Bariatric Times

FEB 2018

A peer-reviewed, evidence-based journal that promotes clinical development and metabolic insights in total bariatric patient care for the healthcare professional

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14 Review Bariatric Times • February 2018 Roux-en-Y gastric bypass (RYGB) is a mixed technique combining both gastric and small bowel mechanisms. It includes generating a small gastric pouch (15–30mL) on the lesser gastric curvature, which is isolated from the gastric remnant and anastomosed to the jejunum, leaving an alimentary or Roux limb of typically 100 to 150cm. Bowel continuity is restored by an entero-enteric anastomosis between the excluded biliopancreatic limb and the alimentary limb (Figure 1b). This anastomosis is usually performed 100 to 150cm distal to the gastro-jejunostomy, although it has been also performed up to 250cm distally in an attempt to create caloric malabsorption. However, most patients after RYGB become constipated, so caloric malabsorption does not appear to play a role. 14 Sleeve gastrectomy (SG) is based on the resection of the main part of the fundus and corpus of the stomach, starting 2 to 8cm proximally to the pylorus (Figure 1c). This procedure was initially used as the first step in a two-staged approach applied in patients with extreme obesity, due to technical difficulties of performing bypass surgical techniques in one single session. However, significant weight loss and metabolic improvement was observed after SG alone, thus making the method very popular as a standalone procedure. Finally, biliopancreatic diversion (BPD), with or without duodenal switch, does create caloric malabsorption. This operation consists of a horizontal gastrectomy and anastomosis between the remaining stomach and the distal 250cm of the small intestine. The bypassed duodenum, jejunum, and part of the proximal ileum carry bile and pancreatic secretions and are connected to the alimentary limb 50cm proximal to the ileocecal valve (Figure 1d). Most procedures are performed laparoscopically, with small operative times and low complication rates. The major limitation of LAGB is that approximately 20 percent of patients do not experience any changes in hunger and hence no weight loss. They often regain weight and need to undergo multiple revisional operations. 15 The major complications associated with the remaining types of surgery include physiological (dumping syndrome, chronic nutritional deficiencies, loss of bone density, and kidney/gallbladder stone formation) and mechanical (abdominal pain, anastomotic stenosis) side effects. 14 PATHOPHYSIOLOGY OF WEIGHT LOSS AND T2DM REMISSION AFTER BARIATRIC SURGERY Metabolic surgery is able to induce and maintain substantial weight loss through a variety of mechanisms, including caloric restriction, as a result of the anatomical remodeling of the gastrointestinal tract; increased meal-induced thermogenesis; modulation of hypothalamic neuronal circuits involved in energy balance and appetite regulation; altered taste, food preferences, and eating behavior patterns; and altered gut-brain signaling pathways. 1,3,14,16–18 With regard to amelioration of the metabolic milieu leading to T2DM remission, the beneficial effects of metabolic surgery are mediated to a significant extent by two important factors: the hypocaloric state due to profound caloric restriction and the significant weight loss achieved. Studies involving patients with T2DM have demonstrated that caloric restriction to the extent observed during the first 10 to 20 days after RYGB has the same immediate effect on insulin sensitivity and blood glucose levels as surgery. 17 However, there is no enhanced incretin effect with caloric restriction alone, and it is essentially impossible for people with obesity and diabetes to maintain this drastic restriction for a prolonged period of time. There are also other well- established weight loss-independent therapeutic effects (specific to bariatric surgery) that can be observed in the early postoperative period preceding major weight loss and cannot be reproduced by comparable diet-induced weight loss. The major pathophysiological mechanisms mediating these beneficial metabolic effects of upper gastrointestinal tract bypass surgery in particular comprise the following: effects on multi-organ insulin sensitivity (hepatic and skeletal muscle), ß-cell functioning, changes in bile acid (BA) composition and flow, modifications of gut microbiota, and intestinal glucose metabolism, and increased metabolic activity of brown adipose tissue. 16 Whether the effects of surgery, particularly RYGB and LAGB, on insulin sensitivity are totally independent of weight loss remains controversial, since a similar improvement of insulin action has been demonstrated in nonsurgically treated patients losing the same amount of weight under a comparable dietary caloric restriction. 16 On the contrary, BPD appears to exert unique effects on insulin sensitivity; studies have shown rapid clamp-assessed insulin sensitivity improvement after a minimal weight loss of less than 10 percent. 16 The short- and long-term effects of metabolic surgery on tissue-specific insulin sensitivity currently represent a highly interesting field of research. Rapid improvement of hepatic insulin sensitivity in the short-term might be a result of the sudden and profound caloric restriction, whereas the beneficial effects on skeletal muscle insulin action are observed later (mid- and long-term effects) and are therefore predominantly driven by weight loss. 1,16 The first phase of insulin secretion and the incretin effect, both of which are severely impaired in patients with T2DM, are rapidly restored to normal after metabolic surgery, especially with RYGB. 14,16 The anatomical bypass of the proximal intestine and the rapid delivery of undigested food from stomach to small intestine lead to a rapid increase of circulating incretin levels (glucagon-like peptide 1 [GLP- 1], glucose-dependent insulinotropic peptide [GIP]), which in turn might promote pancreatic insulin release and gradually improve ß-cell function (hindgut hypothesis). Beyond incretins, additional gastrointestinal postprandial satiety hormones, such as peptide YY (PYY), are significantly elevated. 16,19 The driving force behind first- phase insulin secretion restoration is still a matter of controversy; severe caloric restriction, massive weight loss, and the robust increase in postprandial incretin secretion might all be implicated. In favor of the first hypothesis, a study that included 11 patients with T2DM who underwent caloric restriction similar to that immediately after bariatric surgery showed beta cell function normalization, increased insulin sensitivity, restoration of first-phase insulin secretion, and ultimately diabetes reversal. 20 In support of the effect of weight loss, studies using intravenous glucose tolerance tests (IGTTs), in which insulin secretion is, by definition, incretin- independent, have also shown major improvements in both bariatric patients with diabetes as well as those without diabetes. 21,22 The merits of the enhanced incretin response cannot, however, be overlooked; in an elegantly conceived study, five patients who had undergone RYGB and, for medical reasons, had a gastrostomy tube placed, exhibited a much lower incretin and insulin response the administration of a glucose load through the gastrostomy (thus negating the effect of proximal gut bypass) than when the same load was given orally. 23 Thus, it is quite plausible that all the above putative mechanisms (and possibly others) act in concert to restore early postprandial insulin secretion in bariatric patients. Regarding the enhanced incretin response, although the hindgut hypothesis appears quite plausible, studies have also focused on the role of the foregut (foregut hypothesis). It has been postulated that diabetogenic "anti-incretin" hormones are normally released when a meal passes through the proximal small intestine, and that rerouting food with bypass surgery reduces their secretion, thus promoting antidiabetic effects. 17 Although research points to a role of the foregut in T2DM remission after RYGB, no such hormones have yet been identified. BA metabolism has recently emerged as an additional important contributor of surgically induced metabolic improvement, with an accumulating body of evidence showing alterations in BA composition and flow after metabolic surgery. It has been postulated that weight loss after RYGB might be associated with increased fasting and postprandial serum BA levels. 3,14,16 However, there is no direct evidence to confirm a causal relationship between circulating BA concentrations and an improved metabolic milieu in surgical patients. Data in this field are conflicting. Contrary to RYGB, however, LAGB has been associated with reduced basal and postprandial serum BA concentrations, in parallel, with a similar improvement in ß-cell function and insulin sensitivity compared to RYBG. The above data, support that changes in BA metabolism are important players, but firm conclusions regarding the causality of this relationship and its clinical implications cannot yet be drawn. RYGB-induced weight loss has been further associated with changes in gut microbiota, namely increased intestinal microbial diversity, and changes in the relative amounts of specific bacterial phyla and species. 14,16 The major factors leading to these modifications include changes in body weight, dietary intake, nutrient flow through the intestine, gut motility, intraluminal pH, and bile flow. Whether the beneficial effects of altered gut microbiota on glucose homeostasis are weight loss-independent remains unclear. Animal data have shown that RYGB induces villus hyperplasia and increases villus height in the Roux limb, thereby leading to increased intestinal glucose uptake. 16 In human studies with positron emission tomography (PET) scans and clamps, an increased insulin-stimulated jejunal glucose uptake six months after RYGB surgery in patients with or without T2DM has been shown. However, the magnitude of intestinal glucose retention after mixed meal ingestion in humans is considered to be too small to induce a clinically relevant improvement of postprandial glycemic control. Finally, it has been proposed that the increased BA and incretin levels The short- and long-term effects of metabolic surgery on tissue-specific insulin sensitivity currently represent a highly interesting field of research.

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