==== Front World J DiabetesWJDWorld Journal of Diabetes1948-9358Baishideng Publishing Group Inc jWJD.v9.i7.pg12710.4239/wjd.v9.i7.127MinireviewsReversibility of diabetes mellitus: Narrative review of the evidence Ang Gary Yee Health Services and Outcomes Research, National Healthcare Group, Singapore 138543, Singapore. gary_ang@nhg.com.sgAuthor contributions: Ang GY contributed to the manuscript. Correspondence to: Gary Yee Ang, MBBS, Doctor, Health Services and Outcomes Research, National Healthcare Group, Fusionopolis 3, Singapore 138543, Singapore. gary_ang@nhg.com.sg Telephone: +65-64966928 Fax: +65-64966257 15 7 2018 15 7 2018 9 7 127 131 26 3 2018 19 4 2018 31 5 2018 ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.2018This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.The global disease burden of diabetes mellitus is high. It is well-established that prediabetes is reversible but it is unclear whether diabetes is reversible once it has been diagnosed. The objective of this narrative review is to review the evidence of reversibility of diabetes mellitus and stimulate interest in prolonged remission as a treatment target. The current evidence for bariatric surgery is stronger than intensive medical management and the evidence is stronger for type 2 diabetes patients compared with type 1 diabetes patients. It is also unclear whether non obese diabetes patients would benefit from such interventions and the duration of diabetes before diabetes become irreversible. Further research is needed in this area especially with regards to the subgroup of diabetes patient who will benefit from these interventions and the long term safety and efficacy remains unknown especially with intensive medical management. DiabetesReversibilityRemissionBariatric surgeryObesity ==== Body Core tip: Diabetes mellitus is potentially reversible especially with bariatric surgery. Intensive medical management is promising but the evidence is weaker. The subgroup that is likely to go into prolonged remission is those with insulin resistance, short duration of diabetes and obesity. Further research is needed to identify those that can go into remission and how to use intensive medical management to achieve this. INTRODUCTION The number of adults with diabetes in the world has increased from 108 million in 1980 to 422 million in 2014 due to rise in prevalence, population growth and ageing[1]. Diabetes Mellitus has been projected to become the 7th leading causes of death in 2030[2]. It has been estimated that the direct medical costs of diabetes to the world is more than United States $827 million[2]. It is well-established that prediabetes is reversible[3-7], but it is unclear whether diabetes is reversible once it has been diagnosed. Type 2 diabetes mellitus is potentially reversible[8]. A better term to use would be remission which is defined to be achieving glucose level below the diabetic range in the absence of active pharmacologic or surgical therapy[9]. It can further be divided into partial or complete and if complete remission lasts for more than 5 years, it would be considered as prolonged remission[9]. In community settings, in the absence of bariatric surgery, the 7-year cumulative incidence of partial, complete or prolonged remission was found to be 1.47% (1.40%-1.54%), 0.14% (0.12%-0.16%) and 0.007% (0.003%-0.020%)[10] which is very low. In this narrative review, the evidence of reversibility of diabetes mellitus will be reviewed in light of new studies recently published. This can help stimulate interest in prolonged remission as a treatment target for patients with established diabetes. BARIATRIC SURGERY There are several systematic reviews on the impact of bariatric surgery on diabetes mellitus[11-13] and some have distinguished between type 1 diabetes[14-16] and type 2 diabetes[17-20] (Table 1). The percentage of diabetes remission after bariatric surgery is estimated to be 76.8%[12] to 92%[11]. However, the exact physiological and molecular mechanisms behind diabetes remission after bariatric surgery remains incompletely understood[21,22]. (Figure 1) There are several reviews that looked at the role of bariatric surgery in managing diabetes mellitus[23-26] and the mechanism behind reversibility of type 2 diabetes mellitus[27,28] All agree that diabetes remission can be an important outcome to look at after bariatric surgery and there are many risk prediction models which can predict diabetes remission[29]. Table 1 Bariatric surgery systematic reviews Ref. Type of diabetes No. of studies included Remission percentage (95%CI) Chang et al[11], 2014 Not specified 164 (37 randomized clinical trials and 127 observational studies) Randomized clinical trials: 92% (85%-97%) Observational studies: 86% (79%-92%) Buchwald et al[12], 2004 Not specified 136 76.8% (70.7%-82.9%) Gloy et al[13], 2013 Not specified 11 59.90% Ashrafian et al[14], 2015 Type 1 diabetes mellitus 27 Weighted mean decrease in insulin requirement: 44.5 units 78.1% (73.8%-82.3%) Chow et al[15], 2016 Type 1 diabetes mellitus 13 Weighted mean total daily insulin requirement decreased from 98 +/- 26 IU/d to 42 +/- 11 IU/d Mahawar et al[16], 2016 Type 1 diabetes mellitus 15 Not reported Buchwald et al[17], 2009 Type 2 diabetes mellitus 621 76.2% insulin free Baskota et al[18], 2015 Type 2 diabetes mellitus 10 61.8% medication free Goh et al[19], 2017 Type 2 diabetes mellitus 24 Remission rate Duodenal-jejunal bypass: 20%-40% Duodenal-jejunal bypass with sleeve gastrectomy: 79%-93% Duodenal-jejunal bypass sleeve: 62.5%-100% Ileal interposition with sleeve gastrectomy: 47%-95.7% Yan et al[20] Type 2 diabetes mellitus 6 Type 2 diabetes mellitus remission rate for roux-en-y gastric bypass vs medical treatment: OR: 76.4 (95%CI: 20.7-281.7) Figure 1 Potential mechanisms contributing to improved glycaemia after roux-en-Y gastric bypass and vertical sleeve gastrectomy. A: Immediate effects of improved glycaemia after roux-en-Y gastric bypass and vertical sleeve gastrectomy due to anatomical changes; B: Potential mediators/mechanisms involved. Cross talk occurs among these factors; C: Effects on glucose homeostasis[21]; RYGB: Roux-en-Y gastric bypass; SG: Sleeve gastrectomy. Besides diabetes remission, bariatric surgery may also reduce inflammation[30,31], improve renal function[31], reduce cardiovascular risk[32] and reduce microvascular and macrovascular complications[33]. The impact of bariatric surgery on all these remains incompletely understood. Even if the evidence is strong for remission of diabetes after bariatric surgery, it is unlikely to be advocated at the population level due to the high cost and lack of surgeons well trained to perform bariatric surgeries. Furthermore, the indication for bariatric surgery is currently for patients with a body mass index above 35 kg/m2 or between 30 and 35 kg/m2 with inadequate glycemic control despite optimal medical treatment[34]. This would not benefit diabetes patients who are non-obese (body mass index < 30 kg/m2) and the remission rate has been shown to be much lower in non-obese diabetes patients[18]. PANCREAS TRANSPLANTATION AND ISLET CELL TRANSPLANTATION A recent review found that there is a need for multicenter randomized trials in pancreas transplantation to define clearly the efficacy, risks, and long term benefits due to lack of high quality evidence[35]. The indications for pancreas transplantation alone are in patients with severe metabolic complications, incapacitating problems with exogenous insulin therapy and failure of insulin based management to prevent acute complication[35]. It would not be to induce diabetes into remission. A systematic review on islet cell transplantation for type 1 diabetes mellitus has also concluded that there is low to very low quality evidence for all outcomes of interest such as remission of diabetes[36]. The next question to ask is whether pancreas transplantation is able to reverse complications of diabetes such as diabetic nephropathy. A recent study has demonstrated that diabetic nephropathy may be reversible after pancreas transplantation[37] that is contrary to current thinking. Further research is needed to look at whether it is possible to reverse diabetes and/or its complications after pancreas or islet cell transplantation. INTENSIVE MEDICAL MANAGEMENT There are relatively fewer studies on non-surgical remission of diabetes mellitus. A randomized controlled trial found that 40.7% of patients with type 2 diabetes for less than 3 years had complete or partial remission at 12 mo[38]. A cluster-randomized trial found that primary care-led weight management achieved a remission rate of 46% at 12 mo in patients with type 2 diabetes for less than 6 years[39]. A retrospective observational study of obese patients with type 2 diabetes found that 4.6 % achieved partial or complete diabetes remission after a 12-wk intensive program for diabetes weight management[40]. These studies did not look at the long term effectiveness of such intervention of the remission of type 2 diabetes mellitus and whether the same effect could be seen in patients with type 1 diabetes, non- obese diabetes patients or those with longer duration of type 2 diabetes. Further research is needed to evaluate the long term effectiveness and safety of intensive medical management before recommending this but the results seem promising. CLUSTERS OF DIABETES MELLITUS A recent study has identified 5 replicable clusters of adult-onset diabetes with different disease progression and risk of diabetes complications[41]. The 5 clusters are severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD)[41](Table 2). Table 2 Subgroups of adult-onset diabetes Subgroups Body-mass index Metabolic control Insulin deficiency/resistance Severe autoimmune diabetes Relatively low Poor Insulin deficiency Severe insulin-deficient diabetes Relatively low Poor Insulin deficiency Severe insulin-resistant diabetes High Fair Insulin resistance Mild obesity-related diabetes High Fair Insulin resistance Mild age-related diabetes Relatively low Fair Insulin resistance Of the 5, it would be interesting to see which are more likely to go into prolonged remission with either bariatric surgery or intensive medical intervention so that clinicians can better define their treatment end-goals and treat accordingly. Based on insulin resistance, it would likely be SIRD, MOD and MARD that could go into prolonged remission. Researchers may want to collect baseline data on glutamate decarboxylase antibodies, age at diagnosis, body mass index, glycated haemoglobin, and homeostatic model assessment 2 estimates of β-cell function and insulin resistance in future studies. CONCLUSION Diabetes Mellitus especially type 2 diabetes can go into prolonged remission via bariatric surgery or intensive medical therapy. The current evidence for bariatric surgery is stronger than intensive medical management but intensive medical management is likely to have a greater impact in type 2 diabetes management. More research is needed to understand the mechanism behind prolonged remission and to identify the group of diabetes patients that will benefit the most from such interventions. Conflict-of-interest statement: No potential conflicts of interest. Manuscript source: Invited manuscript Peer-review started: March 27, 2018 First decision: April 13, 2018 Article in press: May 31, 2018 Specialty type: Endocrinology and metabolism Country of origin: Singapore Peer-review report classification Grade A (Excellent): 0 Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P- Reviewer: Cheungpasitporn W, Pecoraro V S- Editor: Cui LJ L- Editor: A E- Editor: Tan WW ==== Refs 1 Siegel R Naishadham D Jemal A Cancer statistics, 2012 CA Cancer J Clin 2012 62 10 29 22237781 2 NCD Risk Factor Collaboration (NCD-RisC) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants Lancet 2016 387 1513 1530 27061677 3 Dunkley AJ Bodicoat DH Greaves CJ Russell C Yates T Davies MJ Khunti K Diabetes prevention in the real world: effectiveness of pragmatic lifestyle interventions for the prevention of type 2 diabetes and of the impact of adherence to guideline recommendations: a systematic review and meta-analysis Diabetes Care 2014 37 922 933 24652723 4 Aziz Z Absetz P Oldroyd J Pronk NP Oldenburg B A systematic review of real-world diabetes prevention programs: learnings from the last 15 years Implement Sci 2015 10 172 26670418 5 Whittemore R A systematic review of the translational research on the Diabetes Prevention Program Transl Behav Med 2011 1 480 491 24073067 6 Joiner KL Nam S Whittemore R Lifestyle interventions based on the diabetes prevention program delivered via eHealth: A systematic review and meta-analysis Prev Med 2017 100 194 207 28456513 7 Neamah HH Sebert Kuhlmann AK Tabak RG Effectiveness of Program Modification Strategies of the Diabetes Prevention Program: A Systematic Review Diabetes Educ 2016 42 153 165 26879459 8 Steven S Hollingsworth KG Al-Mrabeh A Avery L Aribisala B Caslake M Taylor R Very Low-Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiological Changes in Responders and Nonresponders Diabetes Care 2016 39 808 815 27002059 9 Buse JB, Caprio S, Cefalu WT, Ceriello A, Del Prato S, Inzucchi SE, McLaughlin S, Phillips GL 2nd, Robertson RP, Rubino F, Kahn R, Kirkman MS How do we define cure of diabetes? Diabetes Care 2009 32 2133 2135 19875608 10 Karter AJ Nundy S Parker MM Moffet HH Huang ES Incidence of remission in adults with type 2 diabetes: the diabetes & aging study Diabetes Care 2014 37 3188 3195 25231895 11 Chang SH Stoll CR Song J Varela JE Eagon CJ Colditz GA The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003-2012 JAMA Surg 2014 149 275 287 24352617 12 Buchwald H Avidor Y Braunwald E Jensen MD Pories W Fahrbach K Schoelles K Bariatric surgery: a systematic review and meta-analysis JAMA 2004 292 1724 1737 15479938 13 Gloy VL Briel M Bhatt DL Kashyap SR Schauer PR Mingrone G Bucher HC Nordmann AJ Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials BMJ 2013 347 f5934 24149519 14 Ashrafian H Harling L Toma T Athanasiou C Nikiteas N Efthimiou E Darzi A Athanasiou T Type 1 Diabetes Mellitus and Bariatric Surgery: A Systematic Review and Meta-Analysis Obes Surg 2016 26 1697 1704 26694210 15 Chow A Switzer NJ Dang J Shi X de Gara C Birch DW Gill RS Karmali S A Systematic Review and Meta-Analysis of Outcomes for Type 1 Diabetes after Bariatric Surgery J Obes 2016 2016 6170719 27375900 16 Mahawar KK De Alwis N Carr WR Jennings N Schroeder N Small PK Bariatric Surgery in Type 1 Diabetes Mellitus: A Systematic Review Obes Surg 2016 26 196 204 26452482 17 Buchwald H Estok R Fahrbach K Banel D Jensen MD Pories WJ Bantle JP Sledge I Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis Am J Med 2009 122 248 256.e5 19272486 18 Baskota A Li S Dhakal N Liu G Tian H Bariatric Surgery for Type 2 Diabetes Mellitus in Patients with BMI < 30 kg/m2: A Systematic Review and Meta-Analysis PLoS One 2015 10 e0132335 26167910 19 Goh YM Toumi Z Date RS Surgical cure for type 2 diabetes by foregut or hindgut operations: a myth or reality? A systematic review Surg Endosc 2017 31 25 37 27194257 20 Yan Y Sha Y Yao G Wang S Kong F Liu H Zhang G Zhang H Hu C Zhang X Roux-en-Y Gastric Bypass Versus Medical Treatment for Type 2 Diabetes Mellitus in Obese Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Medicine (Baltimore) 2016 95 e3462 27124041 21 Batterham RL Cummings DE Mechanisms of Diabetes Improvement Following Bariatric/Metabolic Surgery Diabetes Care 2016 39 893 901 27222547 22 Haluzík M Bariatric surgery and the mechanism of diabetes remission: are we getting there? J Clin Endocrinol Metab 2013 98 4336 4338 24194619 23 Roslin MS Cripps CN Bariatric surgery in managing diabetes mellitus Curr Opin Gastroenterol 2016 32 481 486 27607341 24 Ugale S Agarwal D Satwalekar V Rao N Ugale A Bariatric surgery as an option for diabetes mellitus prevention and treatment in obese persons Minerva Endocrinol 2016 41 469 476 27270500 25 Nguyen NT Varela JE Bariatric surgery for obesity and metabolic disorders: state of the art Nat Rev Gastroenterol Hepatol 2017 14 160 169 27899816 26 Koliaki C Liatis S le Roux CW Kokkinos A The role of bariatric surgery to treat diabetes: current challenges and perspectives BMC Endocr Disord 2017 17 50 28797248 27 Perugini RA Malkani S Remission of type 2 diabetes mellitus following bariatric surgery: review of mechanisms and presentation of the concept of ‘reversibility’ Curr Opin Endocrinol Diabetes Obes 2011 18 119 128 21522001 28 le Roux CW Heneghan HM Bariatric Surgery for Obesity Med Clin North Am 2018 102 165 182 29156184 29 Zhang R Borisenko O Telegina I Hargreaves J Ahmed AR Sanchez Santos R Pring C Funch-Jensen P Dillemans B Hedenbro JL Systematic review of risk prediction models for diabetes after bariatric surgery Br J Surg 2016 103 1420 1427 27557164 30 Hafida S Mirshahi T Nikolajczyk BS The impact of bariatric surgery on inflammation: quenching the fire of obesity? Curr Opin Endocrinol Diabetes Obes 2016 23 373 378 27455515 31 Neff KJ Frankel AH Tam FW Sadlier DM Godson C le Roux CW The effect of bariatric surgery on renal function and disease: a focus on outcomes and inflammation Nephrol Dial Transplant 2013 28 Suppl 4 iv73 iv82 24071659 32 Vest AR Heneghan HM Agarwal S Schauer PR Young JB Bariatric surgery and cardiovascular outcomes: a systematic review Heart 2012 98 1763 1777 23077152 33 Adams TD Arterburn DE Nathan DM Eckel RH Clinical Outcomes of Metabolic Surgery: Microvascular and Macrovascular Complications Diabetes Care 2016 39 912 923 27222549 34 Dixon JB, Zimmet P, Alberti KG, Rubino F; International Diabetes Federation Taskforce on Epidemiology and Prevention Bariatric surgery: an IDF statement for obese Type 2 diabetes Diabet Med 2011 28 628 642 21480973 35 Dean PG Kukla A Stegall MD Kudva YC Pancreas transplantation BMJ 2017 357 j1321 28373161 36 Health Quality Ontario Pancreas Islet Transplantation for Patients With Type 1 Diabetes Mellitus: A Clinical Evidence Review Ont Health Technol Assess Ser 2015 15 1 84 37 Fioretto P Barzon I Mauer M Is diabetic nephropathy reversible? Diabetes Res Clin Pract 2014 104 323 328 24513120 38 McInnes N Smith A Otto R Vandermey J Punthakee Z Sherifali D Balasubramanian K Hall S Gerstein HC Piloting a Remission Strategy in Type 2 Diabetes: Results of a Randomized Controlled Trial J Clin Endocrinol Metab 2017 102 1596 1605 28324049 39 Lean ME Leslie WS Barnes AC Brosnahan N Thom G McCombie L Peters C Zhyzhneuskaya S Al-Mrabeh A Hollingsworth KG Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial Lancet 2018 391 541 551 29221645 40 Mottalib A Sakr M Shehabeldin M Hamdy O Diabetes Remission after Nonsurgical Intensive Lifestyle Intervention in Obese Patients with Type 2 Diabetes J Diabetes Res 2015 2015 468704 26114120 41 Ahlqvist E Storm P Käräjämäki A Martinell M Dorkhan M Carlsson A Vikman P Prasad RB Aly DM Almgren P Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables Lancet Diabetes Endocrinol 2018 6 361 369 29503172