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Weight Loss and the Prevention and Treatment of Type 2 Diabetes Using Lifestyle Therapy, Pharmacotherapy, and Bariatric Surgery: Mechanisms of Action

  • Obesity Treatment (CM Apovian, Section Editor)
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Abstract

Weight loss, whether achieved by lifestyle intervention, pharmacotherapy, or bariatric surgery, is highly effective as a primary interventional strategy in both the prevention and treatment of type 2 diabetes. In high-risk patients with prediabetes and/or metabolic syndrome, weight loss effectively prevents progression to type 2 diabetes mellitus (T2DM) and improves cardiovascular risk factors. These benefits are the result of improvements in insulin resistance, which is central to the pathophysiology of cardiometabolic disease. In patients with T2DM, weight loss improves glycemia, while reducing the need for conventional glucose-lowering medicines, by affecting all three processes that produce and sustain the hyperglycemic state, namely via increments in peripheral insulin sensitivity with improvements in insulin signal transduction at the cellular level, more robust insulin secretory responses, and reduced rates of hepatic glucose production. In both nondiabetic and diabetic subjects, hypocaloric feeding (e.g., treatment with very low-calorie diet or bariatric surgery) produces a rapid improvement in insulin sensitivity due to mobilization of fat from the intramyocellular, intrahepatocellular, and intra-abdominal compartments, and via a more long-term mechanism that correlates with the loss of total body fat. In diabetes, by improving glycemia, weight loss also enhances glucose homeostasis by reversing the defects in insulin action and secretion attributable to glucose toxicity. Regardless of the therapeutic approach, weight loss of ∼10 % maximally prevents future diabetes in patients with prediabetes or metabolic syndrome. In T2DM, greater degrees of weight loss lead to progressive improvements in glucose homeostasis. Therefore, when accompanied by greater weight loss, the metabolic benefits following bariatric surgery are generally more pronounced than those achieved following lifestyle and medical treatment. In addition, the mechanisms by which bariatric operations improve diabetes may include both weight-dependent and weight-independent mechanisms, and the latter may involve changes in gut hormones, bile acids, or gut microflora.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of childhood and adult obesity in the United States, 2011–2012. J Amer Med Assoc. 2014;311:806–14.

    CAS  Google Scholar 

  2. Finkelstein EA, Trogdon JG, Cohen JW, et al. Annual medical spending attributable to obesity: payer-and-service-specific estimates. Health Aff. 2009;28:w822–w31.

    Google Scholar 

  3. Garber AJ, Handelsman Y, Einhorn D, et al. Diagnosis and management of prediabetes in the continuum of hyperglycemia: when do the risks of diabetes begin? A consensus statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists. Endocr Pract. 2008;14:933–46.

    PubMed  Google Scholar 

  4. American Diabetes Association. Standards of medical care in diabetes—2015. Diabetes Care. 2015;38 Suppl 1:S8–S16.

    Google Scholar 

  5. Grundy SM, Brewer Jr HB, Cleeman JI, American Heart A. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433–38.

    PubMed  Google Scholar 

  6. Eckel R, Grundy S, Zimmet P. The metabolic syndrome. Lancet. 2005;365:1415–28.

    CAS  PubMed  Google Scholar 

  7. Milicevic Z, Raz J, Beattie SD, et al. Natural history of cardiovascular disease in patients with diabetes: role of hyperglycemia. Diabetes Care. 2008;31(2):S155–60.

    CAS  PubMed  Google Scholar 

  8. Van Gaal LF, Mentens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–80.

    PubMed  Google Scholar 

  9. Guo F, Moellering DR, Garvey WT. The progression of cardiometabolic disease: validation of a new cardiometabolic disease staging system applicable to obesity. Obesity. 2014;22:110–18.

    PubMed Central  PubMed  Google Scholar 

  10. Nigro J, Osman N, Dart AM, et al. Insulin resistance and atherosclerosis. Endocr Rev. 2006;27:242–59.

    CAS  PubMed  Google Scholar 

  11. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.

    CAS  PubMed  Google Scholar 

  12. Després J-P, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–7.

    PubMed  Google Scholar 

  13. Ärnlöv J, Ingelsson E, Sundström J, et al. Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men. Circulation. 2010;121:230–6.

    PubMed  Google Scholar 

  14. Nathan DM, Davidson MB, DeFronzo RA, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007;30:753–9.

    CAS  PubMed  Google Scholar 

  15. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15:540–59.

    PubMed  Google Scholar 

  16. UKPDS Group. UK prospective diabetes study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients. Metabolism. 1990;39:905–12.

    Google Scholar 

  17. Bosello O, Armellini F, Zamboni M, et al. The benefits of modest weight loss in type II diabetes. Int J Obes Relat Metab Disord. 1997;21 Suppl 1:S10–3.

    PubMed  Google Scholar 

  18. Garber AJ, Abrahamson MJ, Barzilay JI, et al. American association of clinical endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement—executive summary. Endocr Pract. 2013;19:536–57.

    PubMed Central  PubMed  Google Scholar 

  19. Norris SL, Zhang X, Avenell A, et al. Long-term non-pharmacological weight loss interventions for adults with type 2 diabetes. Cochrane Database Syst Rev. 2005;CD005270.

  20. Li Z, Maglione M, Tu W, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med. 2005;142:532–46.

    CAS  PubMed  Google Scholar 

  21. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. the Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537–44.

    CAS  PubMed  Google Scholar 

  22. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–50.

    CAS  PubMed  Google Scholar 

  23. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.

    CAS  PubMed  Google Scholar 

  24. Deedwania PC, Volkova N. Current treatment options for the metabolic syndrome. Curr Treat Options Cardiovasc Med. 2005;7:61–74.

    PubMed  Google Scholar 

  25. Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 2008;168:1609–16.

    PubMed  Google Scholar 

  26. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med. 2008;168:1617–24.

    PubMed  Google Scholar 

  27. Meigs JB, Wilson PW, Fox CS, et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab. 2006;91:2906–12.

    CAS  PubMed  Google Scholar 

  28. Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet. 2005;366:1640–9.

    PubMed  Google Scholar 

  29. Hamman RF, Wing RR, Edelstein SL, et al. Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes Care. 2006;29:2102–7.

    PubMed Central  PubMed  Google Scholar 

  30. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677–86.

    PubMed Central  Google Scholar 

  31. Laaksonen DE, Lindstrom J, Lakka TA, et al. Physical activity in the prevention of type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes. 2005;54:158–65.

    CAS  PubMed  Google Scholar 

  32. Lindström J, Ilanne-Parikka P, Peltonen M, et al. Finnish Diabetes Prevention Study Group. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;368:1673–9.

    PubMed  Google Scholar 

  33. Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diab Endocrinol. 2014;2:474–80.

    Google Scholar 

  34. Barte JC, ter Bogt NC, Bogers RP, et al. Maintenance of weight loss after lifestyle interventions for overweight and obesity, a systematic review. Obes Rev. 2010;11:899–906.

    CAS  PubMed  Google Scholar 

  35. Wadden TA, Fujioka K, Toubro S, et al. A randomized trial of lifestyle modification and taranabant for maintaining weight loss achieved with a low-calorie diet. Obesity. 2010;18:2301–10.

    PubMed  Google Scholar 

  36. Torgerson JS, Hauptman J, Boldrin MN, et al. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155–61.

    CAS  PubMed  Google Scholar 

  37. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297–308.

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Garvey WT, Ryan DH, Henry R, et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care. 2014;37:912–21.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Wentworth JM, Hensman T, Playfair J, et al. Laparoscopic adjustable gastric banding and progression from impaired fasting glucose to diabetes. Diabetologia. 2014;57:463–8.

    PubMed  Google Scholar 

  40. Sjöholm K, Anveden A, Peltonen M, et al. Evaluation of current eligibility criteria for bariatric surgery: diabetes prevention and risk factor changes in the Swedish Obese Subjects (SOS) study. Diabetes Care. 2013;36:1335–40.

    PubMed Central  PubMed  Google Scholar 

  41. Carlsson LM, Peltonen M, Ahlin S, et al. Bariatric surgery and prevention of type 2 diabetes in Swedish Obese Subjects. N Engl J Med. 2012;367:695–704.

    CAS  PubMed  Google Scholar 

  42. Magliano DJ, Barr EL, Zimmet PZ, et al. Glucose indices, health behaviors, and incidence of diabetes in Australia: the Australian Diabetes, Obesity and Lifestyle study. Diabetes Care. 2008;31:267–72.

    PubMed  Google Scholar 

  43. Sjöström L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. J Amer Med Assoc. 2012;307:56–65.

    Google Scholar 

  44. Booth H, Khan O, Prevost T, et al. Incidence of type 2 diabetes after bariatric surgery: population-based matched cohort study. Lancet Diab Endocrinol. 2014;2:963–8. This study demonstrates that bariatric surgery is associated with a reduced incidence of T2DM in patients with obesity.

    Google Scholar 

  45. Guare JC, Wing RR, Grant A. Comparison of obese NIDDM and nondiabetic women: short- and long-term weight loss. Obes Res. 1995;3:329–35.

    CAS  PubMed  Google Scholar 

  46. Wing RR, Marcus MD, Epstein LH, et al. Type II diabetic subjects lose less weight than their overweight nondiabetic spouses. Diabetes Care. 1987;10:563–6.

    CAS  PubMed  Google Scholar 

  47. Henry RR, Chilton R, Garvey WT. New options for the treatment of obesity and type 2 diabetes mellitus (narrative review). J Diab Complic. 2013;27:508–18.

    Google Scholar 

  48. Wing RR, Lang W, Wadden TA, The Look AHEAD Research Group, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Group TLAR, Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010;170:1566–75.

    Google Scholar 

  50. Belalcazar LM, Haffner SM, Lang W, et al. Lifestyle intervention and/or statins for the reduction of C-reactive protein in type 2 diabetes: from the look AHEAD study. Obesity. 2013;21:944–50.

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–54.

    Google Scholar 

  52. Gregg EW, Chen H, Wagenknecht LE, Look AHEAD Research Group, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. J Amer Med Assoc. 2012;308:2489–96.

    CAS  Google Scholar 

  53. Foster GD, Borradaile KE, Sanders MH, for the Sleep AHEAD Research Group of the Look AHEAD Research Group, et al. A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes: the Sleep AHEAD study. Arch Intern Med. 2009;169:1916–26.

    PubMed  Google Scholar 

  54. Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care. 1998;21:1288–94.

    CAS  PubMed  Google Scholar 

  55. Kelley DE, Bray GA, Pi-Sunyer FX, et al. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care. 2002;25:1033–41.

    CAS  PubMed  Google Scholar 

  56. Garvey WT, Ryan DH, Bohannon NJ, et al. Weight-loss therapy in type 2 diabetes: effects of phentermine and topiramate extended-release. Diabetes Care. 2014;37:3309–16.

    CAS  PubMed  Google Scholar 

  57. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341–52.

    CAS  PubMed  Google Scholar 

  58. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity. 2012;20:1426–36.

    PubMed  Google Scholar 

  59. Hollander P, Gupta AK, Plodkowski R, COR-Diabetes Study Group, et al. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36:4022–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Sjöström L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. J Amer Med Assoc. 2014;311:2297–304.

    Google Scholar 

  61. Schauer PR, Bhatt DL, Kirwan JP, STAMPEDE Investigators, et al. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N Engl J Med. 2014;370:2002–13. This study reports 3-year outcomes of the STAMPEDE trial comparing bariatric surgery with medical therapy alone. It demonstrates improved outcomes in glycemic control, body weight, use of glucose-lowering medications, and quality of life in the surgery group.

    PubMed  Google Scholar 

  62. O’Brien PE, Macdonald L, Anderson M, et al. Long-term outcomes after bariatric surgery: fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature. Ann Surg. 2013;257:87–94.

    PubMed  Google Scholar 

  63. Adams TD, Davidson LE, Litwin SE, et al. Gastrointestinal surgery: cardiovascular risk reduction and improved long-term survival in patients with obesity and diabetes. Curr Atheroscler Rep. 2012;14:606–15.

    CAS  PubMed  Google Scholar 

  64. Garvey WT. New tools for weight-loss therapy enable a more robust medical model for obesity treatment: rationale for a complications-centric approach. Endocr Pract. 2013;19:864–74.

    PubMed Central  PubMed  Google Scholar 

  65. Garvey WT, Garber AJ, Mechanick JI, et al, On Behalf Of The AACE Obesity Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology consensus conference on obesity: building an evidence base for comprehensive action. Endocrine Practice. 2014;20:956--76.

  66. Garvey WT, Garber AJ, Mechanick JI, et al, On Behalf Of The AACE Obesity Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocrine Practice. 2014; 20:977--89.

  67. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342--62.

  68. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient-2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Endocrine Practice. 2013;19:337--72.

  69. Heneghan HM, Nissen S, Schauer PR. Gastrointestinal surgery for obesity and diabetes: weight loss and control of hyperglycemia. Curr Atheroscler Rep. 2012;14:579–87.

    CAS  PubMed  Google Scholar 

  70. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. J Amer Med Assoc. 2004;292:1724–37.

    CAS  Google Scholar 

  71. Mingrone G, Panunzi S, Gaetano AD, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577–85.

    CAS  PubMed  Google Scholar 

  72. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery vs intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366:1567–76.

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Ikramuddin S, Korner J, Lee W-J, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the diabetes surgery study randomized clinical trial. J Amer Med Assoc. 2013;309:2240–9.

    CAS  Google Scholar 

  74. Liang Z, Wu Q, Chen B, et al. Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: a randomized controlled trial. Diabetes Res Clin Pract. 2013;1:50–6.

    Google Scholar 

  75. Courcoulas AP, Goodpaster BH, Eagleton JK, et al. Surgical vs medical treatments for type 2 diabetes mellitus: a randomized clinical trial. JAMA Surg. 2014;149:707–15.

    PubMed  Google Scholar 

  76. Halperin F, Ding S-A, Simonson DC, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014;149:716–26.

    PubMed  Google Scholar 

  77. Gill RS, Birch DW, Shi X, et al. Sleeve gastrectomy and type 2 diabetes mellitus: a systematic review. Surg Obes Relat Dis. 2010;6:707-13.

  78. Garvey WT, Lara-Castro C. Diet, Insulin Resistance, and Obesity: Zoning in on Data for Atkins Dieters Living in South Beach. J Clin Endocrinol Metab. 2004;89:4197-205.

  79. Weiss R, Taksali SE, Dufour S, et al. The "obese insulin-sensitive" adolescent: importance of adiponectin and lipid partitioning. J Clin Endocrinol Metab. 2005;90:3731-7.

  80. Lara-Castro C, Newcomer BR, Rowell J, et al. Effects of short-term very low calorie diet on intramyocellular lipid and insulin sensitivity in nondiabetic and type 2 diabetic subjects. Metabolism. 2008;57:1–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Vitola E, Deivanayagam S, Stein RI, et al. Weight loss reduces liver fat and improves hepatic and skeletal muscle insulin sensitivity in obese adolescents. Obesity. 2009;17:1744–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus. Diabetes. 1986;35:990–8.

    CAS  PubMed  Google Scholar 

  83. Garvey WT, Olefsky JM, Griffin J, et al. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34:222–34.

    CAS  PubMed  Google Scholar 

  84. Garvey W, Birnbaum M. Insulin resistance and disease. Bailliere’s clinical endocrinology and metabolism, edited by Ferrannini E: Bailliere Tindall:785–873, 1994.

  85. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care. 1990;13:610–30.

    CAS  PubMed  Google Scholar 

  86. Richter EA, Hansen BF, Hansen SA. Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake. Biochem J. 1988;252:733–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Baron AD, Zhu JS, Zhu JH, et al. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. J Clin Invest. 1995;96:2792–801.

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Garvey WT, Olefsky JM, Matthaei S, et al. Glucose and insulin co-regulate the glucose transport system in primary cultured adipocytes. A new mechanism of insulin resistance. J Biol Chem. 1987;262:189–97.

    CAS  PubMed  Google Scholar 

  89. Bailey CJ, Turner SL. Glucosamine-induced insulin resistance in L6 muscle cells. Diabetes Obes Metab. 2004;6:293–8.

    CAS  PubMed  Google Scholar 

  90. Marshall S. Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Sci STKE. 2006;2006:re7.

    PubMed  Google Scholar 

  91. Scarlett JA, Kolterman OG, Ciaraldi TP, et al. Insulin treatment reverses the postreceptor defect in adipocyte 3-O-methylglucose transport in type II diabetes mellitus. J Clin Endocrinol Metab. 1983;56:1195–201.

    CAS  PubMed  Google Scholar 

  92. Friedman JE, Dohm GL, Leggett-Frazier N, et al. Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4. J Clin Invest. 1992;89:701–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Greenfield MS, Doberne L, Rosenthal M, et al. Effect of sulfonylurea treatment on in vivo insulin secretion and action in patients with non-insulin-dependent diabetes mellitus. Diabetes. 1982;31:307–12.

    CAS  PubMed  Google Scholar 

  94. Yki-Jarvinen H, Helve E, Koivisto VA. Hyperglycemia decreases glucose uptake in type I diabetes. Diabetes. 1987;36:892–6.

    CAS  PubMed  Google Scholar 

  95. Bradley D, Magkos F, Klein S. Effects of bariatric surgery on glucose homeostasis and type 2 diabetes. Gastroenterology. 2012;143:897–912.

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Isbell JM, Tamboli RA, Hansen EN, et al. The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en Y gastric bypass surgery. Diabetes Care. 2010;33:1438–42.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Kadera BE, Lum K, Grant J, et al. Remission of type 2 diabetes after Roux-en Y gastric bypass is associated with greater weight loss. Surg Obes Relat Dis. 2009;5:305–9.

    PubMed  Google Scholar 

  98. Dixon JB. Obesity and diabetes: the impact of bariatric surgery on type-2 diabetes. World J Surg. 2009;33:2014–21.

    PubMed  Google Scholar 

  99. Hamza N, Abbas MH, Darwish A, et al. Predictors of remission of type 2 diabetes mellitus after laparoscopic gastric banding and bypass. Surg Obes Relat Dis. 2011;7:691–6.

    PubMed  Google Scholar 

  100. Chikunguwo SM, Wolfe LG, Dodson P, et al. Analysis of factors associated with durable remission of diabetes after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2010;6:254–9.

    PubMed  Google Scholar 

  101. D’Alessio DA, Prigeon RL, Ensinck JW. Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes. A physiological role of glucagon-like peptide I. Diabetes. 1995;44:1433–7.

    PubMed  Google Scholar 

  102. Gutzwiller JP, Drewe J, Göke B, et al. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999;276:R1541–4.

    CAS  PubMed  Google Scholar 

  103. Flint A, Raben A, Ersbøll AK, et al. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes. 2001;25:781–92.

    CAS  Google Scholar 

  104. le Roux CW, Aylwin SJB, Batterham RL, et al. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg. 2006;243:108–14.

    PubMed Central  PubMed  Google Scholar 

  105. Morínigo R, Moizé V, Musri M, et al. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2006;91:1735–40.

    PubMed  Google Scholar 

  106. Laferrère B, Heshka S, Wang K, et al. Incretin levels and effect are markedly enhanced 1 month after Roux-en-Y gastric bypass surgery in obese patients with type 2 diabetes. Diabetes Care. 2007;30:1709–16.

    PubMed Central  PubMed  Google Scholar 

  107. Laferrère B. Diabetes remission after bariatric surgery: is it just the incretins. Int J Obes. 2011;35:S22–5.

    Google Scholar 

  108. Jørgensen NB, Dirksen C, Bøjsen-Moller KN, et al. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. Diabetes. 2013;62:3044–52.

    PubMed Central  PubMed  Google Scholar 

  109. Salehi M, Prigeon RL, D’Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes. 2011;60:2208–14.

    Google Scholar 

  110. Gill RS, Birch DW, Shi X, et al. Sleeve gastrectomy and type 2 diabetes mellitus: a systematic review. Surg Obes Relat Dis. 2010;6:707–13.

    PubMed  Google Scholar 

  111. Nannipieri M, Baldi S, Mari A, et al. Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. J Clin Endocrinol Metab. 2013;98:4391–9.

    CAS  PubMed  Google Scholar 

  112. Korner J, Bessler M, Inabnet W, et al. Exaggerated GLP-1 and blunted GIP secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding. Surg Obes Relat Dis. 2007;3:597–301.

    PubMed Central  PubMed  Google Scholar 

  113. Laferrère B, Teixeira J, McGinty J, 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;93:2479–85.

    PubMed Central  PubMed  Google Scholar 

  114. Bojsen-Møller KN, Dirksen C, Jørgensen NB, et al. Early enhancements of hepatic and later of peripheral insulin sensitivity combined with increased postprandial insulin secretion contribute to improved glycemic control after Roux-en-Y gastric bypass. Diabetes. 2014;63:1725–37.

    PubMed  Google Scholar 

  115. Knop FK, Taylor R. Mechanism of metabolic advantages after bariatric surgery. Diabetes Care. 2013;36:S287–91. This is a recent review of the mechanisms of bariatric surgery focusing on gastrointestinal factors versus food restriction.

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Elahi D, Galiatsatos P, Rabiee A, et al. Mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2014;10:1028–40.

    PubMed  Google Scholar 

  117. Lingvay I, Guth E, Islam A, et al. Rapid improvement in diabetes after gastric bypass surgery: is it the diet or surgery? Diabetes Care. 2013;36:2741–7.

    PubMed Central  PubMed  Google Scholar 

  118. Dirksen C, Hansen DL, Madsbad S, et al. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion. Diabetes Care. 2010;33:375–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Hylemon PB, Zhou H, Pandak WM, et al. Bile acids as regulatory molecules. J Lipid Res. 2009;50:1509–20.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147–91.

    CAS  PubMed  Google Scholar 

  121. Glicksman C, Pournaras DJ, Wright M, et al. Postprandial plasma bile acid responses in normal weight and obese subjects. Ann Clin Biochem. 2010;47:482–4.

    CAS  PubMed  Google Scholar 

  122. Prawitt J, Caron S, Staels B. Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr Diab Rep. 2011;11:160–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Patti M-E, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity. 2009;17:1671–7.

    CAS  PubMed  Google Scholar 

  124. Nakatani H, Kasama K, Oshiro T, et al. Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. Metabolism. 2009;58:1400–7.

    CAS  PubMed  Google Scholar 

  125. Jansen PLM, van Werven J, Aarts E, et al. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis. 2011;29:48–51.

    PubMed  Google Scholar 

  126. Pournaras DJ, Glicksman C, Vincent RP, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology. 2012;153:3613–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Ahmad NN, Pfalzer A, Kaplan LM. Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity. Int J Obes. 2013;37:1553–9.

    CAS  Google Scholar 

  128. 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;36:1859–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  129. 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.

    PubMed Central  CAS  PubMed  Google Scholar 

  130. Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147–91.

    CAS  PubMed  Google Scholar 

  131. Knop FK. Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes? Am J Physiol Endocrinol Metab. 2010;299:E10–3.

    CAS  PubMed  Google Scholar 

  132. Kohli R, Kirby M, Setchell KDR, et al. Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities. Am J Physiol Gastrointest Liver Physiol. 2010;299:G652–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Kohli R, Setchell KDR, Kirby M, et al. A surgical model in male obese rats uncovers protective effects of bile acids post-bariatric surgery. Endocrinology. 2013;154:2341–51.

    PubMed Central  CAS  PubMed  Google Scholar 

  134. 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. This study reports that sleeve gastrectomy is associated with increased circulating bile acids and may act through FXR to improve glucose tolerance in a rodent model.

  135. Goncalves D, Barataud A, De Vadder F, et al. Bile routing modification reproduces key features of gastric bypass in rat. Ann Surg. 2015. doi:10.1097/SLA.0000000000001121.

    PubMed  Google Scholar 

  136. Ley RE, Turnbaugh PJ, Klein S, et al. Human gut microbes associated with obesity. Nature. 2006;444:1022–3.

    CAS  PubMed  Google Scholar 

  137. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.

    PubMed  Google Scholar 

  138. Cani PD, Delzenne NM. Gut microflora as a target for energy and metabolic homeostasis. Curr Opin Clin Nutr Metab Care. 2007;10:729–34.

    PubMed  Google Scholar 

  139. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Diamant M, Blaak EE, de Vos WM. Do nutrient-gut-microbiota interactions play a role in human obesity, insulin resistance and type 2 diabetes? Obes Rev. 2010;12:272–81.

    PubMed  Google Scholar 

  141. Larsen N, Vogensen FK, van den Berg FWJ, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. Plos One. 2010;5:e9085.

    PubMed Central  PubMed  Google Scholar 

  142. Asrafian H, Beuter M, Ahmed K, et al. Metabolic surgery: an evolution through bariatric animal models. Obes Rev. 2010;11:907–20.

    Google Scholar 

  143. Furet J-P, Kong L-C, 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;59:3049–57.

    PubMed Central  CAS  PubMed  Google Scholar 

  144. le Roux CW, Bueter M, Theis N, et al. Gastric bypass reduces fat intake and preference. Am J Physiol Regul Integr Comp Physiol. 2011;301:R1057–66.

    PubMed Central  PubMed  Google Scholar 

  145. Aron-Wisnewsky J, Doré J, Clement K. The importance of the gut microbiota after bariatric surgery. Nat Rev Gastroenterol Hepatol. 2012;9:590–8.

    PubMed  Google Scholar 

  146. Seto CT, Jeraldo P, Orenstein R, et al. Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility. Microbiome. 2014;2:42.

    PubMed Central  PubMed  Google Scholar 

  147. Zhang H, DiBaise JK, Zuccolo A, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106:2365–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  148. Graessler J, Qin Y, Zhong H, et al. Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters. Pharmacogenom J. 2013;13:514–22.

    CAS  Google Scholar 

  149. Kong L-C, Tap J, Aron-Wisnewsky J, et al. Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes. Am J Clin Nutr. 2013;98:16–24.

    CAS  PubMed  Google Scholar 

  150. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110:9066–71.

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101:15718–23.

    PubMed Central  PubMed  Google Scholar 

  152. Brun Paola, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2006;292:G518–25.

    Google Scholar 

  153. Gill SR, Pop M, DeBoy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312:1355–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  154. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72.

    CAS  PubMed  Google Scholar 

  155. Creely SJ, McTernan PG, Kusminski CM, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E740–7.

    CAS  PubMed  Google Scholar 

  156. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57:1470–81.

    CAS  PubMed  Google Scholar 

  157. Schwiertz A, Taras D, Schäfer K, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity. 2010;18:190–5.

    PubMed  Google Scholar 

  158. Li JV, Ashrafian H, Bueter M, et al. Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut. 2011;60:1214–23.

    PubMed Central  CAS  PubMed  Google Scholar 

  159. Liou AP, Paziuk M, Luevano Jr J-M, et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013;5:1–11. This study uses a mouse model of RYGB and transfers microbiota from mice post-RYGB, sham surgery, or sham surgery with caloric restriction into germ-free mice.

  160. Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341:1241214.

    PubMed  Google Scholar 

  161. Vrieze A, van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterolology. 2012;143:913–6. To our knowledge, this is the only study in humans investigating the impact of transfer of intestinal microbiota on insulin sensitivity.

  162. Aron-Wisnewsky J, Tordjman J, Poitou C, et al. Human adipose tissue macrophages: M1 and M2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab. 2009;94:4619–23.

    CAS  PubMed  Google Scholar 

  163. Clement K. Bariatric surgery, adipose tissue and gut microbiota. Int J Obes. 2011;35:S7–15.

    Google Scholar 

  164. Barres R, Kirchner H, Rasmussen M, et al. Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Rep. 2013;3:1020–7.

    CAS  PubMed  Google Scholar 

  165. Kirchner H, Nylen C, Laber S, et al. Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2014;10:671–8.

    PubMed  Google Scholar 

  166. Heneghan HM, Miller N, Kerin MJ. Role of microRNAs in obesity and the metabolic syndrome. Obes Rev. 2010;11:354–61.

    CAS  PubMed  Google Scholar 

  167. Bruckmueller H, Oswald S, Häsler R, et al. Influence of Roux-en-Y gastric bypass surgery on the gene expression and microRNA in the small intestine. Proc Br Pharmacol Soc. 2013. http://www.pA2online.org/abstracts/Vol11Issue2abst017P.pdf.

  168. Ortega FJ, Mercader JM, Catalán V. Targeting the circulating microRNA signature of obesity. Endocrinol Metab. 2013;59:781–92.

    CAS  Google Scholar 

  169. Arterburn DE, Bogart A, Sherwood NE, et al. A multisite study of long-term remission and relapse of type 2 diabetes mellitus following gastric bypass. Obes Surg. 2013;23:93–102.

    PubMed  Google Scholar 

  170. Wang GF, Yan YX, Xu N, et al. Predictive factors of type 2 diabetes mellitus remission following bariatric surgery: a meta-analysis. Obes Surg. 2015;25:199–208.

    PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Institutes of Health (DK-038765, DK-083562), by the Merit Review Program of the Department of Veterans Affairs, and by a Career Development Award from the Society for Surgery of the Alimentary Tract. We also acknowledge support from the UAB Diabetes Research Center (P30 DK079626).

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J. Grams declares that he has no conflict of interest.

W. Timothy Garvey reports personal fees from Novo Nordisk, Boehringer-Ingelheim, Takeda, Vivus, LipoScience, Daiichi-Sankyo, Eisai, Janssen, Alkermes, and Astra Zeneca. He also reports grants from Merck, Vivus, Weight Watchers, Astra Zeneca, Sanofi, Eisai, and Pfizer.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Obesity Treatment

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Grams, J., Garvey, W.T. Weight Loss and the Prevention and Treatment of Type 2 Diabetes Using Lifestyle Therapy, Pharmacotherapy, and Bariatric Surgery: Mechanisms of Action. Curr Obes Rep 4, 287–302 (2015). https://doi.org/10.1007/s13679-015-0155-x

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