An In-Depth Look at Metabolic Surgery: What Is It and Where Is It Going?

by Natan Zundel MD, FACS; Majed Maalouf, MD; Soni Chousleb, MD

Morbid obesity has risen to epidemic levels in western countries. It is now a grave public health burden in terms of the related medical illnesses and the cost of treatments. Bariatric surgery is the most effective treatment to accomplish sustained weight loss and address medical comorbidities. Candidates for bariatric surgery must fulfill the National Institute of Health (NIH) criteria for obesity, which includes a body mass index (BMI) greater than 40kg/m2 without associated comorbid conditions or a BMI greater than 35kg/m2 with medical problems.1

Type 2 diabetes and obesity will likely become the two greatest health problems in the next decade, with an estimated 333 million people expected to be affected worldwide by the year 2025.2 In the United States, from 1980 to 2005 the number of Americans with diabetes increased from 5.6 million to 15.8 million. These conditions are strongly linked to each other, with the increased prevalence of type 2 diabetes mellitus (T2DM) correlating with the increased prevalence in obesity. The adjusted relative risk of developing T2DM in participants with a BMI greater than 35 is 93% for women and 42% for men.3

Weight loss surgery has dramatically gained acceptance in the last decade. Its role and the metabolic outcomes are being described with positive results all over the world. Observational evidence suggests that bariatric surgery results in resolution of obesity in 60 to 80 percent of patients.3 Multiple surgical procedures have been developed to help with weight loss: restrictive, malabsorptive, and a combination of both. Most comorbidities can be prevented or cured by bariatric surgery in severely obese patients.4,5 Resolution of diabetes is procedure-dependent with 47- to 70-percent cure after restrictive procedures, 80- to 98-percent cure after Roux-en-Y gastric bypass (RYGB), and 92- to 100-percent cure after biliopancreatic diversion (BPD).6,7

The mechanism by which bariatric surgery results in resolution of comorbidities is not fully understood. Multiple theories have been proposed. The most beneficial effect of bariatric surgery is the resolution of diabetes. Most of these patients are medication-free shortly after surgery.
Antidiabetic agents, oral or injectable, have multiple limitations and side effects.8 Furthermore, glycemic control tends to deteriorate over time even after treatment.9 Surgical management of T2DM might have several advantages over conventional therapies. First, long-term glycemic control would not be impaired by a patient’s lack of compliance, as happens with diets, exercise, or complex medical regimens.10 These results lead to the development of “metabolic surgery.” Metabolic surgery is performed to treat metabolic diseases, especially diabetes and dyslipidemia. These procedures are performed in patients that do not fit the criteria for obesity surgery.

In this review, we will discuss the different mechanisms that contribute to the resolution of comorbidities, especially diabetes, and the different procedures performed for this purpose.

Pathophysiology
Diabetes control is closely related to multiple enzymes. These include insulin, glucagon, glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), leptin, and incretin effect.

Glucagon-like peptide 1(GLP-1). GLP-1 is a peptide stored in the L-cells of the ileum and colon, and is released in response to the presence of food in contact with distal small bowel mucosa.11,12 GLP-1 stimulates insulin secretion by promoting pancreatic b-cell proliferation, suppresses postprandial glucagon, and slows gastric emptying.13-15 GLP-1 acts as a satiety hormone by suppressing appetite at the brain level during a meal.13-15 In the human pancreas, GLP-1 promotes the secretion of somatostatin and inhibits that of glucagon.16,17 GLP-1 promotes glycogenogenesis and lipogenesis.18-21 Patients with type 2 diabetes as well as obese patients have low GLP-1 concentrations at base and in response to a meal.22,23 In experimental settings, perfusion of nutrients into the distal gut or ileal transposition in experimental animals increases the release of GLP-1.24,25 Multiple studies have shown that administration of GLP-1, either subcutaneous or intravenous, was effective in controling blood sugar in diabetic patients.26-29 In animal models with ileojejunal transposition, the early arrival of food to the interposed isoperistaltic ileal L-cells produces an increase in GLP-1.30,31 Increased levels are also seen after gastric bypass surgery.32

Gastric inhibitory peptide (GIP). Gastric inhibitory peptide (GIP) or glucose-dependent insulinotropic peptide is a peptide stored in the K cells of the proximal jejunum that is released in response to direct contact with a meal rich in carbohydrates or fat.33,34 GIP helps to maintain blood glucose homeostasis; however, its mechanism of action is not well defined.35,36 It may increase insulin secretions by b cells of the pancreas. It also stimulates lipoprotein lipase activity. Patients with T2DM have decreased sensitivity to GIP with either normal or increased concentrations.22 High concentrations are also seen after bariatric surgery.37,38

Leptin. Leptin is an adipocyte-derived hormone and is the hormone of satiety. It reflects the total amount of fat present in the body. Low leptin levels are usually seen among weight loss patients39 and after bypass surgery.40 In a series of nonobese diabetic rats who underwent gastrojejunal bypass, leptin levels decreased one week after surgery and remained low at one month. However, in this series, GIP and GLP-1 levels remained unchanged. This suggests that leptin may be regulated by the proximal bowel and enhancement of leptin sensitivity results in improvement of glycemic control.41

Incretin effect. The incretin effect is defined by a greater insulin response of the pancreas to oral than intravenous glucose load. This is thought to be due to glucose-dependent insulinotropic peptide (GIP) and GLP-1.35 The improvement in glycemic control occurs during the first week after bypass surgery,40 suggesting that weight loss is not the only mechanism responsible for the resolution of diabetes. Multiple theories have been proposed.

Pories proposed that excessive stimulation of incretins by food in the foregut of vulnerable individuals was the cause of T2DM, and cure by bypass operations was due to removal of the excessive stimulation and exclusion of the site responsible for the production of the incretin.42,43

Mason proposed the hindgut hypothesis: Early arrival of undigested food to the terminal ileum is responsible for the improvement of glucose tolerance.44 The hindgut hypothesis holds that diabetes control results from the expedited delivery of nutrient chyme to the distal intestine, enhancing a physiologic signal that improves glucose metabolism.45 The mediator of this effect can potentially be GLP-1 secreted by the L cells of the terminal ileum and the peptide tyrosine-tyrosine PYY3-36, which share an anorectic effect. GLP-1 stimulates the production of insulin. Jejunoileal bypass supports this hypothesis.

An alternate hypothesis is the foregut hypothesis. Bariatric operations that exclude the duodenum and the jejunum from the transit of nutrients improve glucose tolerance. This hypothesis was tested on nonobese diabetic rats.45 Bypass of the duodenum and proximal jejunum is responsible for the glycemic control by alternating the enteroinsulinic axis and incretin production of GLP-1 and GIP.45 BPD and gastric bypass are two examples. In a series of 10 morbidly obese women with T2DM undergoing BPD, insulin sensitivity increased as early as one week after surgery with decreased GIP levels and inceased GLP-1.46 These changes occurred before any modification in body weight. A reduction in GIP secretion was obtained after both RYGBP and BPD as a result of bypassing the duodenum and the proximal jejunum, the areas with the highest K-cell content.47

Surgical Procedures
Common surgical methods are restrictive, malabsorptive, or a combination of these two. These operations exert appetite regulation at the level of both the central and the enteric nervous system. The main advantages of restrictive procedures are the simplicity of the operation and the low mortality rates. Malabsorptive procedures confer better results in weight loss and resolution of comorbidities.

Jejunoileal bypass. Jejunoileal bypass was first described in the early 1950s to promote weight loss.48 This procedure consists of dividing the proximal jejunum and performing a jejunoileal anastomosis just proximal to the ileocecal valve. Different segment length has been described, but satisfactory weight loss was reported in patients in whom 30 to 35cm of jejunum was anastomosed to 10 to 15cm of terminal ileum.49 Weigth loss was successfully achieved as well as resolution of diabetes.50,51 However, multiple complications have been reported including malnutrition, diarrhea, and cirrhosis. The extent of these complications led to a public repudiation of JIB in 1979 and favored gastric bypass as a surgical treatment for morbid obesity.52

Duodenojejunal bypass (DJB). DJB consists of excluding the duodenum and proximal jejunum without restriction of the gastric volume. It was first described by Rubino and Marescaux in 2004 on an animal model.53 They performed a stomach-preserving gastrojejunal bypass on nonobese type 2 diabetic rats and proved that bypassing the duodenum and jejunum reduces fasting glycemia and improves both glucose tolerance and insulin action without any changes in weight. In addition, lower levels of FFA and cholesterol were obtained in the feeding state.

Cohen perfomed this procedure laparoscopically on two nonobese patients with T2DM and BMIs of 22 and 34.2 The duodenum is transected 1 to 2cm distal to the pylorus. The biliopancreatic limb is divided 30cm distal to the ligament of Treitz and a 50cm Roux limb is constructed. A pylorojejunostomy is performed. Complete resolution of diabetes was obtained by the fifth postoperative week. The hemoglobin A1c levels were 6g/dL at the last follow-up visit nine months postoperatively. No weight loss was noted after nine months.2

Pacheco randomized 12 nonobese diabetic rats to gastrojejunal bypass or no intervention. No weight loss was obtained in the two groups. There was an improvement in glycemic control and in basal glucose level in the gastrojejunal bypass group.41

Ileal transposition. The concept of “ileal brake” was first introduced in 1983.54 Mason suggested that the combination of a restrictive procedure with ileal interposition could be appropriate in mildly obese diabetic patients.44 Early arrival of nutriments to distal small bowel results in increased levels of GLP-1, which is responsible for diabetes control.30,44 In a series of 19 patients with a mean BMI of 40kg/m2, de Paula from Brazil performed laparoscopic ileal interposition with sleeve gastrectomy. The biliopancreatic limb is divided 50cm distal to the ligament of Treitz and a 100-cm Roux-en-Y ileal limb is created 50cm proximal to the ileocecal valve. After one month, all the diabetic patients were normoglycemic and with a percentage of mean weight loss from perioperative weight less than 10 percent.55

Biliopancreatic diversion. BPD combines an antrectomy, a Roux-en-Y limb of 2.5m, and a common channel of 50cm. The residual volume of the stomach is 400mL. The small bowel is transected at 2.5m from the ileocecal valve and is anastomosed to the remaining stomach. The biliopancreatic limb is anastomosed in an end-to-side fashion to the bowel 50cm proximal to the ileocecal valve.46

Pories and Albrecht56 suggested that the improvement in glycemic control is the result of the exclusion of food from the proximal intestinal tract and an alteration of incretin secretions. BPD cures diabetes by altering the enteroinsular axis by diverting nutrients away from the proximal gastrointestinal tract down, regulating GIP secretion, and by delivering incompletely digested nutrients to the ileum, enhancing the secretion of GLP-1.57

Scopinaro in a series of 312 patients showed that BPD can reverse diabetes, hypertension, and hypercholesterolemia in morbidly obese patients, and this effect persisted up to 10 years after surgery.58 He reported resolution of diabetes as early as one month after BPD in diabetic obese patients, when the excess weight was still more than 80 percent.57

A biliopancreatic diversion was performed on two patients with diabetes and familial hypertriglyceridemia.The procedure was performed to better control the lipid disorder. The BMIs of the patients were 21 and 20. After surgery, the blood sugar normalized in the two patients. Bariatric surgery is also effective in curing diabetes in normal-weight subjects.59

Roux-en-Y gastric bypass (RNYGB). Rubino et al reported that after Roux-en-Y gastric bypass, insulin as well as GIP levels decreased to normal values in obese diabetic patients, whereas GIP increased slightly but not significantly in obese nondiabetic subjects.32
Cohen et al in a series of 37 patients with BMI of 32 to 35kg/m2 and poorly controlled comorbidities reported resolution of T2DM and dyslipidemia in 100 percent of patients and hypertension in 97 percent after laparoscopic RYGB.6

The improvement in insulin sensitivity after RYGP is due not only to weight loss, but also to the exclusion of the duodenum and jejunum from food transit, with the consequent modifications on enteroinsular axis.56

The second mechanism underlying the resolution of diabetes after RYGB is related to the restoration of the impaired GIP/GIP receptor axis.60

Surgery is the only treatment that achieves significant weight loss in the morbidly obese patient. Minimal invasive techniques allow performance of complex bariatric surgeries with minimal morbidity and mortality. This successful experience with bariatric surgery lead to the concept of metabolic surgery. Metabolic surgery is performed in nonobese patients with severe metabolic diseases. The surgical procedure consists of bypassing the proximal small bowel. Good results have been obtained in animal models. The only human experience is the result of small series of case reports. Encouraging short-term results have been reported. However, the safety and long-term effect of such procedures are not yet very well defined. Metabolic surgery is a new concept that will represent a new era of surgical procedures.

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Category: Past Articles, Review