Gastric Bypass for Obesity: Mechanisms of Weight Loss and Diabetes Resolution
Abstract
Obesity is now a global pandemic that continues to accelerate despite the often Herculean efforts by afflicted individuals to lose weight. These efforts are thwarted by a physiological system that regulates body weight in a manner analogous to that by which a thermostat controls ambient temperature. For each individual, there is a highly genetically influenced level of adiposity that is defended by this adipostatic control system, wherein alterations in body fat stores trigger compensatory changes in appetite and energy expenditure that resist weight change (1). It is hypothesized that these processes evolved to defend against malnutrition in times of famine, and hence, the adaptive responses to weight loss appear to be more robust than are those to weight gain (as any dieter can attest). Because of this body weight regulation system, known as energy homeostasis, nonsurgical methods are notoriously ineffective at achieving major, long-term weight reduction. In general, no more than 5–10% of body weight is lost through dieting, exercise, and the few available antiobesity medications, and recidivism after dietary weight reduction is nearly universal (2–5). Importantly, even mild weight loss confers disproportionate health benefits, in terms of ameliorating obesity-related comorbidities (6). Nevertheless, more substantial and durable weight reduction would improve these ailments even more effectively, as well as lessen the stigmatization and emotional suffering often endured by obese individuals. At present, bariatric surgery is the most effective method to achieve major, long-term weight loss (7, 8). The best operations reduce body weight by 35–40%, and most of this effect is maintained for at least 15 yr (Refs.7–10 ; and Pories, W. J., personal communication). Postsurgical weight loss improves all obesity-related comorbidities examined to date, including diabetes, hypertension, dyslipidemias, nonalcoholic steatohepatitis, sleep apnea and obesity-hypoventilation syndrome, cardiac dysfunction, reflux esophagitis, pseudotumor cerebri, arthritis, infertility, stress incontinence, and venous stasis ulcers (4, 8, 9). The net effect is an increase in quality of life and decrease in overall mortality (11, 12). Estimates of the cost of bariatric surgery per quality-adjusted life year (QALY) range from $5,400 to $36,600/QALY, well under the $50,000/QALY benchmark that is generally regarded in the United States as being cost effective (13, 14). Unquestionably, obesity surgery is a drastic approach that is not without risks; but these are usually outweighed by the risks of morbid obesity, especially when considering the most modern and increasingly safe bariatric operations. Among these, Roux-en-Y gastric bypass (RYGB) appears to offer the best balance of effectiveness vs. risk, and it is the most widely used surgery for morbidly obese people in the United States (15). Not surprisingly, massive weight loss after this procedure reduces obesity-related comorbidities and mortality; but the operation may improve glucose homeostasis through physiological changes not explained by weight loss alone (16). The mechanisms underlying the effects of RYGB on body weight and glucose metabolism are incompletely understood. Elucidating these mechanisms is a high priority, because such knowledge may facilitate the development of novel antiobesity medications that could achieve at least some of the weight loss caused by RYGB, without surgical risks. Here, we examine the known and hypothesized mechanisms mediating the effects of RYGB, hopefully highlighting avenues for future research to help uncover the secrets of this intriguing operation. Intestinal malabsorption and gastric restriction are the two most obvious mechanisms to explain weight loss after bariatric surgery, and the types of operations are traditionally categorized based on which of these changes they induce (Figs. 1 and 22). Malabsorptive procedures reconstruct the small intestine to reduce the area of mucosa available for nutrient absorption. The earliest incarnation of this strategy was the jejunoileal bypass (JIB) (17). Imposing no restriction on the flow of food, this procedure simply diverted enteral nutrients around most of the small intestine, via an anastomosis between the proximal jejunum (∼14 in. from the ligament of Treitz) and the terminal ileum (∼4 in. from the cecum; Fig. 1A). Weight loss was impressive, but the operation was plagued with complications that ultimately led to its abandonment from clinical practice. These included oxalate nephrolithiasis, protein malnutrition, metabolic bone disease, hypocalcemia, arthritis, and deficiencies of vitamins B12 and D (8). The most serious morbidity of JIB was hepatic cirrhosis, hypothesized to result from bacterial overgrowth in the blind-loop intestinal segment, leading to chronic hepatic inflammation from foreign antigens in portal blood. The procedure was succeeded by the biliopancreatic diversion (BPD), with or
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The modality of weight loss, not just the degree, may have independent effects on neurohormonal regulators of energy balance and glucose homeostasis.
“Recently there has been greater recognition that the modality of weight loss, not just the degree, may have independent effects on neurohormonal regulators of energy balance and glucose homeostasis (5, 6).”
From Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass (2009) · cites this paper as [5]
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Ueno, T., Shibata, C., Naito, H., et al. (2002) · Diseases of the Colon & Rectum · doi:10.1007/s10350-004-6122-3 · Cited by 16 · see citing works
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Cancello, R., Henegar, C., Viguerie, N., Taleb, S., Poitou, C., Rouault, C., Coupaye, M., Pelloux, V., Hugol, D., Bouillot, J.-L., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.8.2277 · Cited by 1,164 · see citing works
Ghrelin and the short- and long-term regulation of appetite and body weight
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Jacobsen, S. H., Olesen, S. C., Dirksen, C., Jørgensen, N. B., Bojsen-Møller, K. N., Kielgast, U., Worm, D., Almdal, T., Naver, L. S., Hvolris, L. E., et al. (2012) · Obesity Surgery · doi:10.1007/s11695-012-0621-4 · Cited by 342 · see citing works
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Korner, J., Inabnet, W., Febres, G., Conwell, I. M., McMahon, D. J., Salas, R., Taveras, C., Schrope, B., & Bessler, M. (2009) · International Journal of Obesity · doi:10.1038/ijo.2009.79 · Cited by 338 · see citing works
Poirier, P., Cornier, M.-A., Mazzone, T., Stiles, S., Cummings, S., Klein, S., McCullough, P. A., Ren Fielding, C., & Franklin, B. A. (2011) · Circulation · doi:10.1161/cir.0b013e3182149099 · Cited by 339 · see citing works
The vagus nerve, food intake and obesity
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Fleischer, J., Stein, E. M., Bessler, M., Badia, M. D., Restuccia, N., Olivero-Rivera, L., McMahon, D. J., & Silverberg, S. J. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0481 · Cited by 278 · see citing works
Meier, J. J., Butler, A. E., Galasso, R., & Butler, P. C. (2006) · Diabetes Care · doi:10.2337/dc06-0392 · Cited by 249 · see citing works
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le Roux, C. W., Borg, C., Wallis, K., Vincent, R. P., Bueter, M., Goodlad, R., Ghatei, M. A., Patel, A., Bloom, S. R., & Aylwin, S. J. B. (2010) · Annals of Surgery · doi:10.1097/sla.0b013e3181d3d21f · Cited by 176 · see citing works
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Self-citationRoux-en-Y gastric bypass surgery changes food reward in rats
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Rothkopf, M. M., Bilof, M. L., Haverstick, L. P., & Nusbaum, M. J. (2009) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2008.09.005 · Cited by 15 · see citing works
- Authors
- Cummings, D. E., Overduin, J., & Foster-Schubert, K. E.
- Affiliations
- University of Washington (US)
- Corresponding author
- Cummings, David E.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-06
- Volume
- 89
- Issue
- 6
- Pages
- 2608-2615
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2128538324
- Cited by
- 503
- References
- 92
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 17 · 2023: 8 · 2022: 12 · 2021: 10 · 2020: 22 · 2019: 11 · 2018: 12 · 2017: 15 · 2016: 22 · 2015: 25 · 2014: 28 · 2013: 38 · 2012: 46
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- University of Washington
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK-61516, R01DK061516)
- Topics
- Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Surgery › Minimally Invasive Surgical Techniques
- Keywords
- gastric bypass, bariatric surgery, obesity, weight loss mechanisms, diabetes resolution, energy homeostasis, energy expenditure, bariatric surgery outcomes, cost-effectiveness, quality-adjusted life years, obesity-related comorbidities, bariatric surgery safety, bariatric surgery complications
- MeSH terms
- Diabetes Mellitus, Diabetes Mellitus, Type 2, Humans, Obesity, Gastric Bypass, Weight Loss
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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