Implantation of an endoluminal sleeve device in the duodenum and proximal jejunum mimics many of the effects of RYGB. In SD rats with diet-induced obesity, ELS implantation causes modest weight loss and substantially improves glucose homeostasis. Presence of this device in the proximal intestine also prevents the development of diet-induced obesity in otherwise susceptible animals. Despite creating a barrier between ingested nutrients and the duodenal mucosa, the ELS does not cause significant malabsorption. Rather, the observed weight loss results primarily from reduced calorie intake. In addition, ELS implantation appears to improve glucose homeostasis by multiple mechanisms. Both fasting blood glucose and insulin levels decrease after this procedure, which is reflected in a 55% decrease in HOMA-IR and is consistent with significant improvement of basal peripheral insulin resistance. Since hepatic glucose output is the major determinant of the fasting glucose level, these data suggest that ELS implantation leads to decreased hepatic glucose output, likely as a result of improved insulin signaling in hepatocytes. Improved oral glucose tolerance with a concurrent decrease in glucose-stimulated insulin levels further underscores an overall improvement in peripheral insulin sensitivity. The similar effect of ELS implantation on IP glucose tolerance suggests a global improvement in glucose homeostasis that is independent of post-prandial signals generated by endoluminal nutrient passage and also consistent with overall improvement of insulin sensitivity. The improvement in glucose tolerance suggests that ELS implantation also enhances glucose disposal. We observed no effect of the device on insulin tolerance, which is predominantly a marker of insulin-stimulated glucose disposal in muscle and adipose tissue. However, insulin tolerance testing is a relatively insensitive measure of peripheral insulin sensitivity, so these data are consistent with a modest effect of the device on glucose disposal in these tissues.
Although the ELS induces only about two-thirds as much weight loss as RYGB in the same strain of rats, the effect on glucose homeostasis is similar to that observed after RYGB (9
). This observation suggests that manipulations of the small bowel leading to duodenal exclusion and enhanced delivery of partially digested nutrients to the jejunum are primary mechanisms by which RYGB alters glucose metabolism. In contrast, the more limited effect of ELS on body weight suggests that other components of RYGB (e.g., gastric manipulation and/or partial vagotomy) likely make a significant contribution to the weight loss induced by this procedure. The differential ability of ELS implantation to mimic some of the effects of RYGB on body weight and glucose homeostasis underscores the complexity of GI regulation of these metabolic functions. It suggests that different components of RYGB contribute to the myriad effects of this operation and that multiple regions of the GI tract participate in the normal regulation of metabolic function. By examining selected components of this complex operation in isolation, we have attempted to dissect the contributions of these manipulations to the regulation of body weight, food intake, and glucose homeostasis. The differential effect of ELS on glucose homeostasis underscores the basic validity of this approach.
Of course, ELS is not merely a component of RYGB, and there are fundamental differences in the manner in which these two manipulations may affect GI anatomy and function. Although the ELS device prevents interaction between the nutrient stream and the mucosa of the proximal intestine, these regions of the gut are not completely bypassed as they are after RYGB. With ELS, nutrients pass through the lumen of the device and retain the opportunity to affect local mechanoreceptors and motor function. In addition, the presence of an endoluminal device in the duodenum (including the fixed anchor at the proximal end) may affect gastric emptying and gastric motility, two biological processes known to acutely regulate satiety (36
) more generally. We have observe by fluoroscopic assessment that gastric emptying seems to be somewhat slowed after ELS implantation. However, gastric emptying has not been formally measured; thus, a possible contribution of gastric motility effects to the observed weight loss, decreased food intake and improved glucose homeostasis cannot be excluded. Similarly, the potential contribution of increased energy expenditure to ELS-induced weight loss is currently unknown. We have observed the resting energy expenditure is increased after RYGB in rats, and pair-feeding (PF) studies suggest that this effect is a significant contributor to RYGB-induced weight loss. Given the similarities in the metabolic effects of the two procedures, we predict that ELS-treatment also affects energy expenditure and this can be experimentally addressed through PF studies and indirect calorimetry.
Within the lumen of the proximal intestine, duodenal, pancreatic, and biliary secretions further digest nutrients previously emulsified in the stomach. The macromolecular components of this chyme are then capable of interacting with chemoreceptors and mechanoreceptors in the mucosa and bowel wall to generate neurohumoral signals of nutrient intake, composition, and availability (6
). Candidate pathways mediating this communication include: (1) peptide hormones secreted by mucosal enteroendocrine cells; (2) non-peptide signals (e.g., lipids and carbohydrates) transported across the mucosal epithelium and released into the portal and lymphatic circulation; (3) enteric neuronal circuits that communicate with other regions of the gut directly or via reflex arcs; and (4) autonomic nervous pathways that communicate with the central nervous system. End-organ targets including other regions of the GI tract, the central nervous system (e.g., hypothalamus, brainstem and reward centers), the liver, and the pancreas (8
, 11 15
) normally coordinate a biological response to these gut-derived signals through the appropriate, compensatory regulation of energy intake, storage, and utilization. Implantation of the ELS appears to alter the luminal microenvironment of the duodenum and proximal jejunum by segregating ingested nutrients both from luminal secretions and from the mucosa of the proximal intestine. Minimally digested nutrients and GI secretions are then delivered to the jejunum. As a result, nutrient binding to chemoreceptors of the proximal intestine is prevented, ingested nutrients pass beyond the region of the ELS to potentially interact with regulatory chemoreceptors of the jejunum, and GI secretions untitrated by their usual substrates are exposed to the mucosa of the proximal small bowel. These alterations of the luminal environment likely modulate efferent gut signals to end-organ targets, thereby contributing to the observed effects of the device on feeding behavior, body weight, and glucose homeostasis.
The specific gut pathways activated in response to ELS-treatment are unknown. We and others have demonstrated that bypass surgery affects gut hormone secretion, particularly hormones implicated in the regulation of feeding behavior, satiety, glucose homeostasis, and the so-called “ileal brake” mechanism (9
). Neutralizing antibodies to peptide YY (PYY) reverse the inhibitory effects of jejunoileal bypass on food intake in thin rodents, suggesting a causal role for gut hormones in at least some of the effects of GIWLS (10
). In addition, ghrelin, a potent peripherally active orexigenic hormone, has been implicated in a compensatory hormonal response to weight loss induced by food restriction or restrictive bariatric procedures (6
). As with RYGB (6
), ELS treatment does not lead to increased ghrelin levels. This finding suggests that weight loss induced by intestinal exclusion and/or accelerated jejunal delivery of ingested nutrients does not stimulate a compensatory stimulus to ghrelin secretion. To date, the roles of specific gut hormones in the physiological effects of RYGB or ELS have not been established. Because of the limited nature of ELS implantation, exploration of the relative effects of ELS and RYGB on hormonal and neuronal signaling from the gut will reveal specific contributions of the proximal small bowel to the regulation of appetite, body weight and metabolic function.
In summary, exclusion of the proximal intestine from ingested nutrients and accelerated nutrient delivery to the jejunum induced by ELS mimic many of the effects of RYGB on body weight, food intake and glucose homeostasis. The substantial effect of ELS on glucose homeostasis compared to weight loss suggests an important role for the duodenum and jejunum in the regulation of this metabolic function. The more limited effect of ELS implantation on food intake and body weight suggests that other components of RYGB, particularly manipulation of the stomach, likely provide a substantial contribution to GI regulation of body weight and ingestive behavior. The degree to which all of these regulatory effects are mediated through the pancreas, liver, or central nervous system remains unknown but is an exciting and interesting area for further study. In the long term, understanding these mechanisms will likely lead to new targets and approaches for the treatment of obesity and diabetes. More immediately, the efficacy of the ELS device in this rat model brightens the prospect that its endoscopically-placed human analog will contribute to the treatment of these important disorders.