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09-02-2017 | Metabolic surgery | Article

Role of the Gut on Glucose Homeostasis: Lesson Learned from Metabolic Surgery

Journal: Current Atherosclerosis Reports

Authors: V. Kamvissi-Lorenz, M. Raffaelli, S. Bornstein, G. Mingrone

Abstract

Purpose of Review

Bariatric surgery was initially intended to reduce weight, and only subsequently was the remission of type two diabetes (T2D) observed as a collateral event. At the moment, the term “metabolic surgery” is used to underline the fact that this type of surgery is performed specifically to treat diabetes and its metabolic complications, such as hyperlipidemia.

Recent Findings

Randomized, controlled studies have recently supported the use of bariatric surgery, and in particular of Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD) as an effective treatment for decompensated T2D. The lesson learned from these randomized and many other non-randomized clinical studies is that the stomach and the small intestine play a central role in glucose homeostasis. Bypassing the duodenum and parts of the jejunum exerts a substantial effect on insulin sensitivity and secretion. In fact, with BPD, nutrient transit bypasses duodenum, the entire jejunum and a small portion of the ileum, resulting in reversal of insulin sensitivity back to normal and reduction of insulin secretion, whereas RYGB has little effect on insulin resistance but increases insulin secretion. Hypotheses concerning the mechanism of action of metabolic surgery for diabetes remission vary from theories focusing on jejunal nutrient sensing, to incretin action, to the blunted secretion of putative insulin resistance hormone(s), to changes in the microbiota.

Summary

Whatever the mechanism, metabolic surgery has the undoubted merit of exposing the central role of the small intestine in insulin sensitivity and glucose homeostasis.

Rubino F, Kaplan LM, Schauer PR, Cummings DE. The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus. Ann Surg. 251 Suppl 3:399–405.

Buchwald H, Varco RL. Metabolic surgery. New York: Grune and Stratton; 1978.

Rubino F, Cummings DE. Surgery: the coming of age of metabolic surgery. Nat Rev Endocrinol. 8 Suppl 12:702–4.

Dixon JB, O’Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316–23.CrossRefPubMed

Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N Engl J Med. 370 Suppl 21:2002–13.

Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 366 Suppl 17:1567–76.

Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 366 Suppl 17:1577–85.

Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Nanni G, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 386 Suppl 9997:964–73.

Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, Wajchenberg BL, Cummings DE. Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. Diabetes Care 35 Suppl 7:1420–8.

10.

Cummings DE, Arterburn DE, Westbrook EO, Kuzma JN, Stewart SD, Chan CP, et al. Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the CROSSROADS randomised controlled trial. Diabetologia 59 Suppl 5:945–53.

11.

Brolin RE, Kenler HA, Gorman JH, Cody RP. Long-limb gastric bypass in the superobese. A prospective randomized study. Ann Surg. 1992;215(4):387–95.CrossRefPubMedPubMedCentral

12.

Scopinaro N, Gianetta E, Civalleri D, Bonalumi U, Bachi V. Bilio-pancreatic bypass for obesity: II. Initial experience in man. Br J Surg. 1979;66(9):618–20.CrossRefPubMed

13.

Gagner M, Rogula T. Laparoscopic reoperative sleeve gastrectomy for poor weight loss after biliopancreatic diversion with duodenal switch. Obes Surg. 2003;13(4):649–54.CrossRefPubMed

14.

Camastra S, Gastaldelli A, Mari A, Bonuccelli S, Scartabelli G, Frascerra S, 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 54 Suppl 8:2093–102.

15.

Dunn JP, Abumrad NN, Breitman I, Marks-Shulman PA, Flynn CR, Jabbour K, et al. Hepatic and peripheral insulin sensitivity and diabetes remission at 1 month after Roux-en-Y gastric bypass surgery in patients randomized to omentectomy. Diabetes Care 35 Suppl 1:137–42.

16.

Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, et al. Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes. 2002;51(1):144–51.CrossRefPubMed

17.

Brozinick Jr JT, McCoid SC, Reynolds TH, Nardone NA, Hargrove DM, Stevenson RW, et al. GLUT4 overexpression in db/db mice dose-dependently ameliorates diabetes but is not a lifelong cure. Diabetes. 2001;50(3):593–600.CrossRefPubMed

18.

• Salinari S, Debard C, Bertuzzi A, Durand C, Zimmet P, Vidal H, et al. Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance. PLoS One 8 suppl 2:e56258. Here it is shown that proteins with a molecular weight between 10 and 100 kDa secreted by the duodenum/jejunum of insulin resistant mice and humans induce insulin resistance in rodent and human myocytes in vitro and in vivo in normal mice.

19.

Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology. 2005;146(3):1473–81.CrossRefPubMed

20.

• Guidone C, Manco M, Valera-Mora E, Iaconelli A, Gniuli D, Mari A, et al. Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Diabetes. 2006;55(7):2025–31. The study is interesting because it proves the weight loss-independent mechanism of metabolic surgery on type 2 diabetes remission.CrossRefPubMed

21.

•• Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G. First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes Care. 2009;32(3):375–80. This study shows that the absence of the first phase of insulin secretion is a functional alteration of beta-cells rather than an irreversible damage linked to diabetes.CrossRefPubMedPubMedCentral

22.

Salinari S, Bertuzzi A, Guidone C, Previti E, Rubino F, Mingrone G. Insulin sensitivity and secretion changes after gastric bypass in normotolerant and diabetic obese subjects. Ann Surg. 257 Suppl 3:462–8.

23.

Kelley DE, Wing R, Buonocore C, Sturis J, Polonsky K, Fitzsimmons M. Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1993;77(5):1287–93.PubMed

24.

DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009;32 Suppl 2:S157–63.CrossRefPubMedPubMedCentral

25.

Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger RH. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes. 1982;31(8 Pt 1):694–700.CrossRefPubMed

26.

Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10.CrossRefPubMed

27.

Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, Sbrana S, et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes. 2005;54(3):727–35.CrossRefPubMed

28.

Pennartz C, Schenker N, Menge BA, Schmidt WE, Nauck MA, Meier JJ. Chronic reduction of fasting glycemia with insulin glargine improves first- and second-phase insulin secretion in patients with type 2 diabetes. Diabetes Care 34 Suppl 9:2048–53.

29.

Little TJ, Pilichiewicz AN, Russo A, Phillips L, Jones KL, Nauck MA, et al. Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses. J Clin Endocrinol Metab. 2006;91(5):1916–23.CrossRefPubMed

30.

Schvarcz E, Palmer M, Aman J, Horowitz M, Stridsberg M, Berne C. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology. 1997;113(1):60–6.CrossRefPubMed

31.

Schvarcz E, Palmer M, Aman J, Berne C. Hypoglycemia increases the gastric emptying rate in healthy subjects. Diabetes Care. 1995;18(5):674–6.CrossRefPubMed

32.

Dirksen C, Jorgensen NB, Bojsen-Moller KN, Jacobsen SH, Hansen DL, Worm D, et al. Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia 55 Suppl 7:1890–901.

33.

Bender MA, Moore GE, Webber BM. Dumping syndrome: an evaluation of some current etiologic concepts. N Engl J Med. 1957;256(7):285–9.CrossRefPubMed

34.

Shultz KT, Neelon FA, Nilsen LB, Lebovitz HE. Mechanism of postgastrectomy hypoglycemia. Arch Intern Med. 1971;128(2):240–6.CrossRefPubMed

35.

Toft-Nielsen M, Madsbad S, Holst JJ. Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia. Diabetologia. 1998;41(10):1180–6.CrossRefPubMed

36.

Kloppel G, Anlauf M, Raffel A, Perren A, Knoefel WT. Adult diffuse nesidioblastosis: genetically or environmentally induced? Hum Pathol. 2008;39(1):3–8.CrossRefPubMed

37.

Parker HE, Reimann F, Gribble FM. Molecular mechanisms underlying nutrient-stimulated incretin secretion. Expert Rev Mol Med. 12:e1.

38.

Saeidi N, Meoli L, Nestoridi E, Gupta NK, Kvas S, Kucharczyk J, et al. Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science 341 Suppl 6144:406–10.

39.

Levin BE, Magnan C, Dunn-Meynell A, Le Foll C. Metabolic sensing and the brain: who, what, where, and how? Endocrinology 152 Suppl 7:2552–7.

40.

Paranjape SA, Chan O, Zhu W, Acharya NK, Rogers AM, Hajnal A, et al. Improvement in hepatic insulin sensitivity after Roux-en-Y gastric bypass in a rat model of obesity is partially mediated via hypothalamic insulin action. Diabetologia 56 Suppl 9:2055–8.

41.

Jiao J, Bae EJ, Bandyopadhyay G, Oliver J, Marathe C, Chen M, et al. Restoration of euglycemia after duodenal bypass surgery is reliant on central and peripheral inputs in Zucker fa/fa rats. Diabetes 62 Suppl 4:1074–83.

42.

Salinari S, Carr RD, Guidone C, Bertuzzi A, Cercone S, Riccioni ME, et al. Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects. Am J Physiol Endocrinol Metab. 305 Suppl 1:E59–66.

43.

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):1–11.CrossRefPubMedPubMedCentral

44.

Mortensen K, Christensen LL, Holst JJ, Orskov C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul Pept. 2003;114(2–3):189–96.CrossRefPubMed

45.

Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002;8(7):738–42.CrossRefPubMed

46.

Flatt PR. Dorothy Hodgkin Lecture 2008. Gastric inhibitory polypeptide (GIP) revisited: a new therapeutic target for obesity-diabetes? Diabet Med. 2008;25(7):759–64.CrossRefPubMed

47.

Speck M, Cho YM, Asadi A, Rubino F, Kieffer TJ. Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1. Am J Physiol Endocrinol Metab. 300 Suppl 5:E923–32.

48.

Laferrere B, Teixeira J, McGinty J, Tran H, Egger JR, Colarusso A, et al. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J Clin Endocrinol Metab. 2008;93(7):2479–85.CrossRefPubMedPubMedCentral

49.

McLaughlin T, Peck M, Holst J, Deacon C. Reversible hyperinsulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. J Clin Endocrinol Metab. 95 Suppl 4:1851–5.

50.

Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623–30.CrossRefPubMed

51.

Wilson-Perez HE, Chambers AP, Ryan KK, Li B, Sandoval DA, Stoffers D, et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency. Diabetes 62 Suppl 7:2380–5.

52.

Chambers AP, Kirchner H, Wilson-Perez HE, Willency JA, Hale JE, Gaylinn BD, et al. The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology 144 Suppl 1:50–2 e5.

53.

Prawitt J, Caron S, Staels B. Glucose-lowering effects of intestinal bile acid sequestration through enhancement of splanchnic glucose utilization. Trends Endocrinol Metab. 25 Suppl 5:235–44.

54.

Shang Q, Liu MK, Saumoy M, Holst JJ, Salen G, Xu G. The combination of colesevelam with sitagliptin enhances glycemic control in diabetic ZDF rat model. Am J Physiol Gastrointest Liver Physiol. Apr 15;302(8):G815-23.

55.

Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006;103(4):1006–11.CrossRefPubMedPubMedCentral

56.

Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk TH, Grefhorst A, Abdelkarim M, et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006;281(16):11039–49.CrossRefPubMed

57.

Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101(44):15718–23.CrossRefPubMedPubMedCentral

58.

Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106(7):2365–70.CrossRefPubMedPubMedCentral

59.

Li JV, Ashrafian H, Bueter M, Kinross J, Sands C, le Roux CW, et al. Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut 60 Suppl 9:1214–23.

60.

Upadhyaya S, Banerjee G. Type 2 diabetes and gut microbiome: at the intersection of known and unknown. Gut Microbes. 6 Suppl 2:85–92.

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