Improvement in glucose homeostasis and insulin sensitivity is an expected outcome of weight loss in obese individuals due to any intervention, whether it is medical or surgical. Concomitant with the profound weight loss following gastrointestinal surgery, there is improvement in insulin sensitivity with elevation in the levels of the insulin-sensitizing hormone adiponectin. The concentration of insulin receptors and markers of insulin signaling increase, and the lipid content within the muscle and liver also decreases after bariatric surgery [9].

It is now abundantly clear, however, that the improvement of glycemia is not determined by weight loss alone. Studies have shown that glycemic control improves within days after Roux-en-Y gastric bypass (RYGB) or biliopancreatic diversion (BPD) prior to any significant weight loss. In addition, glycemic control after equivalent weight loss is superior after RYGB as compared to that after laparoscopic adjustable gastric banding (LAGB) or caloric restriction [2, 7, 8]. Experimental evidence in favor of weight-independent mechanisms is derived from animal investigations using the duodenojejunal bypass (DJB) model developed by Rubino in rodents to study the effects of gastric bypass on glucose homeostasis [5]. In lean diabetic Goto-Kakizaki (GK) rats, Rubino and colleagues found that DJB (a bypass of the proximal intestine by the same amount as RYGB but without gastric restriction) rapidly and durably improved fasting glucose and postprandial hyperglycemia. These effects were not observed in sham-operated animals that had undergone equivalent weight loss by caloric restriction. Other investigators have subsequently made similar observations in nonobese diabetic GK rats and obese diabetic Zucker rats.

The gut is the largest endocrine organ secreting numerous hormones and factors involved not only in digestion but also regulation of body weight and glucose homeostasis. It is now recognized that surgical manipulation of the gut results in a change in the levels of various gut hormones including glucagon-like peptide-1 (GLP-1), peptide-YY (PYY), and ghrelin, which can significantly impact glycemic control and body weight.

GLP-1 is an incretin hormone that increases glucose tolerance by enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, inhibiting gastric emptying, increasing β-cell mass, and possibly improving insulin insensitivity [10]. GLP-1 is produced primarily in the ileum and colon by nutrient-stimulated L cells. The postprandial GLP-1 response is consistently observed to be augmented during an oral glucose tolerance test or mixed meal test after the RYGB or BPD in obese nondiabetic and diabetic patients [9, 11]. The rise in GLP-1 level occurs as early as 2 days after surgery and has been shown to persist at 6 months and 1 year postoperatively [12]. Restrictive procedures, such as vertical banded gastroplasty (VBG) and LAGB, have not shown to be associated with any changes in the levels of GLP-1 postoperatively [13].

Ghrelin is an orexigenic hormone produced primarily bVBy the stomach, and administration of ghrelin and its analogs stimulates food intake. Ghrelin levels have an inverse relationship with body weight, and consequently obese individuals have lower ghrelin levels. Weight loss induced by caloric restriction results in an increase in the levels of ghrelin, which subsequently may contribute to the resistance to lifestyle interventions for obesity. Ghrelin may play a role in glucose homeostasis and has been shown to inhibit insulin secretion and suppress the insulin-sensitizing hormone adiponectin [14]. Ghrelin deletion in diabetic obese mice models has shown to reduce fasting glucose and insulin and thus improve glucose tolerance [15]. Several groups have reported a decrease in the levels of ghrelin after RYGB, which may partly account for the improved glycemia [12, 16]. This has not been consistently reported with other studies showing either unchanged or increased ghrelin levels [9, 17]. As expected, ghrelin levels are markedly suppressed following resection of the ghrelin-rich gastric fundus as with a sleeve gastrectomy. However, ghrelin levels show the normal physiological rise with weight loss after LAGB and VBG.

PYY is an anorexigenic hormone co-secreted with GLP-1 from intestinal L cells in response to food intake. PYY has been shown to decrease food intake in humans when injected. Experimental studies in rodents suggest that PYY may directly ameliorate insulin resistance [18]. Several studies have reported elevated PYY levels after RYGB. In a prospective, nonrandomized controlled study comparing the effects of medical and surgical treatment on PYY levels after similar weight loss, it was observed that PYY’s area under the curve increased following RYGB and sleeve gastrectomy, but remained unchanged in the medical arm [19].

Korner et al. [7] conducted a prospective study of gut hormone and metabolic changes after LAGB and RYGB and suggested that the changes in hormone secretion may contribute to the efficacy of the particular procedure in improving obesity-related comorbidities. It is established that PYY and GLP-1 are secreted shortly after food intake from L cells in the distal small bowel and colon. Both decrease appetite, increase satiety, slow gut motility, and improve insulin sensitivity. GLP-1 also functions as an incretin to potentiate glucose-stimulated insulin release. In contrast, ghrelin stimulates appetite, profoundly promotes food intake and gut motility, and decreases insulin sensitivity [20]. Korner et al. [7] found that in LAGB patients, the postprandial rise of GLP-1 measured at 30 min did not change after surgery, whereas in contrast, postprandial GLP-1 levels after RYGB were significantly greater compared with 30-min values before surgery and threefold higher compared with the same time points after LAGB. Fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were also shown to decrease to a greater extent after RYGB. The degree of suppression of ghrelin levels post-meal did not differ significantly presurgery to week 52 in either the LAGB or RYGB and did not differ between groups. Laferrère et al. [8] suggested that the markedly increased incretin levels and effect observed after the RYGB may well be one of the mediators of the antidiabetic effects of the surgery, and they set out to determine whether the magnitude of change of the incretin levels is greater after the RYGB compared to a hypocaloric diet at an equivalent weight loss. Their results showed a markedly increased GLP-1 response to oral glucose after the RYGB, but GLP-1 levels tended to decrease after diet intervention, although this decrease was not significant. The incretin effect markedly increased after an RYGB, but not with diet, and suggests that this effect was not likely to be weight loss related. Therefore, this could play a key role in the remission and resolution of T2DM after an RYGB. Data from various studies has shown that beneficial changes of incretin levels occur rapidly after the RYGB, which is secondary to the bypass procedure, thus resulting in an improved insulin secretion profile and decreased postprandial glucose [21].

Another mechanism proposed in recent years is the effect of bariatric surgery on the alteration of taste. This novel weight loss mechanism involves alterations in food preferences, which may be secondary to changes in taste detection and reward. Miras et al. [22] have shown that after RYGB, patients’ eating behavior changes, and they start to adopt healthier food preferences by avoiding high-calorie and high-fat foods. Patients find sweet and fatty meals less pleasant than preoperatively, and this may be attributed to changes in the sense of taste. A putative mechanism to explain this is that RYGB may reverse the higher activation of brain taste reward and addiction centers in response to high calorie and fat tasting.

Two hypotheses have been proposed to explain improved glycemia following gastrointestinal surgery. The “hindgut hypothesis” posits that the expedited delivery of ingested nutrients to the lower bowel, due to an intestinal bypass, stimulates L cells, which results in an increased secretion of incretin hormones and an improved glucose homeostasis [5]. Consistent with the hindgut hypothesis, the bariatric operations most noted for rapid T2DM remission, RYGB and BPD, create GI shortcuts for food to access the distal bowel. However, a significant improvement in glycemia and remission of diabetes with elevated incretin levels is also noted to occur after a sleeve gastrectomy, which does not involve an intestinal bypass. It must be noted that GLP-1 secretion is stimulated not only by direct nutrient contact with distal intestinal L cells but also by proximal nutrient-related signals that are transmitted from the duodenum to the distal bowel by neural pathways and other unknown mechanisms [9]. The alternative hypothesis is the “foregut hypothesis,” which depends on the exclusion of the duodenum and proximal jejunum from the transit of nutrients, possibly preventing secretion of a putative signal that promotes insulin resistance and T2DM [6]. Rubino et al. conducted a study to investigate these mechanisms by testing both hypotheses and found that the exclusion of the proximal small intestine from contact with ingested nutrients is a critical component in the mechanism improving glucose tolerance after the DJB in GK rats, thus supporting the foregut hypothesis [6].

Other hypothesized antidiabetic mechanisms after bariatric surgery include changes in intestinal nutrient-sensing mechanisms regulating insulin sensitivity, disruption of vagal afferent and efferent innervations, bile acid perturbations, changes in gut microbiota, and alterations in undiscovered gut factors.

The outcomes of bariatric surgery on diabetes and the metabolic profile in patients with a BMI of >35 kg/m² have been well documented over many years.

Buchwald et al. [23] conducted a meta-analysis including 22,094 patients with T2DM reported an overall 77 % remission rate of T2DM (defined as persistent normoglycemia without diabetes medication after bariatric surgery). The mean procedure-specific resolution of T2DM was 48 % for LAGB, 68 % for VBG, 84 % for RYGB, and 98 % for BPD. The drawback of this study is that the majority of these studies included was retrospective and had a short follow-up duration of 1–3 years. The multicenter Swedish Obese Subjects (SOS) study, a large prospective observational study [24], compared bariatric surgery (LAGB n = 156, VBG n = 451, RYGB n = 34) with conservative medical management in a group of well-matched obese patients. At 2 years, 72 % of diabetic subjects in the surgical group achieved remission of T2DM compared to 21 % in the medically treated arm. At 10 years, the relative risk of incident T2DM was three times lower, and the rates of recovery from T2DM were three times greater, for patients who underwent surgery than for individuals in the control group. The proportion of subjects in whom the remission was sustained at 10 years declined to 36 % in the surgical group and 13 % in the medical group. It must be noted, however, that approximately 95 % of patients in the SOS study underwent gastric restrictive procedures rather than RYGB.

Recently, Schauer et al. [25] published results from their randomized, non-blinded, single-center trial and compared intensive medical therapy alone versus medical therapy plus RYGB or sleeve gastrectomy (SG) in 150 obese patients (BMI 27–43 kg/m²) with uncontrolled T2DM. The primary end point was the proportion of patients with a glycated hemoglobin (HbA1c) level of 6.0 % or less 12 months after treatment. The proportion of patients who reached the primary end point was 12 % for the medical group, 42 % in the RYGB group, and 37 % in the SG group. Glycemic control was demonstrated to improve in all three groups with a mean HbA1c level of 7.5 ± 1.8 % in the medical therapy group, 6.4 ± 0.9 % in the gastric bypass group, and 6.6 ± 1.0 % in the sleeve gastrectomy group. It was demonstrated that many patients in the surgical groups, particularly in the RYGB group, achieved glycemic control without the use of diabetes medications after 1-year follow-up. Secondary end points, including BMI, body weight, waist circumference, and the HOMA-IR, improved more significantly in the surgical groups than the medical therapy group. It was also shown that the reduction in the use of glycemic pharmacotherapy occurred before achievement of maximal weight loss, thus supporting the weight-independent mechanisms of surgery. This trial also supported the notion that bariatric surgery represents a useful management strategy for uncontrolled T2DM.

Mingrone et al. [26] published results from an RCT conducted including 60 patients (BMI ≥ 35 kg/m²) with a history of at least 5 years of T2DM, and an HbAlc level of 7.0 % or more. They compared conventional medical therapy to the RYGB or BPD. The primary end point was the rate of diabetes remission at 2 years (defined as a fasting glucose level of <100 mg/dL and an HbA1c level of <6.5 % in the absence of pharmacological therapy). At 2 years follow-up, diabetes remission had occurred in no patients in the medical therapy group versus 75 % in the RYGB group, and 95 % in the BPD group. All patients in the surgical groups had discontinued their pharmacotherapy (oral hypoglycemic agents and insulin) within 15 days after the operation. At 2 years, the average baseline HbA1c level (8.65 ± 1.45 %) had decreased in all groups, but patients in the two surgical groups had the greatest degree of improvement (average HbA1c levels, 7.69 ± 0.57 % in the medical therapy group, 6.35 ± 1.42 % in the RYGB group, and 4.95 ± 0.49 % in the BPD group). The findings support the conclusion that bariatric surgery may be more effective than conventional medical therapy in controlling hyperglycemia in severely obese patients with T2DM.

The effects of bariatric surgery in the morbidly obese population (>35 kg/m²) are well documented. The field of metabolic surgery has become increasingly researched in recent years, investigating the effects and benefits of operating on those patients with a BMI of less than 35 kg/m². The aims of metabolic surgery differ slightly from bariatric surgery; in that, there is a shift in goals of surgery from weight reduction to the control of metabolic disease, with the aim of “curing” T2DM or putting this prevalent condition into remission. Recently, prospective RCTs have been conducted in lower BMI patients (<35 kg/m²) in order to compare various gastrointestinal surgical procedures versus intensive medical management, to identify the differences between conventional treatment and metabolic surgery.

Dixon et al. [27] conducted an RCT comparing the LAGB versus conventional therapy in 60 obese patients (BMI > 30 and <40 kg/m²) with recently diagnosed (<2 years) T2DM. The primary outcome measure was the remission of T2DM (defined as fasting plasma glucose < 126 mg/dL and an HbA1c level of <6.2 % while taking no glycemic therapy). After a 2-year follow-up, remission of T2DM was achieved in 73 % in the surgical group and 13 % in the conventional therapy group, and it was found to be related to weight loss. Mean levels of fasting plasma glucose and HbA1c were significantly lower in the LAGB group at 2 years. There was also a significant reduction in the use of pharmacotherapy for glycemic control in the LAGB group at 2 years. Secondary outcome measures, such as insulin sensitivity and levels of triglycerides and HDL, were also improved in the surgical group. It was concluded that this trial presents evidence to support the early consideration of surgery in the treatment of obese patients with T2DM.

Lee et al. designed a randomized, double-blind trial [28] in order to compare the RYGB versus SG on T2DM resolution (remission defined as fasting plasma glucose < 126 mg/dL, HbA1c < 6.5 % without the use of oral hypoglycemics or insulin) in non-morbidly obese patients (BMI < 35 kg/m²) who had T2DM that was inadequately controlled. The resolution rate was 93 % in the RYGB group compared with 47 % in the SG group. These results are consistent with the RYGB being more effective than restrictive-type procedures. The RYGB group also achieved a lower waist circumference, fasting plasma glucose level, HbA1c level, and blood lipid level. Therefore, the RYGB group had a higher remission rate for the metabolic syndrome than the SG group. This study concluded that RYGB is more effective than SG for surgical treatment of inadequately controlled T2DM, suggesting that duodenal exclusion plays a role in the mechanism behind the remission of T2DM.