Mechanism of diabetes control after metabolic surgery

Introduction

The notion that gastro-intestinal (GI) surgery may alter glucose tolerance curve in peptic ulcer patients was first reported in 1930’s (1). Then, Evensen described the development of hypoglycemia several years after gastrectomy for peptic ulcer disease in 1942 (2). Increased insulin sensitivity as the underlying mechanism was proposed. However, the initiation of metabolic surgery started from the report by Pories et al. in 1995 (3). In this landmark paper, the authors reported that gastric bypass is the most effective therapy for type 2 diabetes (T2D) in morbidly obese patients and 90% of them remained diabetes free 10 years later. He suggested that caloric restriction played a key role and the relative Rubino, then, rejuvenated the metabolic surgery by publishing the provoke concept of duodenum exclusion for the treatment of diabetes by an elaborate animal experiment in 2004 (4). Historically, bariatric operations were thought to promote weight loss by causing gastric restriction and/or mal-absorption. However, discrete parts of GI tract differentially influence glucose homeostasis and may be influenced by various types of bariatric/metabolic procedures. Rubino’s study initiated many elaborated basic studies, in parallel with establishment of the GI tract as a key regulator of energy and glucose homeostasis, improved the understanding of the mechanism of T2D remission after metabolic surgery. Diabetes remission after metabolic surgery results from improvement in both insulin resistance and beta-cell dysfunction, mainly the increase in early phase insulin release (5,6). Nevertheless, the dramatic resolution of T2D was induced by the interaction of multiple organ-related pathways involving the brain, gut, liver, pancreas, muscle, adipose tissue and others (7-9). Different type of metabolic surgery have different degree of their improvement and provide a best chance for scientist to investigate the mechanism involved in T2D remission after surgery. Understanding which part of the anatomical rearrangement of GI metabolic surgery is essential for the glycemic control of T2D and may help us to elucidate the molecular mechanism of T2D control. Despite a lot of progress in the past decade, the physiology of remission is still incompletely understood. This review will describe the anatomic and physiologic changes in GI metabolic surgery. The main proposed hypotheses of the possible mechanism underlying the glycemic effects of metabolic surgery are also discussed below.

Anatomic changes and GI reroute

Metabolic surgery is a GI surgery and its effect is through various GI anatomic changes and reroute. It can be summarized into:

Gastric restriction

Intestinal total bypass was the first bariatric surgery but failed in high incidence of severe malnutrition causing protein deficiency, liver cirrhosis and mortality (10). Instead of total intestinal bypass, partial jejunoileal bypass was proposed for the control of hyperlipidemia (11). This procedure was effective in lipid control and only a minimal weight loss effect at 25-year follow-up. Vertical banded gastroplasty (VBG) was the first successful bariatric procedure with a pure gastric restriction effect. Laparoscopic adjustable gastric banding (LAGB) is another pure gastric restrictive procedure. Both procedures can provide about an average of 15% total weight loss in a long-term but many patients required revision for weight regain (12). The gastric restrictive effect of gastric bypass was provided by a small gastric pouch and small gastro-jejunal anastomosis. Weight regain after gastric bypass was commonly attributed to dilated gastric pouch and wide anastomosis (13). Proposed management of weight regain after gastric bypass were resizing the gastric pouch or endoscopic downsizing the gastrojejunostomy (14,15). Therefore, gastric restrictive effect was considered to be the most important part of metabolic surgery and consisted about 70% of the effect of gastric bypass (16).

Exclusion of duodenum and upper intestine

Duodenum and upper intestine plays an important role on nutrient absorption and glycemic control through a complex series of hormonal and neural responses (9). The duodenum and upper jejunum sense nutrients and initiate feed-back mechanisms through a gut-brain-liver neuron axis to regulate glycemia (17). The pathophysiology of T2D may be due to a malfunction of duodenum glycemic regulation mechanism (4). Reroute the GI tract by Roux-en-Y reconstruction cause exclusion of duodenum and upper part of the jejunum from exposure to ingestion nutrients. This anatomic change may change the physiologic response of digestive enzyme secretion from duodenum, gut hormone changes and nutrient sensing of upper small intestine (18,19). For example, duodenojejunal bypass (DJB), was a procedure to exclude the duodenum and proximal jejunum without gastric restriction, improved glycemic control without reduction of food intake and weight loss (20). A recent developed new device, duodenum jejuna sleeve tube, also had the similar effect as DJB (21).

Rapid delivery of food to distal intestine or short common channel

Reroute GI tract of gastric bypass not only exclude the duodenum but also exclude the function of pylorus. Therefore, may rapidly deliver incompletely digested food to the distal bowl which may induce a strong gut hormone change, mainly glucagon-like peptide (GLP-1) and peptide YY (PYY) (22,23). This effect may also cause the fluctuation of bile acid and change of microbiota (24,25). Interestingly, sleeve gastrectomy was found to have this effect without reroute GI tract possibly due to rapid intestine transit time (26).

Mechanism of effect

Overwhelming evidence have supported that effective diabetes resolution was achieved in obese T2D patients after undergoing metabolic surgery. The underlying mechanism for diabetes remission after metabolic surgery is intriguing. Initially, five possible mechanisms had been proposed, including the starvation-followed-by weight-loss hypothesis, the ghrelin hypothesis, the lower intestinal (hind-gut) hypothesis and the upper intestinal (fore-gut) hypothesis. More theories were proposed recently, including bile acid and microbiota. None of these theories necessarily precludes the others. Therefore, any combination of these mechanisms may contribute to some degree in T2D remission and it is very difficult to design a study to elucidate the exact mechanism. The main proposed mechanism underlying the glycemic effects of metabolic surgery are discussed below.

Calorie restriction and weight loss

The gastric restriction part of various type of metabolic surgery may contribute to calorie restriction and subsequent weight loss which can have potent effects on insulin sensitivity. Simply calorie restriction to 1,100 kcal/d for 48 h could result in improved hepatic insulin sensitivity with reduced hepatic gluconeogenesis (27). A longer calories restriction with very low-calorie diet (VLCD) of 500 kcal/d may not only improve insulin resistance but also beta-cell function, evident by restoration of early phase insulin secretion (28). Using VLCD up to 8 weeks may reduce the pancreatic fat content which can restore the first-phase insulin secretion of T2D patients (29,30). However, improvement of skeletal muscle insulin resistance required greater weight loss (>20%) after gastric bypass or gastric banding (31,32).

Ghrelin effect

Ghrelin is an orexigenic gut hormone mainly secreted from the gastric fundus and displays a cyclic rhythm with an increase before meals and decrease after meals. Ghrelin has been shown to have diabetogenic effects because ghrelin injection in human suppresses insulin secretion and may induce hyperglycemia (33). It was found that weight loss induced by diet control may lead to compensatory homeostatic changes, including increased hunger, increased circulating ghrelin, and reduced circulating GLP-1 and PYY (34). These changes are likely to contribute to the high degree of weight recidivism with dieting. However, ghrelin is undoubtedly decreased long-term after fundus resection which may play an important role in the sustainable effect of weight after sleeve gastrectomy (35,36). The data after gastric bypass are inconsistent and contradict each other when the gastric segment is disconnected from food contact but not resected in gastric bypass procedure (37-39). Therefore, the maintenance of weight loss after gastric bypass may rely on the change of GLP-1 and PYY than ghrelin (21,40).

Foregut effect

Duodenum and upper intestine plays an important role on glycemic by incretin effect. Incretin effect is a phenomenon known as when oral glucose will promote greater insulin release than dose isoglycemic glucose administered parentally. Incretin effect is predominantly mediated by the incretins GLP-1 and gastric inhibitory polypeptide (GIP). Anti-incretin or decretin was first proposed by Rubino to play as a counterbalance the effects of incretin (41). Patients with T2D are characterized by a blunt incretin effect control and may be due to the overproduction of anti-incretins and can be treated by duodenum exclusion (4). Many clinical studies supported the efficacy of duodenum exclusion on T2D treatment (20, 42-44). Although specific human anti-incretins have not yet been found, a strong candidates, name as decretin, was recently been identified in animal (45). DJB tube was a concept pioneered by Rubino for the treatment of T2D in animal model (46). A recent developed new device, duodenum jejuna sleeve tube or liner, was demonstrated having a similar glycemic control effect in human (21). Duodenum exclusion might create a biliopancreatic (BP) limb which consisted of duodenum and upper intestine without food exposure. The role BP limb is intriguing because the finding of nutrient sensing and gut-brain talk of upper jejunum (17). A recent animal study reported the importance of BP limb length, the longer the better, in glycemic control (47). A more important finding of this study was the existing of BP limb is essential for the glycemic control because excision of the BP limb will abolish the glycemic effect.

Hindgut effect

The rapid delivery of nutrients to the distal bowel will stimulate the secretion of GLP-1 and PYY. GLP-1 is an incretin hormone, promoting post-prandial insulin release and improving pancreatic beta cell function. GLP-1 is suppressed in T2D (48) and GLP-1 agonists is now widely used in the treatment of T2D (49). Some reports using elegant study design have found that GLP-1 is playing a significant role in T2D resolution after gastric bypass (50,51). This response was also observed after sleeve gastrectomy (22,23). However, the role of GLP-1 in T2D resolution after metabolic surgery was questioned by some reviews (52,53) as well as in some studies of mouse in which GLP-1 was not required for either T2D resolution or weight loss after bypass or sleeve gastrectomy (54-56).

PYY is an anorexic hormone co-secreted with GLP-1 from the “L-cell” of distal bowel in response to nutrients. PYY acts to decrease food intake with faster satiation and may reduce insulin resistance. The elevation of PYY was usually associated with the elevation of GLP-1 but was not observed after gastric banding (57).

Recent studies had shown that hindgut theory might involve the molecular mediator that ameliorated T2D, including bile acid and microbiota. These two important molecular mechanisms will be discussed in following.

Bile acid

Bile acids are synthesized from cholesterol in the liver and secreted into duodenum through bile duct to facilitate the absorption of lipids via formation of micelles. Most of the bile acid (95%) was absorbed from small bowel and recycling of bile acid occurs about 6–12 times per day. Bile acids not only function in lipid absorption but also play an important role in glucose metabolism. Bile acids are a ligand of the farnesoid X receptor (FXR) in the liver and small intestine, affecting hepatic metabolism and G-protein-coupled bile acid activated receptors (TGR-5) of the L-cell and promoting the release of incretin (58-60). Systematic bile acid levels were found to be elevated in patients following gastric bypass but not in gastric banding (56,61-63), suggesting an increase stimulation of FXR after gastric bypass. In contrast to systematic reaction, bile acid release in the gut can selectively activates intestinal FXR and promotes adipose tissue browning, reduces obesity and insulin assistance (64). Bile acid was found in many clinical studies and animal models support the key role of bile acids and bile acid receptor is a potential target for new drug development (65). Recently FXR has also been shown to be the key role for the anti-diabetic effect of sleeve gastrectomy (66). Bile acids signaling through FXR may be a common mechanism involved in the mechanism of bariatric/metabolic surgery. Further delineation of the molecular mechanisms underlying these beneficial effects could provide targets for the development of new nonsurgical treatments.

Microbiota

Bacteria colonize the gut soon after birth and become stabilized after the age 2. The gut microbiota was recently recognized to play an important role in energy metabolism and might contribute to the epidemics of obesity and T2D (67). Studies have demonstrated that obesity is associated with increased Firmicutes and decreased Bacteroides levels compared with normal person (68,69). In addition, obesity was also found to have reduced bacterial diversity (70). Bariatric surgery was found to decrease firmicutes and increase Bacteroides level, as well as increase the bacterial diversity (71,72). However, these changes can also be induced by diet changes (73,74). Another factor which may contribute to the change of microbiota after surgery is the change of bile acid concentration and fecal composition in distal gut. Fecal waters were found to be highly cytotoxic after surgery which may cause change of microbiota (75). A study in human observed that change of bile acid concentration and composition was associated with dysbiosis of the gut microbiota (76). Overall, it seems that surgery induced food intake change, weight loss and GI reroute all have important role in microbiota composition after metabolic surgery but microbiota change is more like to a result rather than a cause.

Conclusions

The success of metabolic surgery for the treatment of T2D depends on several mechanisms. Three important anatomic changes after metabolic surgery may initiate several important mechanisms for T2D remission. Gastric restriction is the first important anatomic change which will induce decreasing calories intake and followed by weight loss. Decrease of ghrelin after sleeve gastrectomy may be important in prevention of weight regain. Duodenum and upper intestine exclusion is the second anatomic change which may decrease fat absorption, change bile acid entero-hepatic flow. Rapid delivery food to distal bowel is the third anatomic change which will induce the GLP-1 and PYY changes but more important may be the change of bile acid recycle and increase bile acid blood level. Bile acid is a molecule that may play an important role in T2D remission after metabolic surgery. Further studies through the application of detailed phenotyping, genomics, metabolomics, and gut microbiome studies will enhance our understanding of metabolic surgery and help identify novel therapeutic targets.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Laparoscopic and Endoscopic Surgery for the series “Laparoscopic Metabolic Surgery for the Treatment of Type 2 Diabetes in Asia”. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ales.2017.07.05). The series “Laparoscopic Metabolic Surgery for the Treatment of Type 2 Diabetes in Asia” was commissioned by the editorial office without any funding or sponsorship. WJL served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Laparoscopic and Endoscopic Surgery from Jun 2016 to May 2018. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Barnes CG. Hypoglycaemia following partial gastrectomy: report of three cases. Lancet 1947;2:536-9. [Crossref] [PubMed]
2. Evensen OK. Alimentary hypoglycemia after stomach operations and influence of gastric emptying on glucose tolerance curve. Oslo Acta Medica Scandinavica 1942;143-153.
3. Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation provides to be the most effective therapy for adult onset diabetes mellitus. Ann Surg 1995;222:339-350. [Crossref] [PubMed]
4. Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann surg 2004;239:1-11. [Crossref] [PubMed]
5. Lee WJ, Ser KH, Chong K, et al. Laparoscopic sleeve gastrectomy for diabetes treatment in non-morbidly obese patients: Efficacy and change of insulin secretion. Surgery 2010;147:664-9. [Crossref] [PubMed]
6. Lee WJ, Chong K, Chen CY, et al. Diabetes remission and insulin secretion after gastric bypass in patients with body mass index < 35 Kg/m2. Obes Surg 2011;21:889-95. [Crossref] [PubMed]
7. Cho YM. A gut feeling to cure diabetes: Potential mechanisms of diabetes remission after bariatric surgery. Diabetes Metab J 2014;38:406-15. [Crossref] [PubMed]
8. Pok EH, Lee WJ. Gastrointestinal metabolic surgery for the treatment for the treatment of type 2 diabetes mellitus. World J Gastroenterol 2014;20:14315-28. [Crossref] [PubMed]
9. Batterham RL, Cummings D. Mechanisms of diabetes improvement following bariatric/metabolic surgery. Diabetes Care 2016;39:893-901. [Crossref] [PubMed]
10. Umemura A, Lee WJ, Sasaki A, et al. History and current status of bariatric and metabolic surgeries in East Asia. Asian J Endosc Surg 2015;8:268-74. [Crossref] [PubMed]
11. Buchwald H. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesteronemia. NEJM 1990;323:946-55. [Crossref] [PubMed]
12. Lin YH, Lee WJ, Ser KH, et al. 15-year follow-up of vertical banded gastroplasty: comparison with other restrictive procedures. Surg Endosc 2016;30:489-494. [Crossref] [PubMed]
13. Dayyeh BA, Lautz DB, Thompson CC. Gastrojejunal stoma diameter predicts weight regain after Roux-en-Y gastric bypass Clin Gastroenterol Hepato 2011;9:228-233.
14. Hamdi A, Julien C, Brwon P, et al. Mid-term outcomes of revisional surgery for gastric pouch and gastrojejunal anastomotic enlargement in patients with weight regain after gastric bypass for morbid obesity. Obes Surg 2014;24:1386-90. [Crossref] [PubMed]
15. Dakin GF, Eid G, Mikami D, et al. Endoluminal revision of gastric bypass for weight regain--a systematic review. Surg Obes Relat Dis 2013;9:335-42. [Crossref] [PubMed]
16. Ochner CN, Gibson C, Shanik M, et al. Changes in neurohormonal gut peptide following bariatric surgery. Int J of Obesity 2011;5:153-66. [Crossref]
17. Wang PY, Caspi L, Lam CK, et al. Upper intestine lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 2008;452:1012-6. [Crossref] [PubMed]
18. Salinari S, le Roux CN, Bertuzzl A, et al. Duodenal jejuna bypass and jejunectomy improve insulin sensitivity in Goto-Kakink diabetes rats without changes incretins or insulin secretion. Diabetes 2014;63:1069-78. [Crossref] [PubMed]
19. Habegger KM, Al-Massadis O, Hepperer KM, et al. Duodenum nutrient exclusion improve metabolic syndrome and stimulate villa hypertrophy. Gut 2014;63:1238-46. [Crossref] [PubMed]
20. Lee HC, Kim MK, Kwon HS, Kim E, Song KH. Early changes in incretin secretion after laparoscopic duodenal-jejunal bypass surgery in type 2 diabetes patients. Obes Surg 2010;20:1530-1535. [Crossref] [PubMed]
21. Escalona A, Pimentel F, Sharp A, et al. Weight loss and metabolic improvement in morbidly obese subjects implanted for 1 year with endoscopic duodenal-jejunal bypass liner. Ann Surg 2012;255:1080-5. [Crossref] [PubMed]
22. Lee WJ, Chen YC, Chong K, et al. Changes in postprandial gut hormones after metabolic surgery: a comparison of gastric bypass and sleeve gastrectomy. Surg Obes Relat Dis 2011;7:683-90. [Crossref] [PubMed]
23. Chen CY, Lee WJ, Askawa A, et al. Insulin secretion and interleukin-1B dependent mechanism in human diabetes remission after metabolic surgery. Current Medicinal Chemistry 2013;20:2374-88. [Crossref] [PubMed]
24. Albaugh VL, Flynn CR, Cai S, et al. Early increases in bile acids post Roux-en-Y gastric bypass are driven by insulin-sensitizing, secondary bile acids. J Clin Endocrinol Metab 2015;100:E1225-33. [Crossref] [PubMed]
25. Kootte RS, Vrieze A, Holleman F, et al. The therapeutic potential of manupilating gut microbiota in obesesity and type 2 diabetes mellitus. Diabetes Obes Metab 2012;14:112-20. [Crossref] [PubMed]
26. Shah S, Shah P, Todkar J, et al. Prospective controlled study of effect of laparoscopic sleeve gastrectomy on small bowel transit time and gastric emptying half-time in morbidly obese patients with type 2 diabetes mellitus. Surg Obes Relat Dis 2010;6:152-7. [Crossref] [PubMed]
27. Kirk E, Reeds DN, Finck BN, et al. Dietary fat and carbohydrates differentially alter insulin sensitivity during calories restriction. Gastroenterology 2009;136:1552-60. [Crossref] [PubMed]
28. Jackness C, Karmally W, Febres G, et al. Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and B-cell function in type 2 diabetic patients. Diabetes 2013;62:3027-3032. [Crossref] [PubMed]
29. Lim EL, Hollingsworth KG, Arbisala BS, et al. Reversal of type 2 diabetes: normalization of beta-cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011;54:2506-14. [Crossref] [PubMed]
30. Steven S, Hollingsworth KG, Small PK, et al. Weight loss decrease excess pancreatic triacylglyderol specifically in type 2 diabetes. Diabetes Care 2016;39:158-165. [Crossref] [PubMed]
31. Campos GM, Rabl C, Peeva S, et al. Improvement in peripheral glucose uptake after gastric bypass surgery is observed only after substantial weight loss has occurred and correlates with the magnitude of weight loss. J Gastrointest Surg 2010;14:15-23. [Crossref] [PubMed]
32. Camastra S, Gastaldelli A, Mari A, et al. Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes. Diabetologia 2011;54:2093-102. [Crossref] [PubMed]
33. Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secretagogue produces insulin secretion in humans. J Clin Endocrinol Metab 2001;86:5083-6. [Crossref] [PubMed]
34. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011;365:1597-1604. [Crossref] [PubMed]
35. Patrikakos P, Toutouzas KG, Gazouli M, et al. Long-term plasma ghrelin and leptin modulation after sleeve gastrectomy in Wistar rats in comparison with gastric tissue ghrelin expression. Obes Surg 2011;21:1432-7. [Crossref] [PubMed]
36. Manning S, Pucci A, Batterham RL. Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms. J Clin Invest 2015;125:939-48. [Crossref] [PubMed]
37. Geloneze B, Tambascia MA, Pilla VF, et al. Ghrelin: a gut-brain hormone: effect of gastric bypass surgery. Obes Surg 2003;13:17-22. [Crossref] [PubMed]
38. Cummings DE, Shannon MH. Role for ghrelin in the regulation of appetite and body weight. Arch Surg 2003;138:389-96. [Crossref] [PubMed]
39. Tymitz K, Engel A, McDonough S, Hendy MP, Kerlakin G. Changes in ghrelin levels following bariatric surgery: review of the literature. Obes Surg 2011;21:125-130. [Crossref] [PubMed]
40. Chan JL, Mun EC, Stoyneva V, et al. Peptide YY levels are elevated after gastric bypass surgery. Obesity 2006;14:194-8. [Crossref] [PubMed]
41. Rubino F, Gagner M. Potential of surgery for curing type 2 diabetes mellitus. Ann Surg 2002;236:554-9. [Crossref] [PubMed]
42. Lee WJ, Chong K, Ser KH, et al. Gastric bypass vs sleeve gastrectomy for type 2 diabetes mellitus: a randomized controlled trial. Arch Surg 2011;146:143-8. [Crossref] [PubMed]
43. Lee WJ, Almulaifi AM, Tsou JJ, et al. Duodenal–jejunal bypass with sleeve gastrectomy versus the sleeve gastrectomy procedure alone: the role of duodenal exclusion. Surg Obes Relat Dis 2015;11:765-70. [Crossref] [PubMed]
44. Lee WJ, Chong K, Lin YH, et al. Laparoscopic sleeve gastrectomy versus single anastomosis (mini-) gastric bypass for the treatment of type 2 diabetes mellitus: 5-year results of a randomized trial and study of incretin effect. Obes Surg 2014;24:1552-62. [Crossref] [PubMed]
45. Alfa RW, Park S, Skelly KR, et al. Suppression of insulin production and secretion by a decretin hormone. Cell Metab 2015;21:323-33. [Crossref] [PubMed]
46. Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small in the pathophysiology of type 2 diabetes. Ann Surg 2006;244:741-9. [Crossref] [PubMed]
47. Miyachi T, Nagao M, Shikashi S, et al. Biliopancreatic limb plays an important role in metabolic improvement after duodenal-jejunal bypass in a rat model of diabetes. Surgery 2016;159:1360-71. [Crossref] [PubMed]
48. Orskov C, Wettergren A, Holst JJ. Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man through out the day. Scand J Gastroenterol 1996;31:665-670. [Crossref] [PubMed]
49. Schwartz S, DeFronzo RA. Is incretin-bases therapy ready for the care of hospitalized patients with type 2 diabetes?: The time has come for GLP-1 receptor agonists! Diabetes Care 2013;36:2107-11. [Crossref] [PubMed]
50. Frühbeck G, Nogueiras R. GLP-1: the oracle for gastric bypass? Diabetes 2014;63:399-401. [Crossref] [PubMed]
51. Schirra J, Goke B. GLP-1 – a candidate humoral mediator for glucose control after Roux-en-Y gastric bypass. Diabetes 2014;63:387-389. [Crossref] [PubMed]
52. Nguyen KT, Koner J. The sum of many parts: potential mechanisms for improvement in glucose homeostasis after bariatric surgery. Current Diabetes Reports 2014;14:481 [Crossref] [PubMed]
53. Madsbad S, Dirksen C, Holst JJ. Mechanisms of changes in glucose metabolism and body weight after bariatric surgery. Lancet Diabetes Endocrinol 2014;2:152-64. [Crossref] [PubMed]
54. Mokadem M, Zechner JF, Margolskee RF, et al. Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis after preserved in two mouse models of functional glucagon-like peptide-1 deficiency. Mol Metab 2013;3:191-201. [Crossref] [PubMed]
55. Ye J, Hao Z, Mumphrey B, et al. GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents. Am J Physiol Regul Integr Comp Physiol 2014;306:R352-62. [Crossref] [PubMed]
56. Kohli R, Bradley D, Setchell KD, et al. Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. J Clin Endocrinol Metab 2013;98:E708-12. [Crossref] [PubMed]
57. Korner J, Inabnet W, Febres G, et al. Prospective study of gut hormones and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int J Obes (Lond) 2009;33:786-95. [Crossref] [PubMed]
58. Gerhard GS, Styer AM, Wood GC, et al. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care 2013;36:1859-1864. [Crossref] [PubMed]
59. Myronovych A, Kirby M, Ryan KK, et al. Vertical sleeve gastrectomy reduce hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner. Obesity 2014;22:390-400. [Crossref] [PubMed]
60. Neuschwander-Tetri BA. Farnesoid x receptor agonists: what they are and how they might be used in treating liver disease. Curr Gastroenterol Rep 2012;14:55-62. [Crossref] [PubMed]
61. Stepanov V, Stankov K, Mikov M. The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic inflammatory and neoplastic disorders. J Recept Signal Transduct Res 2013;33:213-223. [Crossref] [PubMed]
62. Parker HE, Wallis K, le Roux CW, et al. Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion. Br J Pharmacol 2012;165:414-423. [Crossref] [PubMed]
63. Lee WJ, Hur KY, Lakadawala M, et al. Gastrointestinal metabolic surgery for the treatment of diabetic patients: a multi-institutional international study. J Gastrointest Surg 2012;16:45-51. [Crossref] [PubMed]
64. Fang S, Suh JM, Relly SM, et al. Intestinal FXR agonist promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21:159-165. [Crossref] [PubMed]
65. Schaap FG, Trauner M, Jansen PLM. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014;11:55-67. [Crossref] [PubMed]
66. Ryan KK, Trmaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 2014;509:183-8. [Crossref] [PubMed]
67. Kootte RS, Vrieze A, Holleman F, et al. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes Metab 2012;14:112-120. [Crossref] [PubMed]
68. Ley RE, Backhed F, Turnbaugh P, et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 2005;102:11070-11075. [Crossref] [PubMed]
69. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027-1031. [Crossref] [PubMed]
70. Turnbaugh PJ, Hamady M, Vatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature 2009;457:480-484. [Crossref] [PubMed]
71. Zhang H, Diabaise JK, Huang S, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA 2009;106:2365-2370. [Crossref] [PubMed]
72. Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss:links with metabolic and low-grade inflammation markers. Diabetes 2010;59:3049-3057. [Crossref] [PubMed]
73. Ravussin Y, Koren O, Spor A, et al. Responses of gut microbiota to diet composition and weight loss in lean and obese mice. Obesity 2012;20:738-747. [Crossref] [PubMed]
74. Nadal I, Santacruz A, Marcos A, et al. Shifts in clostridia, bacteroids and immunoglobulin-coating fecal bacteria associated with weight loss in obese adolescents. Int J Obes (Lond) 2009;33:758-767. [Crossref] [PubMed]
75. Islam KB, Fukiya S, Hagio M, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011;141:1773-1781. [Crossref] [PubMed]
76. Li JV, Reshat R, Wu Q, et al. Experimental bariatric surgery in rats generates a cytotoxic chemical environment in the gut contents. Front Microbiol 2011;2:183 [Crossref] [PubMed]