces of information that may be useful for generating new approaches to enhance secretion. The most important is the inhibition of secretion by paracrine somatostatin secretion, which has led to a full project on development of somatostatin subtype 5 receptor antagonists for obesity/diabetes treatment. Our results clearly point to Pept-1 as an important transporter for protein stimulation of secretion and subsequent basolateral calcium sensing receptor activation as a means for stimulation of secretion. All in all very promising results, which inspire to intensified research regarding these mechanisms. We expect the ongoing research to be able to map in detail the factors responsible for the exaggerated gut hormone secretion after bypass and to identify more nutrients that may play a role as functional food/neutraceuticals. We expect to be able to complete a comprehensive project on the clinical development of somatostatin antagonists during the rest of the project period. In addition, we are working on the development of coagonists/combinations of gut hormones for the treatment of obesity/diabetes. A new development is the increasing use of sleeve gastrectomy for both weight loss and diabetes therapy, also in our group. We have decided to investigate the mechanisms of action of these new operations in a similar detail as we have done with RYGB, because sleeve gastrectomy is nearly as effective and our studies will provide new information about the gut derived mechanisms involved. A future focus will be on ghrelin secretion and action, where we will do mimicry experiments in patients, and we also hope to be able to work with ghrelin antagonists, in particular based on LEAP 2, the newly identified naturally occurring antagonist.