18.1 18.1 Introduction Being pathologically overweight is an epidemic problem, with increasing numbers; global obesity rates have doubled in the last two decades, reaching 500 million in 2008. The current prevalence of 7–10% in children and adolescents is predicted to double by 2025, leading to a significant increase in obesity-related diseases [1, 2]. A large number of those patients will have multiple comorbidities, which will create a drastic negative impact on society, healthcare systems, and life expectancy. Nonsurgical approaches to treating obesity, including a combination of lifestyle modifications, diets, and drugs, have shown limited long-term success. This concept is particularly true for obese people with type 2 diabetes mellitus (T2DM). The estimated worldwide prevalence of T2DM among adults was 285 million in 2010, and this is projected to increase to 439 million by 2030. Managing diabetes has historically been medical, based on lifestyle interventions combined with pharmacotherapy. However, although the pharmacological armamentarium to treat T2DM has expanded considerably, few patients are able to achieve and maintain optimal glycemic targets in the long term [3, 4]. In contrast to nonsurgical treatments, bariatric surgery has been consistently shown to induce greater and more sustained weight loss; a systematic review reported an overall percentage of excess weight loss (%EWL) of >60% with bariatric surgery and ~70 with gastric bypass. Moreover, with the widespread adoption of minimally invasive laparoscopic techniques, bariatric surgery has become safer. Current mortality risk rates are in the range of 0.2–0.5%, similar to those of other commonly performed operations, such as laparoscopic cholecystectomy . Long-term results are as equally encouraging. The Swedish Obese Subjects Research Program, a nonrandomized but controlled longitudinal study, documented sustained weight loss at 10, 15 and 20 years (17, 16, and 18% respectively) in operated patients compared with minimal or no results in matched controls undergoing conventional weight loss treatment . Several gastrointestinal operations have been described over recent years aimed primarily at producing significant and durable weight loss in morbidly obese patients. These procedures have also been shown in multiple trials to induce remission or dramatic improvement of T2DM and other obesity-related comorbidities. While improvement of diabetes and other metabolic disorders is an expected outcome of weight loss by any means, evidence from both experimental animal studies and clinical investigations suggests that these effects are partly independent of weight loss. This knowledge provided a rational to the idea of a “diabetes surgery” specifically aimed at treating T2DM . Following this new option for diabetic patients, the concept of “metabolic surgery” has rapidly emerged in the scientific community to more broadly indicate a surgical approach aimed at controlling metabolic illnesses, not just excess weight. Efficacy and safety of bariatric surgery to treat T2DM in obese patients have been demonstrated in many papers published in recent years. The scientific community has recommended the use of bariatric surgery in patients with diabetes and body mass index (BMI) >35 kg/m2 and as an alternative treatment option in patients with BMI 30–35 kg/m2 inadequately controlled with optimal medical regimens . 18.2 18.2 Metabolic Surgery: Mechanisms of Glycemic Control Morbidly obese individuals with T2DM undergoing bariatric surgery reach sustained weight loss and substantial improvement in glucose metabolism. In many cases, good glycemic control is maintained without insulin injections or even medications [16, 17]. The first explanation for this effect is major weight loss; indeed, surgery is a primary trigger for increased insulin sensitivity, accompanied by cellular and tissue changes at multiple levels in the metabolism of glucose. However, growing evidence indicates that the antidiabetic mechanisms of some of these operations cannot be explained by changes in caloric intake and body weight alone. In fact, rearrangement of the gastrointestinal anatomy seems to play an important role, independently of weight loss, as shown at different levels: Using the duodenojejunal bypass (DJB) model in rodents, excluding the proximal small intestine (duodenum and proximal jejunum) from the passage of food contributes to the resolution (or improvement) of diabetes after other diversionary procedures [Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion (BPD)] independently of weight loss. Diabetic patients after surgery, mainly RYGB and BPD, show a rapid improvement or resolution of T2DM long before substantial weight loss occurs. Different bariatric procedures can achieve similar weight loss but different glucose homeostasis. For example: RYGB achieves greater improvement of glucose tolerance and beta-cell function than an equivalent magnitude of weight loss achieved by purely gastric-restrictive bariatric surgery, such as laparoscopic adjustable gastric banding (LAGB) or following calorie restrictions. The exact molecular mechanisms underlying improved glycemic control after gastrointestinal surgery remain unclear. In spite of anatomical and functional differences between procedures, glucose homeostasis is improved after all these types of operations, probably as an expression of partial overlap in the mechanisms of action. However, given the specific physiological role of the stomach and various intestinal segments in regulating glucose homeostasis, it is also plausible that different gastrointestinal surgeries may have distinct effects and mechanisms of action. Several studies showed the involvement of many key peptides believed to have a role in regulating insulin secretion, including incretin peptides, especially glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) . These factors are produced by intestinal enteroendocrine cells in response to ingestion of carbohydrates or fats, which in turn cause the release of insulin from the pancreas and induce satiety/reduced appetite; their changes after bariatric surgery could potentially explain the effects on obesity and diabetes. The surgical trigger for these changes is not clear; recent studies suggest the importance of modifications of gastric anatomy and physiology (emptying) more than the intestinal bypass per se . One antidiabetic effect of bariatric surgery is weight independent; a number of experimental investigations have postulated changes in intestinal nutrient-sensing, regulating insulin sensitivity; disruption of vagal afferent and efferent innervations; perturbations of bile acid metabolism; taste alterations; enhancement of intestinal glucose uptake in the alimentary limb after diversionary procedures; and downregulation of one or more anti-incretin factors [7, 20‐23]. However, despite much research, the exact pathway to diabetes improvement remains unidentified. 18.3 18.3 Bariatric/Metabolic Surgery in Patients with Type 2 Diabetes 18.3.1 18.3.1 Patients with BMI >35 kg/m2 Several papers in recent years have clearly documented results of metabolic surgery on T2DM and associated comorbidities in patients with a BMI >35 kg/m2. Buchwald et al. in a meta-analysis of 22,094 diabetic patients, reported an overall 77% remission rate. The mean procedure-specific resolution of T2DM was 48% for LAGB, 68% for vertical banded gastroplasty (VBG), 84% for RYGB, and 98% for BPD. However, these results were mainly from retrospective studies with short follow-up . The multicentre Swedish Obese Subjects (SOS) study, a large prospective observational study, compared bariatric surgery LAGB (n = 156), VBG (n = 451), and RYGB (n = 34) versus conservative medical management in a group of well-matched obese patients. At 2 years, 72% of patients in the surgical group achieved remission of T2DM compared with 21% in the medically treated arm. At 10 years, the relative risk (RR) of incident T2DM was three times lower and the rates of recovery from T2DM three times greater for patients who underwent surgery compared with individuals in the control group. The proportion of individuals in whom remission was sustained at 10 years declined to 36% in the surgical group and 13% in the medical group . More recently, sleeve gastrectomy (SG) has gained popularity because of its low morbidity, reasonably quick operative time, no anastomosis, and its effectiveness in obtaining effective weight loss and controlling metabolic disease. A systematic review by Gill et al. of 27 studies involving 673 patients (mean follow-up of 13.1 months) reported a T2DM resolution rate of 66.2% in obese individuals and improved glycemic control in 26.9%. This result has been confirmed by many other papers, showing that SG also represents a very effective procedure both in terms of weight reduction and control of T2DM . Efficacy of bariatric/metabolic surgery has been showed also in several randomized controlled trials (RCT) comparing medical versus surgical management of T2DM. The STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) trial compared intensive medical therapy alone versus medical therapy plus RYGB or SG in 150 obese patients (BMI 27–43 kg/m2) with uncontrolled T2DM. The proportion of patients who reached the primary end point [glycolated hemoglobin (HbA1c) of 6.0% at 1 year) was 12% in the medical group, 42% in the RYGB group, and 37% in the SG group. No patient in the RYGB group required diabetes medications, unlike patients in the SG group (although the study was not powered to demonstrate differences between surgical procedures, these findings suggest a potentially greater antidiabetic effect of RYGB). Surgery showed a better outcome also for secondary end points, including BMI, body weight, waist circumference, and the homeostasis model assessment of insulin resistance (HOMA-IR). Although the study presented promising results, follow-up was limited to 12 months, with no reports about long-term control and risk of disease relapse . In the Diabetes Surgery Study (DSS) trial, 120 patients were randomized to receive intensive lifestyle and medical therapy with or without RYGB. The primary endpoint was a composite outcome including achievement of HbA1c <7.0%, low-density lipoprotein (LDL) cholesterol <100 mg/dL, and systolic blood pressure <130 mmHg. After 12 months, 28 participants [49%; 95% confidence interval (CI) 36–63%) in the gastric bypass group and 11 (19%; 95% CI 10–32%) in the lifestyle-medical management group achieved the primary end points . In 2012, a randomized clinical trial by Mingrone et al. reported results at 2 years of 60 patients (BMI ≥35 kg/m2) with T2DM of at least 5-year duration and an HbA1c level of ≥7.0% comparing conventional medical therapy to RYGB and BPD. Diabetes remission (fasting glucose level <100 mg/dL and an HbA1c level of <6.5% in the absence of pharmacological therapy) occurred in no patient in the medical therapy group versus 75% in the RYGB group and 95% in the BPD group. All patients in the surgical group were able to discontinue pharmacotherapy (oral hypoglycemic agents and insulin) within 15 days after the operation. At 2 years, surgical patients had the greatest degree of improvement in HbA1c levels . Published literature data about long-term remission of T2DM after metabolic surgery are limited. The SOS study in 2014 presented results of the prospective matched-cohort study on diabetes control and micro-macrovascular diabetes complication comparing 270 controls to 343 surgical patients. Surgery was in the form of gastric banding (GB) (61), vertical banded gastroplasty (VBG) (227), or RYGB (55). For diabetes assessment, the median follow-up time was 10 years in both groups. For diabetes complications, the median follow-up time was 17.6 and 18.1 years in control and surgery groups, respectively. Diabetes remission (defined as blood glucose <110 mg/dL and no medication) at 15 years was 6.5% for control patients and 30.4% for bariatric surgery patients (p<0.001). With long-term follow-up, the cumulative incidence of microvascular complications was 41.8:1000 person-years for controls and 20.6:1000 person-years in the surgery group (p<0.001). Macrovascular complications were observed in 44.2:1000 person-years in controls and 31.7:1000 person-years for the surgical groups(p=0.001). This long-term data, although not randomized, shows how metabolic surgery is associated with more frequent diabetes remission and fewer complications than standard medical treatments . The first longer-term results from a randomized trial were published by Mingrone et al. in 2015 . The authors reported data of 5-year outcome from a trial specifically designed to assess management of T2DM comparing surgery versus medical treatments. From the group of 60 patients recruited between April and October 2009, they analyzed glycemic and metabolic control, cardiovascular risk, medication use, quality of life, and long-term complications. Overall, 19 (50%) of the 38 surgical patients [seven (37%) of 19 in the gastric bypass group and 12 (63%) of 19 in the BPD group] maintained diabetes remission at 5 years compared with none of the 15 patients in the medically treated group (p=0.0007). Hyperglycemia relapse occurred in eight (53%) of the 15 patients who achieved 2-year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2-year remission in the BPD group. Eight (42%) patients who underwent gastric bypass and 13 (68%) who underwent BPD had an HbA1c concentration of ≤6.5% (≤47.5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p=0.0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use. Five major complications of diabetes (including one fatal myocardial infarction) arose in four (27%) patients in the medical group compared with only one complication in the gastric bypass group and no complications in the BPD group . These findings show that bariatric surgery is more effective than medical treatment for the long-term control of obese patients with T2DM. Compared with medical treatments, surgery results in sustained remission of diabetes in a significant number of patients and in a greater reduction of cardiovascular risk, diabetes-related complications, and medication use, including use of insulin and cardiovascular drugs. 18.3.2 18.3.2 Patients with BMI <35 kg/m2 Observational studies and RCTs show with growing evidence that patients with lower BMI may obtain benefits regarding T2DM and comorbidity control following metabolic surgery. A prospective study of 66 diabetic patients with BMI 30–35 kg/m2 who underwent RYGB showed remission of diabetes in ~90% and T2DM improvement in ~10% after a follow-up of 6 years. This was also associated with a cessation of pharmacotherapy for T2DM in the majority of patients and reduction of medication use (and withdrawal of insulin when previously used) in the remaining . An RCT by Dixon et al. in 2008 included individuals with BMI 30–35 kg/m2 comparing LAGB to medical treatment. They showed at 2-year follow-up remission of T2DM in 73% in the surgical group and 13% in the conventional therapy group; moreover, insulin sensitivity and levels of triglycerides and high-density lipoprotein (HDL) cholesterol were improved after surgery . Positive results were also seen in the DSS trial including less obese patients with diagnosis of T2DM and follow-up of 12 months. Surgery was associated with greater improvement in HbA1c, LDL-cholesterol, and blood pressure that with medical treatment . These preliminary results highlight the possible role of metabolic surgery even in treating T2DM in patients not classified as morbidly obese. However, despite this data, to define the exact role of surgery in this setting, more RCTs and longer follow-up results are required, along with assessments of the impact of surgery on vascular complications of diabetes. 18.4 18.4 Diabetes Surgery: A New Point of View Over the years, the term used for surgical procedures in morbidly obese patients has been primarily “bariatric surgery.” The main endpoint of these procedures is reduction of body weight and BMI. However, it became clear early that benefits and mechanisms of action of bariatric surgery extend beyond weight loss: T2DM and associated comorbidities can dramatically improve after surgery. This has led to the development of a new concept of surgery, called diabetes or metabolic surgery. The primary intent of this surgical approach is to control metabolic alterations/hyperglycemia, not only to reduce weight. This influences patient selection, with important clinical care implications. A recent study demonstrated that patients treated in metabolic surgery units have a higher incidence of T2DM and comorbidities plus lower BMI than those undergoing surgery in a bariatric unit . Applying the concept of diabetes/metabolic surgery parameters to evaluate outcomes of surgery need to be redefined. Success and failure of this treatment should be assessed by remission or improvement of T2DM and associated comorbidities of the metabolic syndrome, rather than simply checking weight loss. In diabetes surgery, success parameters to consider are then no longer BMI and weight but mainly HbA1c levels, C peptide, fasting glycemia, insulin levels, lipid profile, and similar indexes. As in other fields of medicine, diabetes and metabolic surgery means integration of knowledge and multidisciplinary expertise to provide a combination of medical and surgical treatments. These have to be seen not as alternative strategies but as complementary options, with the same goal of optimizing disease control and achieving cure when possible.