**4. Mechanisms involved in diabetes control or remission**

It is very clear that weight loss has a profound impact on diabetes control and much of the effects of bariatric surgery on glucose homeostasis were attributed to its impact on weight. However, several investigators demonstrated the very rapidly normalisation in glucose metabolism (in a few days), way before the weight loss becomes significant [24]. This suggests that diabetes remission may be due to mechanisms involving the surgical technique, aside from weight loss. The most common hypothesis are:

#### **4.1. Caloric restriction hypothesis**

It is well-known that very low calories diets may significantly and early improve glycemic control in diabetes patients [25], as caloric restriction can improve hyperglycemia through regulation of hepatic glucose production [26]. Considering the level of caloric absorption from the intestinal tract, all bariatric procedures are restrictive; caloric intake can be restricted by the inhibition of eating, as in AGB, SG or RYGB, or by the insufficient intestinal surface, as in BPD or other so-called "malabsorbtive" procedures.

In a recent study, Jackness et al compared the effect of a very low–calorie diet (VLCD) (500 kcal/day) and RYGB on β-cell function in type 2 diabetic patients during the first 3 weeks after intervention and reported similar degrees of weight loss and no significant differences in βcell function between the groups [27]. Similar results were presented by Plourde et al in a study regarding the improvement of insulin sensitivity and β-cell function following bilio-pancreatic diversion with duodenal switch (BPD-DS) [28]. Both groups concluded that caloric restriction was primarily responsible for the early effects of bariatric surgery procedures on glucose metabolism. However, this theory doesn't explain the long term differences in efficiency between the different bariatric procedures, despite the similar caloric restriction.

#### **4.2. The neural networks hypothesis**

The intestinal tract has important parasympathetic and sympathetic innervations. Vagally mediated reflexes are critical to the control, regulation and organization of appropriate GI functions, including hunger, appetite and satiety. Several studies have demonstrated that the behavior, activity and responsiveness of vagal afferents are altered by diet and obesity [29]. As shown by Browning et al [30], RYGB reversed some of the alteration of dorsal motor nucleus of the vagus neurons induced by high fat diet and improved vagal neuronal health in the brain. Sympathetic gut innervation, on the other hand, is involved in glucose production and release, inhibition of peristalsis and inhibition of gastrointestinal enzyme secretion. Weight loss induced by bariatric surgery may trigger profound sympathoinhibitory effects [31]

#### **4.3. The hindgut hypothesis**

**Figure 4.** Biliopancreatic diversion with duodenal switch

200 Treatment of Type 2 Diabetes

from weight loss. The most common hypothesis are:

BPD or other so-called "malabsorbtive" procedures.

**4.1. Caloric restriction hypothesis**

**4. Mechanisms involved in diabetes control or remission**

It is very clear that weight loss has a profound impact on diabetes control and much of the effects of bariatric surgery on glucose homeostasis were attributed to its impact on weight. However, several investigators demonstrated the very rapidly normalisation in glucose metabolism (in a few days), way before the weight loss becomes significant [24]. This suggests that diabetes remission may be due to mechanisms involving the surgical technique, aside

It is well-known that very low calories diets may significantly and early improve glycemic control in diabetes patients [25], as caloric restriction can improve hyperglycemia through regulation of hepatic glucose production [26]. Considering the level of caloric absorption from the intestinal tract, all bariatric procedures are restrictive; caloric intake can be restricted by the inhibition of eating, as in AGB, SG or RYGB, or by the insufficient intestinal surface, as in

In a recent study, Jackness et al compared the effect of a very low–calorie diet (VLCD) (500 kcal/day) and RYGB on β-cell function in type 2 diabetic patients during the first 3 weeks after intervention and reported similar degrees of weight loss and no significant differences in βcell function between the groups [27]. Similar results were presented by Plourde et al in a study This is probably the most accepted hypothesis that focuses on the expedited delivery of nutrients to the ileum after most of the bariatric procedures, which results in the accentuated production of peptides produced by L cells in the distal small intestine, including glucagonlike peptide (GLP)-1, peptide YY (PYY), and oxyntomodulin [32]. GLP-1 and PYY are both secreted by the L cells located in the distal gastrointestinal tract in response to nutrient ingestion and elicit almost the same metabolic responses. Together with GIP, they are respon‐ sible for the incretin effect, which consists in the greater insulin response after oral ingestion of glucose as compared with the insulin response after intravenous infusion of glucose when plasma glucose concentrations are the same [33].

It was shown that GLP-1 amplifies important steps in insulin synthesis and transcription, stimulates beta cell proliferation, reduces appetite and gastrointestinal motility [34]. It has been shown that GLP-1 is reduced in patients with type 2 diabetes and this have resulted in the development of t two drug classes currently approved for the treatment of T2DM: the longacting analogues of GLP-1, and the inhibitors of dipeptidyl peptidase 4 (the enzyme respon‐ sible for the rapid degradation of GLP-1) [33]. After RYGB, postprandial secretion of GLP-1 increases approximately 20 times [32]; this effect has been demonstrated as early as one week after surgery and persists for at least 10 years thereafter [35]. The improvement in incretin levels is not dependent on weight loss and, in diabetic patients, it has been paralleled by improved glucose tolerance [33]. An increased of postprandial GLP-1 levels has also been reported following gastric sleeve, apparently comparable to that obtained after RYGB, in the short and in the long term [36]. However, several recent studies suggest that the dramatic increase in GLP-1 secretion observed in the long term after RYGB surgery contributes to improved beta-cell function but does not appear to be the key determinant for the resolution of T2DM following this type of surgery [36]. Likewise, data from a rodent model have shown that blocking the action of GLP-1 does not influence the dramatic improvement in glucose tolerance observed after sleeve gastrectomy and therefore that GLP-1 receptor activity is not necessary for the beneficial metabolic effects of SG [37].

#### **4.4. The foregut hypothesis**

This theory suggests that the bypass of the duodenum and proximal jejunum after RYGB, or the lack of food exposure to these areas of the small intestine, might determine the decrease in secretion of an unknown duodenal factor (an antiincretin) influencing glucose homeostasis. The anti-incretin hypothesis, embraced by Rubino [38], postulates that, in addition to the wellknown incretin effect, nutrient passage in the bowel can also cause activation of negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms. Supporters of this theory suggest the physiologic necessity of these control mechanisms to prevent the risk for postprandial hyperinsulinemic hypoglycemia and uncontrolled beta cell proliferation induced by incretins. Excess of anti-incretin signals, perhaps stimulated by macronutrient composition or chemical additives of modern diets, might cause insulin resistance, reduced insulin secretion, and beta cell depletion, leading to type 2 diabetes [38]. On the other hand, bariatric surgery, by resecting or excluding parts of the small bowel from nutrients transit, changes the incretins/anti-incretins balance; this might explain the improvement or even the cure of type 2 diabetes, but also the postprandial hyperinsulinemic hypoglycaemia that can complicate RYGB [39]

#### **4.5. Other theories**

#### *4.5.1. Bile acids hypothesis*

Among the changes to intestinal physiology that occur after bariatric surgery is the altered enterohepatic circulation of bile acids. Bile acids are now recognized to be involved in the regulation of various metabolic processes including lipids, glucose, and energy homeostasis. Their binding to a nuclear receptor (farsenoid-X-receptor or FXR) produces alterations in hepatic glucose production and intestinal glucose absorption influences on peripheral insulin sensitivity and incretin effects [40]. After RYGB, fasting and postprandial serum concentrations of bile acids increase. Gerhard et al reported that patients with postoperative remission of diabetes after RYGB showed larger increases in fasting bile acids than did patients who did not achieve diabetes remission or who did not have diabetes preoperatively [41]. A recent study published by Karen Ryan and colleagues from the University of Cincinnati showed that VSG is associated with increased circulating bile acids and that, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signaling as an important molecular underpinning for the beneficial effects of bariatric surgery [42].

#### *4.5.2. Gut microbiota hypothesis*

The gut microbiota is recognized to have an important role in energy storage and the subse‐ quent development of obesity. It is well-known that obese individuals have an increased ratio of Firmicutes to Bacteroidetes bacteria and decreased bacterial diversity compared with lean controls—differences that disappear in response to weight loss, whether surgical or dietary intervention [43]. Recent studies proved the change in gut flora after RYGB; in addition to the standard decrease in the Firmicutes to Bacteroidetes ratio that accompanies weight loss, a major finding from microbial sequencing analyses after RYGB is the comparative overabun‐ dance of the phylum Proteobacteria in the distal gut microbiome [44]. In a murine bariatric model changes in gut microbiota were similar to those seen in humans after RYGB, and transfer of the surgically altered microbial species to non-operated, germ-free mice resulted in weight loss; this suggests that changes in gut microbiota might contribute to the beneficial effect of RYGB [45].

that blocking the action of GLP-1 does not influence the dramatic improvement in glucose tolerance observed after sleeve gastrectomy and therefore that GLP-1 receptor activity is not

This theory suggests that the bypass of the duodenum and proximal jejunum after RYGB, or the lack of food exposure to these areas of the small intestine, might determine the decrease in secretion of an unknown duodenal factor (an antiincretin) influencing glucose homeostasis. The anti-incretin hypothesis, embraced by Rubino [38], postulates that, in addition to the wellknown incretin effect, nutrient passage in the bowel can also cause activation of negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms. Supporters of this theory suggest the physiologic necessity of these control mechanisms to prevent the risk for postprandial hyperinsulinemic hypoglycemia and uncontrolled beta cell proliferation induced by incretins. Excess of anti-incretin signals, perhaps stimulated by macronutrient composition or chemical additives of modern diets, might cause insulin resistance, reduced insulin secretion, and beta cell depletion, leading to type 2 diabetes [38]. On the other hand, bariatric surgery, by resecting or excluding parts of the small bowel from nutrients transit, changes the incretins/anti-incretins balance; this might explain the improvement or even the cure of type 2 diabetes, but also the postprandial

Among the changes to intestinal physiology that occur after bariatric surgery is the altered enterohepatic circulation of bile acids. Bile acids are now recognized to be involved in the regulation of various metabolic processes including lipids, glucose, and energy homeostasis. Their binding to a nuclear receptor (farsenoid-X-receptor or FXR) produces alterations in hepatic glucose production and intestinal glucose absorption influences on peripheral insulin sensitivity and incretin effects [40]. After RYGB, fasting and postprandial serum concentrations of bile acids increase. Gerhard et al reported that patients with postoperative remission of diabetes after RYGB showed larger increases in fasting bile acids than did patients who did not achieve diabetes remission or who did not have diabetes preoperatively [41]. A recent study published by Karen Ryan and colleagues from the University of Cincinnati showed that VSG is associated with increased circulating bile acids and that, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signaling as an important molecular underpinning

The gut microbiota is recognized to have an important role in energy storage and the subse‐ quent development of obesity. It is well-known that obese individuals have an increased ratio

necessary for the beneficial metabolic effects of SG [37].

hyperinsulinemic hypoglycaemia that can complicate RYGB [39]

for the beneficial effects of bariatric surgery [42].

*4.5.2. Gut microbiota hypothesis*

**4.4. The foregut hypothesis**

202 Treatment of Type 2 Diabetes

**4.5. Other theories**

*4.5.1. Bile acids hypothesis*
