Periodic Reporting for period 4 - BYPASSWITHOUTSURGERY (Reaching the effects of gastric bypass on diabetes and obesity without surgery)
Reporting period: 2021-07-01 to 2023-06-30
Gastric bypass surgery results in massive weight loss and diabetes remission showing that mechanisms in the body can cure diabetes and obesity. Revealing the nature of these mechanisms could lead to new treatments. We think hyper-secretion of gut hormones mediates the effect of surgery but what is the mechanism behind the hypersecretion? We have addressed all elements of these responses by detailed analyses of food items but also the importance of the anatomical rearrangement for the molecular mechanisms leading to hypersecretion. Novel approaches for studies of human gut hormone secreting cells, including specific expression analysis, are combined with advanced experimental models. 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 was to identify factors which cause hypersecretion of gut hormones after RYGB. Many factors have been proposed based on studies in mice, which rarely apply to humans. After bypass, nutrients pass very rapidly to lower sections of the gut where cells producing appetite-regulating hormones are more plentiful. Here, the nutrients are digested and absorbed extremely rapidly and this leads to exaggerated hormone secretion. Using isolated perfused gut (rats and mice), we can reproduce this and map the cellular processes leading to secretion. For instance, bile salts have to be specifically taken up by the cells and transported through the cells to interact from the basolateral side with a specific receptor which, in turn, via a now characterized signal system, leads to secretion. Thus, the exaggerated exposure of segments that are not normally exposed is mechanism behind the hypersecretion. This can be mimicked in unoperated subjects with certain carbohydrates (e.g. isomaltulose). We identified further regulating mechanisms that can be manipulated pharmacologically (e.g. the regulation by an inhibitory transmitter, somatostatin). We also carry out experiments with administration of cocktails of exogenous hormones and have demonstrated strong subchronic inhibition of food intake, suggesting that this approach may be developed into future therapies
Surprisingly we found that the carbohydrate component of mixed meals is responsible for the strongest stimulation of GLP-1 secretion, whereas for PYY stimuli are more complex. Simple monosaccharides including glucose in particular are important, but more complex carbohydrates (e.g. isomaltulose) and also combinations with glycosidase inhibitors in healthy subjects can mimic the profiles after RYGB. We mapped the intestinal bile kinetics after RYGB and identified the bile salts as major players for both ileal and colonic hormone secretion. Bile and lipids are particularly important for neurotensin secretion, but even very high infusions rates of neurotensin had very little effect on appetite and food intake. Studies in RYGB and Sleeve Gastrectomy patients with bile acid sequestrants (cholesevelam) for several weeks are currently being performed. If bile is indeed essential for weight loss and diabetes resolution , this should impair both glucose control and weight maintenance. We identified somatostatin as the most powerful regulator of GLP-1 secretion. And we have identified somatostatin subtype 5 receptor antagonists as potential agents for obesity/diabetes treatment, a project which we are currently following up with clinical studies. Other results clearly point to the amino acid transporter Pept-1 with subsequent basolateral calcium sensing receptor activation as being essential for protein stimulation of GLP-1 secretion. GPR 142 activation caused GIP secretion but was ineffective regarding GLP-1 and PYY secretion. Currently we are mapping the contribution of each of the dietary amino acids. Surprisingly, we identified in both rodents and in humans a release after bypass from the distal ileum of secretin, and this may have metabolic consequences. Regarding the colon, we will look at metabolites generated by the intestinal microbiota, suggested to act on metabolism via secretion of gut hormones. We continue to work on the development of co-agonists/combinations of gut hormones for the treatment of obesity/diabetes, currently in collaboration with Imperial College London regarding triple agonism (PYY, oxyntomodulin and GLP-1). Extensive comparative studies of sleeve gastrectomy (SG) and RYGB suggested involvement of GIP and ghrelin in SG. We have recently performed experiments with a GIP receptor antagonist, developed in our lab and suitable for human use, which in combination with a GLP-1 antagonist clearly demonstrated the superior importance of GLP-1 for the results obtained with gastric bypass, whereas GIP is more important in healthy controls and after sleeve gastrectomy. We also look at the role of ghrelin by restoring levels by infusions in operated patients (which is important for insulin secretion it turns out). We have also completed both metabolomics and proteomics studies , the results of which need further digestion. We recently could definitively weaken the decretin hypothesis supported by many (the upper gut hypothesis) showing that the favorite candidate neuromedin U was unlikely to play a role. We also studied studies of changes in the gut microbiota after RYGB. Our study of lipids as stimuli for gut hormone secretion, the first of its kind, is out and showed that also lipid digestion is accelerated and a hierarchy for lipid components to stimulate gut hormones was established. We identified FGF 19 as possible metabolic factor, and now use isolated perfused intestine to investigate FGF 19 secretion further and FGF 19 was identified associated in a clinical study with proteomics analysis in RYGB patients with and without hypoglycemia. Our tracer studies in the operated patients have given us accurate and detailed information about the postoperative kinetics of nutrient flow (e. g. an extensive study published in the prestigious journal Gastroenterology, comparing digestion and absorption of meals in SG and RYGB patients). We have performed major randomized longitudinal studies comparing consecutive SG and RYGB patients with Norwegian colleagues (emphasizing the importance of GLP-1 secretion ofr the superiority of bypass compared to sleeve gastrectomy) and we completed a major study of responder-non-responders to RYGB using sham-feeding technology and pancreatic polypeptide responses to study vagal function, as well as somatostatin-induced inhibition of the gut hormone secretion (now published in major journal) . Responders showed markedly enhanced ad lib food intake, whereas the non-responders did not react at all. Thus, non-responsiveness is due to insensitivity to the anorectic gut hormones, clearly pointing to differential probably genetic receptive mechanisms, which , in spite of major efforts, could not be identified! However these efforts will be continued using deeper sequencing of the receptor genes.