Introduction: Type 2 diabetes mellitus (T2DM) and obesity are pandemic diseases that lead to a great deal of morbidity and mortality. The most effective treatment for obesity and T2DM is bariatric or metabolic surgery; it can lead to long-term diabetes remission with 4 in 10 of those undergoing surgery having normal blood glucose on no medication 1 year postoperatively. However, surgery carries risks and, additionally, due to resource limitations, there is a restricted number of patients who can access this treatment. Moreover, not all those who undertake surgery respond equally well metabolically. The objective of the current research is to prospectively investigate predictors of T2DM response following metabolic surgery, including those directly involved in its aetiopathogenesis such as fat distribution and genetic variants. This will inform development of a clinically applicable model to help prioritise this therapy to those predicted to have remission.
Methods and analysis: A prospective multicentre observational cohort study of adult patients with T2DM and obesity undergoing Roux-en-Y gastric bypass surgery. Patients will be comprehensively assessed before surgery to determine their clinical, metabolic, psychological, genetic and fat distribution profiles. A multivariate logistic regression model will be used to assess the value of the factors derived from the preoperative assessment in terms of prediction of diabetes remission.
Ethics and dissemination: Formal ethics review was undertaken with a favourable opinion (UK HRA RES reference number 18/LO/0931). The dissemination plan is to present the results at conferences, in peer-reviewed journals as well as to lay media and to patient organisations.
Park YS, Park DJ, Lee JH, Lee HJ, Ha TK, Kim YJ, Ryu SW, Han SM, Yoo MW, Park S, Han SU, Heo Y.BMJ Open. 2017 Oct 16;7(10):e018044. doi: 10.1136/bmjopen-2017-018044.PMID: 29042391 Free PMC article.
Wei L, Li M, Zeng N, Liu Y, Bai R, Zhang N, Song J, Zhang P, Yao Q, Yang Z, Zhao X, Zhang Y, Zhang P, Zhang Z.BMC Surg. 2021 Jun 24;21(1):298. doi: 10.1186/s12893-021-01296-y.PMID: 34167531 Free PMC article.
International Diabetes Federation IDF diabetes atlas. 8th edn, 2017.
Neeland IJ, Turer AT, Ayers CR, et al. . Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA 2012;308:1150–9. 10.1001/2012.jama.11132 - DOI - PMC - PubMed
InterAct Consortium, Langenberg C, Sharp SJ, et al. . Long-Term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study. PLoS Med 2012;9:e1001230. 10.1371/journal.pmed.1001230 - DOI - PMC - PubMed
Taylor R Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. Diabetologia 2008;51:1781–9. 10.1007/s00125-008-1116-7 - DOI - PubMed
Heymsfield SB, Peterson CM, Thomas DM, et al. . Why are there race/ethnic differences in adult body mass index-adiposity relationships? A quantitative critical review. Obes Rev 2016;17:262–75. 10.1111/obr.12358 - DOI - PMC - PubMed
Taylor R, Holman RR. Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci 2015;128:405–10. 10.1042/CS20140553 - DOI - PubMed
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). JAMA Intern Med 2008;168:1617–24. - PubMed
Bouchard C, Tremblay A, Després JP, et al. . The response to long-term overfeeding in identical twins. N Engl J Med 1990;322:1477–82. 10.1056/NEJM199005243222101 - DOI - PubMed
Shai I, Jiang R, Manson JE, et al. . Ethnicity, obesity, and risk of type 2 diabetes in women: a 20-year follow-up study. Diabetes Care 2006;29:1585–90. 10.2337/dc06-0057 - DOI - PubMed
Després J-P, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881–7. 10.1038/nature05488 - DOI - PubMed
Ferrara D, Montecucco F, Dallegri F, et al. . Impact of different ectopic fat depots on cardiovascular and metabolic diseases. J Cell Physiol 2019;234:21630–41. 10.1002/jcp.28821 - DOI - PubMed
Jaghutriz B, Wagner R, Machann J, et al. . Association of pancreas fat with impaired insulin secretion depends on liver fat and circulating fatty acids. Diabetes 2018;67:1819-P 10.2337/db18-1819-P - DOI
Langenberg C, Lotta LA. Genomic insights into the causes of type 2 diabetes. Lancet 2018;391:2463–74. 10.1016/S0140-6736(18)31132-2 - DOI - PubMed
Fuchsberger C, Flannick J, Teslovich TM, et al. . The genetic architecture of type 2 diabetes. Nature 2016;536:41–7. 10.1038/nature18642 - DOI - PMC - PubMed
Shungin D, Winkler TW, Croteau-Chonka DC, et al. . New genetic loci link adipose and insulin biology to body fat distribution. Nature 2015;518:187–96. 10.1038/nature14132 - DOI - PMC - PubMed
Pedersen HK, Gudmundsdottir V, Pedersen MK, et al. . Ranking factors involved in diabetes remission after bariatric surgery using machine-learning integrating clinical and genomic biomarkers. NPJ Genom Med 2016;1:16035. 10.1038/npjgenmed.2016.35 - DOI - PMC - PubMed
Khera AV, Chaffin M, Aragam KG, et al. . Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet 2018;50:1219–24. 10.1038/s41588-018-0183-z - DOI - PMC - PubMed
Schauer PR, Bhatt DL, Kirwan JP, et al. . Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes. N Engl J Med 2017;376:641–51. 10.1056/NEJMoa1600869 - DOI - PMC - PubMed
Schauer PR, Kashyap SR, Wolski K, et al. . Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012;366:1567–76. 10.1056/NEJMoa1200225 - DOI - PMC - PubMed
Mingrone G, Panunzi S, De Gaetano A, et al. . Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012;366:1577–85. 10.1056/NEJMoa1200111 - DOI - PubMed
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. JAMA 2014;311:2297–304. 10.1001/jama.2014.5988 - DOI - PubMed
Courcoulas AP, Christian NJ, Belle SH, et al. . Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA 2013;310:2416–25. 10.1001/jama.2013.280928 - DOI - PMC - PubMed
Lim EL, Hollingsworth KG, Aribisala BS, et al. . Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011;54:2506–14. 10.1007/s00125-011-2204-7 - DOI - PMC - PubMed
Al-Najim W, Docherty NG, le Roux CW. Food intake and eating behavior after bariatric surgery. Physiol Rev 2018;98:1113–41. 10.1152/physrev.00021.2017 - DOI - PubMed
Faria SL, Faria OP, Buffington C, et al. . Energy expenditure before and after Roux-en-Y gastric bypass. Obes Surg 2012;22:1450–5. 10.1007/s11695-012-0672-6 - DOI - PubMed
Wilms B, Ernst B, Thurnheer M, et al. . Resting energy expenditure after Roux-en Y gastric bypass surgery. Surg Obes Relat Dis 2018;14:191–9. 10.1016/j.soard.2017.10.014 - DOI - PubMed
Laferrère B Diabetes remission after bariatric surgery: is it just the incretins? Int J Obes 2011;35:S22–5. 10.1038/ijo.2011.143 - DOI - PMC - PubMed
Dirksen C, Jørgensen NB, Bojsen-Møller KN, et al. . Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia 2012;55:1890–901. 10.1007/s00125-012-2556-7 - DOI - PubMed
Ramracheya RD, McCulloch LJ, Clark A, et al. . PYY-dependent restoration of impaired insulin and glucagon secretion in type 2 diabetes following Roux-en-Y gastric bypass surgery. Cell Rep 2016;15:944–50. 10.1016/j.celrep.2016.03.091 - DOI - PMC - PubMed
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. 10.1210/jc.2013-2538 - DOI - PubMed
Torekov SS, Kipnes MS, Harley RE, et al. . Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes. Diabetes Obes Metab 2011;13:639–43. 10.1111/j.1463-1326.2011.01388.x - DOI - PubMed
le Roux CW, Welbourn R, Werling M, et al. . Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg 2007;246:780–5. 10.1097/SLA.0b013e3180caa3e3 - DOI - PubMed
Nielsen MS, Ritz C, Wewer Albrechtsen NJ, et al. . Oxyntomodulin and glicentin may predict the effect of bariatric surgery on food preferences and weight loss. J Clin Endocrinol Metab 2020;105e1064–74. 10.1210/clinem/dgaa061 - DOI - PubMed
Kaska L, Sledzinski T, Chomiczewska A, et al. . Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World J Gastroenterol 2016;22:8698–719. 10.3748/wjg.v22.i39.8698 - DOI - PMC - PubMed
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. 10.1038/oby.2009.102 - DOI - PMC - PubMed
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. 10.2337/dc12-2255 - DOI - PMC - PubMed
Wang W, Cheng Z, Wang Y, et al. . Role of bile acids in bariatric surgery. Front Physiol 2019;10:374. 10.3389/fphys.2019.00374 - DOI - PMC - PubMed
Turnbaugh PJ, Hamady M, Yatsunenko T, et al. . A core gut microbiome in obese and lean twins. Nature 2009;457:480–4. 10.1038/nature07540 - DOI - PMC - PubMed
Magouliotis DE, Tasiopoulou VS, Sioka E, et al. . Impact of bariatric surgery on metabolic and gut microbiota profile: a systematic review and meta-analysis. Obes Surg 2017;27:1345–57. 10.1007/s11695-017-2595-8 - DOI - PubMed
Li JV, Ashrafian H, Bueter M, et al. . Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut 2011;60:1214–23. 10.1136/gut.2010.234708 - DOI - PMC - PubMed
Cani PD, Van Hul M, Lefort C, et al. . Microbial regulation of organismal energy homeostasis. Nat Metab 2019;1:34–46. 10.1038/s42255-018-0017-4 - DOI - PubMed
British Obesity & Metabolic Surgery Society Clinical outcomes 2017-18, 2018.
Ahmad A, Laverty AA, Aasheim E, et al. . Eligibility for bariatric surgery among adults in England: analysis of a national cross-sectional survey. JRSM Open 2014;510.1177/2042533313512479 - DOI - PMC - PubMed
Panunzi S, De Gaetano A, Carnicelli A, et al. . Predictors of remission of diabetes mellitus in severely obese individuals undergoing bariatric surgery: do BMI or procedure choice matter? A meta-analysis. Ann Surg 2015;261:459–67. 10.1097/SLA.0000000000000863 - DOI - PubMed
Lee W-J, Hur KY, Lakadawala M, et al. . Predicting success of metabolic surgery: age, body mass index, C-peptide, and duration score. Surg Obes Relat Dis 2013;9:379–84. 10.1016/j.soard.2012.07.015 - DOI - PubMed
Still CD, Wood GC, Benotti P, et al. . Preoperative prediction of type 2 diabetes remission after Roux-en-Y gastric bypass surgery: a retrospective cohort study. Lancet Diabetes Endocrinol 2014;2:38–45. 10.1016/S2213-8587(13)70070-6 - DOI - PMC - PubMed
Zhang R, Borisenko O, Telegina I, et al. . Systematic review of risk prediction models for diabetes after bariatric surgery. Br J Surg 2016;103:1420–7. 10.1002/bjs.10255 - DOI - PubMed
Tharakan G, Scott R, Szepietowski O, et al. . Limitations of the DiaRem score in predicting remission of diabetes following Roux-en-Y gastric bypass (RYGB) in an ethnically diverse population from a single institution in the UK. Obes Surg 2016. - PMC - PubMed
Blakemore AIF, Buxton JL. Obesity, genetic risk, and environment. BMJ 2014;348:g1900. 10.1136/bmj.g1900 - DOI - PubMed
Fava C, Sjögren M, Olsson S, et al. . A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case-control study. Eur J Hum Genet 2015;23:969–74. 10.1038/ejhg.2014.212 - DOI - PMC - PubMed
Hsieh FY, Bloch DA, Larsen MD. A simple method of sample size calculation for linear and logistic regression. Stat Med 1998;17:1623–34. 10.1002/(sici)1097-0258(19980730)17:14<1623::aid-sim871>3.0.co;2-s - DOI - PubMed
Kaul S, Rothney MP, Peters DM, et al. . Dual-energy X-ray absorptiometry for quantification of visceral fat. Obesity 2012;20:1313–8. 10.1038/oby.2011.393 - DOI - PMC - PubMed
Micklesfield LK, Goedecke JH, Punyanitya M, et al. . Dual-energy X-ray performs as well as clinical computed tomography for the measurement of visceral fat. Obesity 2012;20:1109–14. 10.1038/oby.2011.367 - DOI - PMC - PubMed
Stegenga H, Haines A, Jones K, et al. . Identification, assessment, and management of overweight and obesity: summary of updated NICE guidance. BMJ 2014;349:g6608. 10.1136/bmj.g6608 - DOI - PubMed
Ugale S, Gupta N, Modi KD, et al. . Prediction of remission after metabolic surgery using a novel scoring system in type 2 diabetes - a retrospective cohort study. J Diabetes Metab Disord 2014;13:89. 10.1186/s40200-014-0089-y - DOI - PMC - PubMed
Aron-Wisnewsky J, Sokolovska N, Liu Y, et al. . The advanced-DiaRem score improves prediction of diabetes remission 1 year post-Roux-en-Y gastric bypass. Diabetologia 2017;60:1892–902. 10.1007/s00125-017-4371-7 - DOI - PubMed
Hayes MT, Hunt LA, Foo J, et al. . A model for predicting the resolution of type 2 diabetes in severely obese subjects following Roux-en Y gastric bypass surgery. Obes Surg 2011;21:910–6. 10.1007/s11695-011-0370-9 - DOI - PubMed
Lee W-J, Chong K, Chen S-C, et al. . Preoperative prediction of type 2 diabetes remission after gastric bypass surgery: a comparison of DiaRem scores and ABCD scores. Obes Surg 2016;26:2418–24. 10.1007/s11695-016-2120-5 - DOI - PubMed
Dixon JB, Hur K-Y, Lee W-J, et al. . Gastric bypass in Type 2 diabetes with BMI < 30: weight and weight loss have a major influence on outcomes. Diabet Med 2013;30:e127–34. 10.1111/dme.12107 - DOI - PubMed
Dixon JB, Chuang L-M, Chong K, et al. . Predicting the glycemic response to gastric bypass surgery in patients with type 2 diabetes. Diabetes Care 2013;36:20–6. 10.2337/dc12-0779 - DOI - PMC - PubMed
Robert M, Ferrand-Gaillard C, Disse E, et al. . Predictive factors of type 2 diabetes remission 1 year after bariatric surgery: impact of surgical techniques. Obes Surg 2013;23:770–5. 10.1007/s11695-013-0868-4 - DOI - PubMed
Pucci A, Tymoszuk U, Cheung WH, et al. . Type 2 diabetes remission 2 years post Roux-en-Y gastric bypass and sleeve gastrectomy: the role of the weight loss and comparison of DiaRem and DiaBetter scores. Diabet Med 2018;35:360–7. 10.1111/dme.13532 - DOI - PMC - PubMed
Debédat J, Sokolovska N, Coupaye M, et al. . Long-term relapse of type 2 diabetes after Roux-en-Y gastric bypass: prediction and clinical relevance. Diabetes Care 2018;41:2086–95. 10.2337/dc18-0567 - DOI - PubMed
Aminian A, Brethauer SA, Andalib A, et al. . Individualized metabolic surgery score: procedure selection based on diabetes severity. Ann Surg 2017;266:650–7. 10.1097/SLA.0000000000002407 - DOI - PubMed
Bhasker AG, Remedios C, Batra P, et al. . Predictors of remission of T2DM and metabolic effects after laparoscopic Roux-en-Y gastric bypass in obese Indian Diabetics-a 5-year study. Obes Surg 2015;25:1191–7. 10.1007/s11695-014-1501-x - DOI - PubMed
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. 10.1016/j.soard.2010.03.292 - DOI - PubMed
Blackstone R, Bunt JC, Cortés MC, et al. . Type 2 diabetes after gastric bypass: remission in five models using HbA1c, fasting blood glucose, and medication status. Surg Obes Relat Dis 2012;8:548–55. 10.1016/j.soard.2012.05.005 - DOI - PubMed
Schauer PR, Bhatt DL, Kirwan JP, et al. . Bariatric surgery versus intensive medical therapy for diabetes — 3-year outcomes. N Engl J Med Overseas Ed 2014;370:2002–13. 10.1056/NEJMoa1401329 - DOI - PMC - PubMed
Hill NR, Levy JC, Matthews DR. Expansion of the homeostasis model assessment of β-cell function and insulin resistance to enable clinical trial outcome modeling through the interactive adjustment of physiology and treatment effects: iHOMA2. Diabetes Care 2013;36:2324–30. 10.2337/dc12-0607 - DOI - PMC - PubMed
Vangoitsenhoven R, Wilson RL, Cherla DV, et al. . Presence of liver steatosis is associated with greater diabetes remission after gastric bypass surgery. Diabetes Care 2021;44:321–5. 10.2337/dc20-0150 - DOI - PubMed
Steven S, Hollingsworth KG, Small PK, et al. . Weight loss decreases excess pancreatic triacylglycerol specifically in type 2 diabetes. Diabetes Care 2016;39:158–65. 10.2337/dc15-0750 - DOI - PubMed