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Endocrine Function after Bariatric Surgery

Ki‐Suk Kim, Darleen A. Sandoval

10.1002/cphy.c160019

Source: Volume 7, Issue 3, July 2017

Published online: June 2017

Full Article on Wiley Online Library



ABSTRACT

Obesity increases the risks of metabolic disorders including type 2 diabetes mellitus (T2DM). Bariatric surgery is the most successful therapeutic option that causes sustained weight loss and improvements in obesity comorbidities. Roux‐en‐Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are two of the most frequently performed bariatric surgeries. Despite their different anatomical rearrangement, they have remarkably similar success in both weight loss and T2DM remission. Interestingly, they also both cause a wide range of endocrine changes. Many of these endocrine changes are reflected specifically within the intestine and are implicated as mechanisms for the metabolic success of surgery. However, while most of the work shows that these hormonal changes are associated with the metabolic changes after surgery, causation has been difficult to ascertain. Here, we review the endocrine changes after RYGB and VSG and explore their mechanistic role in the success of bariatric surgery. Further, we explore important changes in gastrointestinal function and the role of these changes in the increase in postprandial endocrine responses after bariatric surgery. © 2017 American Physiological Society. Compr Physiol 7:783‐798, 2017.

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Figure 1. Figure 1. Changes in GI tract anatomy after RYGB and VSG. In RYGB, small gastric pouch is made and is anastomosed to the jejunum. The stomach and duodenum remain in the peritoneal cavity, and the distal end of the duodenum is anastomosed about 1 m distal to the pouch‐intestine juncture. Therefore, ingested foods bypass 95% of stomach and the majority of the upper intestinal tract. In VSG, 80% of the stomach along the greater curvature is removed.
Figure 2. Figure 2. Hormonal responses to a meal after RYGB and VSG and their hypothesized role in body weight and glucose regulation. RYGB and VSG cause many similar postprandial hormonal changes. For example, both surgeries increase total bile acids, FGF19, insulin, GLP‐1, PYY, and at least acutely after surgery, glucagon. However, while VSG reduces ghrelin and GIP, consistent changes in ghrelin are not seen after RYGB. RYGB additionally increases obestatin, motilin, GIP, and neurotensin. Based on the known physiological role of these hormones, we hypothesize that they could play a role in regulating either body weight (dashed lines), or glucose homeostasis (solid lines), or both.
Figure 3. Figure 3. Preproglucagon‐derived peptides expression and processing. Preproglucagon genes are predominantly found in the enteroendocrine L‐cells, pancreatic α‐cells, and within the nucleus of the solitary tract (NTS) in the hindbrain. Once the preproglucagon gene is translated into the proglucagon peptide, it is processed into several different peptides by tissue‐specific posttranslational modification. In pancreatic α‐cells, prohormone convertase 2 (Pcsk2) predominantly cleaves proglucagon to glicentin‐related pancreatic polypeptide (GRPP), glucagon, intervening peptide 1 (IP1), and major proglucagon fragment. Meanwhile in the enteroendocrine L‐cells and in the brain, Pcsk1 cleaves proglucagon into GRPP, oxyntomodulin (OXM), glucagon‐like peptide‐1 (GLP‐1), GLP‐2, and IP2.
Figure 4. Figure 4. Bile acid production and signaling. Bile acids are initially synthesized in the liver from cholesterol. These primary bile acids, cholic acid (CA), and chenodeoxycholic acid (CDCA) are usually stored in the gallbladder. When a meal is ingested, the primary bile acids flow into the small intestine to help with fat digestion. In the small intestine, some primary bile acids are processed into the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), by intestinal microbiota. These primary and secondary bile acids are reabsorbed by passive diffusion and active transport in the distal small intestine and consequently circulate back to the liver through the portal vein. The primary and secondary bile acids can be conjugated with taurine or glycine in the liver. This process is called enterohepatic circulation of bile acids. In addition to acting as a detergent, bile acids activate a G protein‐coupled receptor called TGR5, which, within the intestine, stimulates GLP‐1 secretion. In parallel, bile acids can activate a nuclear receptor transcription factor called FXR, which, in the intestine, stimulates the release of fibroblast growth factor 19 (FGF19). Both the RYGB and VSG increase total bile acids secretion but whether this is necessary for the increase in FGF19 and GLP‐1 increases are still unclear. However, genetic KO models suggest that both receptors are necessary for at least some surgical outcome.
Figure 5. Figure 5. Changes in digestive processes after RYGB and VSG. In both RYGB and VSG, there is a surgical restructuring of the stomach, which reduces peristalsis but increases gastric emptying rate (GER). While it remains unknown how these surgeries alter digestive enzyme content, there is limited macronutrient malabsorption after VSG and only fat malabsorption, as opposed to normal carbohydrate and protein absorption, is seen with RYGB. In addition, glucose absorption seems to be increased by both RYGB and VSG. Lastly, the increased GER likely contributes to the increased delivery of nutrients to the distal enteroendocrine cells (EEC) and this may contribute to the increase in gut peptide secretions.
Figure 6. Figure 6. The gut‐morphological changes after RYGB and VSG. The invasive surgical processes after RYGB and VSG cause different gut‐morphological changes. After RYGB, there are increases in villus height within the enterocytes and crypt cell proliferation and maturation within the Roux and common limb. Increased enteroendocrine cell (EEC) number and density in the Roux limb and common limb may contribute the increased gut peptide secretion. On the other hand, VSG has no impact on intestinal growth and crypt maturation, but does seem to cause villus height elongation and increased L‐cells numbers.


Figure 1. Changes in GI tract anatomy after RYGB and VSG. In RYGB, small gastric pouch is made and is anastomosed to the jejunum. The stomach and duodenum remain in the peritoneal cavity, and the distal end of the duodenum is anastomosed about 1 m distal to the pouch‐intestine juncture. Therefore, ingested foods bypass 95% of stomach and the majority of the upper intestinal tract. In VSG, 80% of the stomach along the greater curvature is removed.


Figure 2. Hormonal responses to a meal after RYGB and VSG and their hypothesized role in body weight and glucose regulation. RYGB and VSG cause many similar postprandial hormonal changes. For example, both surgeries increase total bile acids, FGF19, insulin, GLP‐1, PYY, and at least acutely after surgery, glucagon. However, while VSG reduces ghrelin and GIP, consistent changes in ghrelin are not seen after RYGB. RYGB additionally increases obestatin, motilin, GIP, and neurotensin. Based on the known physiological role of these hormones, we hypothesize that they could play a role in regulating either body weight (dashed lines), or glucose homeostasis (solid lines), or both.


Figure 3. Preproglucagon‐derived peptides expression and processing. Preproglucagon genes are predominantly found in the enteroendocrine L‐cells, pancreatic α‐cells, and within the nucleus of the solitary tract (NTS) in the hindbrain. Once the preproglucagon gene is translated into the proglucagon peptide, it is processed into several different peptides by tissue‐specific posttranslational modification. In pancreatic α‐cells, prohormone convertase 2 (Pcsk2) predominantly cleaves proglucagon to glicentin‐related pancreatic polypeptide (GRPP), glucagon, intervening peptide 1 (IP1), and major proglucagon fragment. Meanwhile in the enteroendocrine L‐cells and in the brain, Pcsk1 cleaves proglucagon into GRPP, oxyntomodulin (OXM), glucagon‐like peptide‐1 (GLP‐1), GLP‐2, and IP2.


Figure 4. Bile acid production and signaling. Bile acids are initially synthesized in the liver from cholesterol. These primary bile acids, cholic acid (CA), and chenodeoxycholic acid (CDCA) are usually stored in the gallbladder. When a meal is ingested, the primary bile acids flow into the small intestine to help with fat digestion. In the small intestine, some primary bile acids are processed into the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), by intestinal microbiota. These primary and secondary bile acids are reabsorbed by passive diffusion and active transport in the distal small intestine and consequently circulate back to the liver through the portal vein. The primary and secondary bile acids can be conjugated with taurine or glycine in the liver. This process is called enterohepatic circulation of bile acids. In addition to acting as a detergent, bile acids activate a G protein‐coupled receptor called TGR5, which, within the intestine, stimulates GLP‐1 secretion. In parallel, bile acids can activate a nuclear receptor transcription factor called FXR, which, in the intestine, stimulates the release of fibroblast growth factor 19 (FGF19). Both the RYGB and VSG increase total bile acids secretion but whether this is necessary for the increase in FGF19 and GLP‐1 increases are still unclear. However, genetic KO models suggest that both receptors are necessary for at least some surgical outcome.


Figure 5. Changes in digestive processes after RYGB and VSG. In both RYGB and VSG, there is a surgical restructuring of the stomach, which reduces peristalsis but increases gastric emptying rate (GER). While it remains unknown how these surgeries alter digestive enzyme content, there is limited macronutrient malabsorption after VSG and only fat malabsorption, as opposed to normal carbohydrate and protein absorption, is seen with RYGB. In addition, glucose absorption seems to be increased by both RYGB and VSG. Lastly, the increased GER likely contributes to the increased delivery of nutrients to the distal enteroendocrine cells (EEC) and this may contribute to the increase in gut peptide secretions.


Figure 6. The gut‐morphological changes after RYGB and VSG. The invasive surgical processes after RYGB and VSG cause different gut‐morphological changes. After RYGB, there are increases in villus height within the enterocytes and crypt cell proliferation and maturation within the Roux and common limb. Increased enteroendocrine cell (EEC) number and density in the Roux limb and common limb may contribute the increased gut peptide secretion. On the other hand, VSG has no impact on intestinal growth and crypt maturation, but does seem to cause villus height elongation and increased L‐cells numbers.
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Article Title: Endocrine Function after Bariatric Surgery
 

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Ki‐Suk Kim, Darleen A. Sandoval. Endocrine Function after Bariatric Surgery. Compr Physiol 2017, 7: 783-798. doi: 10.1002/cphy.c160019