Owing to its pathogenic features, the pandemic clinical manifestation of type 2 diabetes is extremely complex. In recent years, the Roux-en-Y gastric bypass surgery, which was originally indicated to treat morbid obesity, has been found to have therapeutic effects on diabetes. However, its precise mechanism still remains unknown.
This review article will focus on how Roux-en-Y gastric bypass surgery is conducted, and the pros and cons of the operation itself. In terms of the advantages, the authors will discuss expected metabolic improvements, obesity resolutions, and morbidity decreases. In terms of disadvantages, the authors will evaluate shot-term perioperative complications and long-term nutrition disorders. Finally, the authors will review the possible underlying mechanism leading to type 2 diabetes resolution after the Roux-en-Y gastric bypass procedure.
Despite the fact that certain complications such as bowel obstruction, anastomotic leakage and nutrition disorders may occur after Roux-en-Y gastric bypass. There has been reported to show a remarkable decrease in mortality, success of weight loss, and resolution of type 2 diabetes. Though the actual mechanism leading to diabetes resolution remains unknown, gastric bypass surgery is certainly an effective method to increase remission rate in a subgroup of type 2 diabetes with morbid obesity.
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Type 2 diabetes mellitus represents a group of metabolic disturbances (or disorders) characterized by high blood glucose levels (hyperglycemia), which results from the defects in insulin secretion and/or insulin actions. Type 2 diabetes has become one of the most important public health issues of metabolic diseases around the world. According to the World Health Organization (WHO), type 2 diabetes mellitus is a rapidly increasing epidemic disease in Southeast Asian and Western Pacific countries, causing millions of people to live under the oxidative pressure of abnormally high blood glucose levels. The incidence rate in Taiwan increased in all age groups among males, and in most age groups among females during 1992~1996,. In a later survey from 1999-2004, the age-standardized incidence rate of type 2 diabetes per 1000 person-years for men was approximately 7.6 and remained stable. But for women the incidence rate decreased from 7.7 to 6.9. However, there is an alarming increase in the incidence of type 2 diabetes in younger adults aged < 40 years.
As a result, the health authorities must be responsible for allocating health-care resources of the pathological outcomes resulting from type 2 diabetes mellitus. Those pathological outcomes can be divided into two basic parts: early and late symptoms. The early phase symptoms mainly contain polyuria (frequent urination), polydipsia (increased thirst), and polyphagia (increased food intake). These symptoms are mainly caused by dehydration and unabsorbed glucose into urine. Another notable early symptom is diabetic ketoacidosis, which results from the inability to store excess metabolized fat and protein from the metabolic pathway due to the low level of blood insulin. The late phase symptoms contain diabetes-specific microvascular complications, such as eye problems, kidney damage, nerve damage, and skin irritation. There are two main causes for eye complications. One being abnormal hyperplasia of retina vessels which leads to spontaneous bleeding and the other being aneurysms of these brittle vessels which cause the vessels to rupture. Both causes may lead to retinal scarring and retinal detachment, which lead to vision impairment. Hyperglycemia causes the eye lens to shrink and swell because of the strong variation in blood glucose levels, inducing the occurrence of cataracts. Kidney damage, termed as diabetic nephropathy, is another outcome caused by damaged vessels. Proteins from these vessels leak into urine at first and progressively cause the damage of the kidney. Nerve damage is also related to the abnormal blood vessels. Once these vessels become dysfunctional, nearby nerves, especially those equipped with less blood supply, die easily. This clinical symptom implies that patients will have trouble recognizing pain at distal limbs. Moreover, there are also some macrovascular complications associated with type 2 diabetes mellitus, such as cardiovascular disease, cerebral vascular disease, and peripheral vascular disease. In short, type 2 diabetes mellitus is associated with serious comorbidity.
Knowing how to deal with this devastating disease of civilization is an important issue. Unlike type 1 diabetes mellitus, which is an early-onset disease caused by autoimmunity against insulin-producing Î²-cells in pancreas, type 2 diabetes mellitus is typically a late-onset disease caused by a progressive insensitivity in the insulin receptors resulting in insulin resistance. There are many well-established pathways to help bring the body back to a normal blood glucose balance. Other than subcutaneous insulin injection or the orally administered insulin under development, there are several anti-diabetic drugs available in the market. Sulfonylureas and meglitinides accelerate the release of insulin hormones by directly acting on pancreatic Î² cells via different binding sites. Biguanides reduce hepatic glucose output and increase uptake of glucose by the peripheral tissues, including skeletal muscle. There are also many different kinds of drugs acting on the amount of enteric hormones, such as incretin mimetics, glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), and dipeptidyl peptidase-4 inhibitors (DPP-4). However, until now, there is no single therapy able to fully cure type 2 diabetes mellitus. The traditional way to control the blood glucose is to take anti-diabetic drugs listed above, and to use a home blood glucose monitor. It can only give temporary control of the blood glucose, but is not an appropriate method for patients trying to recover from diabetes mellitus. Moreover, since an adequate prognosis relies on the patient's good compliance to keep a near-normal blood glucose level, it is hard to really control a patient's medication condition.
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Other than antidiabetic medications and lifestyle modification, which reduces the risk and helps the management of type 2 diabetes mellitus, in recent decades, physicians and surgeons have progressively constructed a new way to control the blood glucose, i.e. gastric bypass surgery to treat type 2 diabetes mellitus patients. In Taiwan, according to the data published in Taoyuan Min-Sheng Hospital by Professor Wei-Jei Lee, the gastric bypass surgery, especially the Reux-en-Y method, has become an emerging therapy on Asian patients who suffer from metabolic syndromes and whose body weight index (BMI) >37 or >32 kg/m2 with diabetes or two other obesity-related co-morbidities. The emerging amount of cases of gastric bypass surgery also represents that it is a functional way to provide a solution to type 2 diabetes mellitus in a subset of obese type 2 diabetes subjects. It is predicted that the long-term health burden of type 2 diabetes can be decreased once this therapy is raised as a mainstream therapy in obese individuals with various metabolic disorders.
This article will focus on both the benefits and risks of this surgery and the mechanism by which the human body regulates homeostasis of glucose control with this new type of therapy.
What is gastric bypass?
Individuals with abdominal obesity defined with ethnicity-specific cutoff of waist circumference, plus two of the following criteria are defined as having metabolic syndrome: high levels of plasma triglycerides and glucose, low levels of high-density lipoprotein cholesterol (HDLc) and high blood pressure. Individuals with metabolic syndrome are at higher risk for developing heart disease and type 2 diabetes. And, the central abnormality is the obesity or abdominal obesity. The first gastric bypass surgery was designed by Edward Mason in the 1950s as a bariatric surgery in treating severe obesity. But the first demonstration of relation between bariatric surgery and type 2 diabetes was accidentally discovered by Dr. Walter Pories in 1980. At first, it was a big surprise finding that the patients undergoing gastric bypass had amazing remission of type 2 diabetes. Those obese patients no longer needed insulin even though they had not lost weight yet. But this outlandish effect of reversing diabetes through surgery was a discovery that Dr. Pories and his team "didn't dare publish." However, it is estimated that over 220,000 bariatric procedures are now being performed yearly in North America, 66,769 in Europe, and13,210 in Asia Pacific. From 2003 to 2008, the number of bariatric procedures being performed doubled in North America and Europe, and tripled in the Asia Pacific region.
Roux-en-Y gastric bypass
There are several types of bariatric surgery. The most commonly performed procedures are laparoscopic adjustable gastric banding (AGB; 42.3%) and laparoscopic standard Roux-en-Y gastric bypass (RYGB; 39.7%). Both AGB and RYGB have a therapeutic effect on type 2 diabetes.
Reduced gastric pouch
Roux limb (jejunal limb)
30-70 cm bypassed
Figure 1. Roux-en-Y gastric bypass.
In 1967, Mason and Ito at the University of Iowa first introduced the Roux-en-Y gastric bypass and it is now considered the gold standard of bariatric procedures. Roux was a Swiss surgeon, who developed the general technique of RYGB. The "Roux limb" is defined as the part of the jejunum brought up behind the colon and lower stomach pouch. Diagrammatically, the Roux-en-Y anastomosis looks like the letter Y. Roux-en-Y gastric bypass can be performed either openly or laparoscopically, but approximately 90% of procedures performed laparoscopically had a better outcome.
Three main types of bypass surgery: proximal, distal, and MGB
There are three types of gastric bypass surgery: proximal, distal, and mini gastric bypass (MGB). The classification depends on which segment of the gastrointestinal tract the surgical device passes through. The Roux-en-Y proximal method is the most commonly performed procedure. It passes through the most part of stomach and about 45 cm intestine distal to the pylorus. The Roux-en-Y distal method preserves lesser intestines. The Y-connection often locates at about 100 to 150 cm from the proximal end of intestine. This procedure may cause nutrition problem more than proximal method. The mini gastric bypass, unlike the two methods above, constructs a shortcut with a loop of intestine rather than Y-shape connection. This method reduces one conjunction during the procedure.
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All of the above surgery can be operated with traditional open surgery or laparoscopic surgery. Traditional open surgery needs to open the patient's abdomen, increasing the probability for post-operative infection. With its progressively improved techniques, laparoscopic surgery has proved to be a safer, though more time-consuming, method of performing a gastric bypass surgery. For this reason, laparoscopic surgery has become the more popular method in recent years. The first case with laparoscopic gastric bypass, Reux-en-Y was performed in 1993 by Dr. Alan C. Wittgrove in San Diego, USA. According to his report, the laparoscopic gastric bypass can significantly reduce the incidence of type 2 diabetes.
However, not all patients with obesity are recommended to receive this surgery. The National Institutes of Health USA offers a suggestion of criteria to those considering to undergo bariatric surgery:
People who have a body mass index (BMI) of 40 kg/m2 or higher. Or,
People with a BMI of 35 kg/m2 or higher with one or more related comorbid conditions.
However, in the Asian pacific region, the standard is a little more flexible than what the NIH offered. The Asia-Pacific Bariatric Surgery Group gave out somewhat different criteria:
People who have a body mass index (BMI) of 37 kg/m2 or higher. Or,
People with a BMI of 32 kg/m2 or higher with one or more related comorbid conditions.
Technique and procedure of Roux-en-Y gastric bypass
Open type Roux-en-Y gastric bypass
Carefully incise fascia in the linea alba to facilitate postoperative wound closure and enter the patients' peritoneal cavity. But incision 2 to 3 cm left to the midline is also recommended owing to the benefit of checking for umbilical hernia. Then start to create proximal pouch. Insert the left hand under body of stomach and cranial to left gastric artery. Then pass two linear staplers around the gastric cardia, fire them, transect the cardia and separate the pouch from the bypassed remainder of stomach. Then transect the proximal jejunum 50 to 100 cm distal to the ligament of Treitz to create a Roux-en-Y limb. Use an end-to-end 21 mm circumference stapler to complete cardiojejunostomy. After that, there is still three defects, including defects on transverse mesocolon, Peterson's hernia and jejunal mesenteric hernia.
Laparoscopic Roux-en-Y gastric bypass
The idea of laparoscopic and open Roux-en-Y gastric bypass surgery is largely the same. The difference is the usage of a liver retractor to elevate the left segment of the liver and a camera to survey and an ultrasonic dissector to do the operation. In comparison with open type procedure, the laparoscopic type Roux-en-Y gastric bypass is more effective in improving comorbidities and quality of life while reducing recovery time and perioperative complications. Occurrence of wound infection in the open type is 7%, much higher than the 2% occurrence of wound infection in patients who undergo laparoscopic RYGB. Under the laparoscopic operation of experienced surgeon, up to 98% of afflicted patients with diabetes can be clinically reversed.
The outcome of Roux-en-Y gastric bypass
Some may argue that bypass surgery does nothing more than alter one's lifestyle. For example, the anatomic reconstruction simply changes the eating behavior of the individual due to uncertain metabolism mechanism. According to 31 follow-up studies after laparoscopic Roux-en-Y gastric bypass, an 82% remission rate and an 18% improvement of type 2 diabetes have been reported. Sleep apnea, common for morbid obesity, is resolved by 74% and by 19% improved. Hypertension is improved by 18% and resolved for 70%. Excess weight loss was 61.6% for patients who underwent gastric bypass. Operative mortality within 30 days was only 0.5% in the experienced operation centers.
Metabolism improvements after gastric bypass
Roux-en-Y gastric bypass has been reported to have beneficial effects on glucose metabolism and serum lipid composition in obese type 2 diabetes. Though little is known for the profiles of metabolic changes after a Roux-en-Y gastric bypass, we can see the improvement from the patients who have undergone surgery; there is a reduction in serum fasting plasma glucose and triglyceride levels, and an increase in HDL-cholesterol levels. Older age, longer duration of diabetes and insulin use are preoperative factors associated with a failure to resolve type 2 diabetes. But usually, patients with diabetes no longer need any insulin before their hospital discharge. More physical activity and lower energy intake helps patients lead a healthier life: most patients (95%) reported significant improvement in life quality.
Gastric bypass helps individuals with apparent body weight reduction, with 80% loss of excess weight after 24-30 months and 30% reduction of total body weight. The mean total weight loss in Asia, however, was reported with 23~29% at the first seven years after surgery. The total weight loss is associated with remission of type 2 diabetes. The median hospital stay for those who have undergone operation is only 2 days, and in 21 days, individuals return to their work and normal activities.
Complications associated with operation
General complications of abdominal surgery include fever, bleeding, vomiting, diarrhea, dyspnea, wound problems and infections which, in total, account for a 7~14% complication rate. The incidence of early major complications has been reported to be 3.3%, and 27% for minor postoperative complications. The mortality rate ranges from 0~0.6%, related to the experience of the surgeon. It is estimated that the learning curve for a surgeon is around 100 cases to become experienced. With the submission of type 2 diabetes, hypoglycemia may occur in the first 2~12 months after the surgery. Dramatic weight loss after surgery may be associated with some atypical complications under the widespread bariatric operation. Superior mesenteric artery syndrome is the one that contributes to postprandial nausea and epigastric pain. But this can be prevented by bypassing the obstruction during operation, and maintaining the weight loss. Below are some significant complications after Roux-en-Y gastric bypass.
Hernia and bowel obstruction
Adhesions, anastomotic strictures, intussusceptions, and volvulus are common complications of RYGB, and cause small bowel obstruction (SBO). According to etiology, the leading cause of SBO, however, is not the above common complications of RYGB, but internal hernias from surgery. For the prevention of bowel obstruction, Arturo R. suggested a few strategies such as leaving the jejuna mesentery intact or closing every created defect which can significantly decrease the incidence of SBO. The internal hernias can also be prevented by careful closure of the mesenteric defects.
Postoperative leakage may occur at the site of the gastrojejunostomy, jejunojejunostomy, gastric staple line, esophagus or small bowel. 1-2% of patients have anastomotic leak in the first 2 weeks after their surgery. Symptoms include tachycardia, dyspnea, abdominal pain, and peritonitis. In addition, unexplained oliguria, the decreased production of urine, may develop in the first 3 days due to renal failure. If not, it should suggest anastomotic leakage.
Inadequate weight loss or weight regain are important issues for a small number of patients during their 6th-18th months after operation. These nutrition disorders may be caused by restricted food intake due to a small gastric pouch, or by bypass of the proximal intestine which can induce malabsorption. Others include postoperative dumping syndrome, celiac disease, and small intestinal bacterial overgrowth (SIBO). The large amount of undigested food bypassing the stomach to the small intestine too rapidly causing an uncomfortable physiological reaction or even diarrhea is defined as dumping syndrome.
Celiac disease is an autoimmunity of small intestine leading to lactose intolerance and gluten-sensitive enteropathy. Gluten-sensitive enteropathy is a difficulty or inability to digest gluten, a protein in wheat, rye, and barley. Small intestinal bacterial overgrowth (SIBO) refers to abnormal intestinal flora or unusually large numbers of bacteria (â‰§ 100,000 bacteria/ml) present in the small intestine. Lactose intolerance and abnormal growth of bacteria in the intestine can be identified by a glucose-hydrogen breath test. Despite the routine use of postoperative nutritional supplements, preventable morbidity may occur in a substantial number of patients because of macronutrient or micronutrient deficiencies, as explained below.
After bypass surgery, patients are recommended to intake 60-70 g of protein daily. But achieving this standard protocol is not easy and may require intensive counseling with a nutritionist. Hair loss is a common syndrome resulting from an early manifestation of protein malnutrition. Long-term symptoms include muscle-mass wasting and severe protein deficiency similar to Kwashiorkor, especially after the distal Roux-en-Y gastric bypass. Careful clinical and nutritional follow-up, with an emphasis on protein intake, presence of edema, and condition of skin and hair loss, is recommended to prevent these uncommon but potentially dangerous complications.
Vitamin D deficiency and Calcium malabsorption
Decreased calcium absorption and insufficient calcium availability with subsequent symptoms such as hypocalcemia, secondary hyperparathyroidism and the development of osteoporosis and osteomalacia are the main reasons for metabolic bone disease after Roux-en-Y gastric bypass. Patients may complain of bone pain, back pain or aching of the limbs. Careful calcium and vitamin D supplementation and long-term screening of urinary calcium excretions and 25-hydroxyvitamin D levels are necessary to prevent deficiencies and the sequelae of secondary hyperparathyroidism.
Thiamine (vitamin B1) deficiency
Thiamine deficiency or vitamin B1 deficiency, affects 49% of patients with small intestinal bacterial overgrowth induced by an altered gut ecology. But most of them are asymptomatic. Beriberi, a severe thiamine deficiency, results in four types of symptoms: neuropsychiatric, neurologic, cardiac and gastrointestinal. Auditory and visual hallucinations may occur in patients with neuropsychiatric beriberi. Neurologic symptoms include numbness, muscle weakness, and exaggerated tendon reflexes. Edema, right ventricular dilation, and respiratory distress develop in cardiac beriberi. Gastrointestinal beriberi presents with nausea, vomiting and constipation. Vitamin B1 deficiency can be treated with oral thiamine HCl 100 mg twice a day.
Vitamin B12 and other vitamin malabsorption
Vitamin B12 deficiency contributes to the late-onset anemia. After Roux-en-Y gastric bypass, 46.6% of the patients developed anemia and 63.6% at 3 years. The inadequate consumption of vitamin B12 by bacterial utilization and the lack of acid, R factor, and intrinsic factor secreted by parietal cells within gastric remnant mainly contribute to the vitamin B12 malabsorption. Folic acid or folate deficiency, in contrast, was not observed and was even reported to have elevated to normal levels following RYGB. However, an isolated case reports of neural tube defects caused by folic acid deficiency in pregnant women who had undergone RYGB without taking the recommended daily folic acid supplementation. Daily oral free vitamin B12 with intramuscular supplements every month is prescribed for vitamin B12 deficiency. Other vitamin deficiencies may occur but with less significant clinical manifestations. Such deficiencies were reported to have an incidence rate of 11% for vitamin A, 34.6% for vitamin C, and 17.6 % for vitamin B6 deficiency one year after surgery.
Iron, Selenium, Zinc and Copper deficiency
Anemia is a common postoperative disorder caused by iron deficiency or malabsorption of vitamin B12 and may affect as many as two-thirds of individuals. However, a significant number of anemia cases remain unexplained and may be attributable to copper, vitamins A and E, or an imbalanced zinc intake. Routine treatment includes iron and vitamin C complex or parenteral iron supplementation. RYGB patients with heart failure, obstructive sleep apnea, or thiamine deficiency must be considered as having selenium deficiency. Selenium is essential for the activation of glutathione peroxidase, an enzyme critical for free radical defense. The lack of selenium may lead to nutritional cardiomyopathy, also known as Keshan disease, or life-threatening heart failure nine months after the surgery.
Zinc is absorbed mainly in the duodenum and proximal jejunum, which are removed by RYGB. Severe zinc deficiency can induce alopecia, glossitis, nail dystrophy, or a dermatologic eruption. However, high supplemental doses of zinc can induce copper deficiency, a common cause of idiopathic myelopathy in adults. Copper deficiency can manifest itself in hematologic disorders such as anemia or neutropenia, as well as neurological symptoms. Early recognition and copper supplementation may prevent neurological deterioration.
Long-term follow-up for evaluation of RYGB
Obesity is an epidemic problem in today's society and is associated with a high rate of morbidity and mortality. Whether there is significant and sustained weight loss and reduced complications after bypass surgery in the long-term outcome is an important issue. Based on the Swedish study of 10 years follow-up, the total body weight had decreased by 16.1% for the surgery group, but increased by 1.6% in the control group. Energy intake is lower and physical activity is higher for individuals after bypass than individuals in the control group. Recovery from symptoms such as diabetes, hypertriglyceridemia, hypertension, low levels of HDL, and hyperuricemia were more favorable in the surgery group, except for hypercholesterolemia.
Long-term mortality was significantly reduced particularly for individuals with diabetes, heart disease, and cancer. Based on a 7.1-year follow-up study, the total mortality rate of individuals who had undergone gastric bypass surgery was decreased by 40%. Specific mortality rate after surgery is decreased by 56% for coronary artery disease, by 92% for diabetes and by 60% for cancer. However, non-diseases related death rate, such as suicide or accidents, was reported 58% higher in the surgery group. Unrecognized pre-surgical mood disorder or post-traumatic stress disorder were revealed in a substantial number of severely obese people. Therefore, psychological evaluation and aggressive follow-up after surgery is recommended. Death rate has been reported with 2.7% after 7.1 year follow-up, with reduction rate of 28% compared to control group for patient with a BMI under 45. And the death rate for BMI of 45 or more is 44% reduction in surgery group. Death rates were lower for all disease combined after gastric bypass surgery.
Mechanism of gastric bypass in improving type 2 diabetes
Roux-en-Y gastric bypass was originally reported to treat obesity. Though an early decrease in body weight may be attributed to the decrease in appetite due to the anatomical limitation of the stomach, the human body would compensate for the reduced stomach and bypassed intestine by forcing patients after RYGB to take meals more frequently to maintain energy homeostasis. Meanwhile, it could also be observed that patients' glucose level decreased, that is to say, type 2 diabetes was cured without any medical treatment except for RYGB. From the observation above, we can infer that hormones may play an important role in body weight loss and diabetes resolution. Researchers have tried to explain this phenomenon. Hormones affecting energy metabolism and food intake will be discussed below to explain the possible mechanisms by which Roux-en-Y cures type 2 diabetes.
The role of ghrelin
Ghrelin is a hormone secreted by the human stomach. It regulates synthesis of several neuropeptides in the hypothalamus that regulate feeding by stimulating hunger sensation.Â In a study that examines ghrelin levels in 13 obese subjects, it has been shown that plasma ghrelin levels are generally higher after diet-induced weight loss. Also, ghrelin levels are lower in obese people than in matched normal-weight controls. Both of which imply that ghrelin has a important role in the long-term regulation of body weight. The procedure in Roux-en-Y may prevent ghrelin-producing cells from contact with ingested nutrients, which may further disrupt ghrelin secretion. This may cause earlier satiation in cases with RYGB than in those without RYGB. In a study that examines ghrelin levels in 5 gastric bypass patients, the ghrelin profile is extremely flat compared to the matched obese control, showing no marked differences or rhythms between meals.
But the detailed mechanism by which gastric bypass can lead to a drop in ghrelin remains unknown. It is hypothesized that the "override inhibition" is responsible: hormones are normally secreted in response to casual stimulation, but they become inhibited if the stimulation becomes continuous. In the case of ghrelin, the emptying of one's stomach between meals stimulates ghrelin secretion. But after RYGB, the emptying of one's stomach becomes continuous, therefore, ghrelin secretion is inhibited. In conclusion, the presence of ghrelin helps cut down weight, but cannot explain the effect on type 2 diabetes.
The role of incretins
Incretins, which are marked by the ability to induce insulin release by Î² cells and to inhibit glucagon release, are mainly composed of GLP-1 and GIP,,. Both of them affect insulin secretion, which is evidenced by less secretion of insulin after inactivation of the gene encoding GLP-1 and GIP receptor. GLP-1 is secreted by the L cell of distal ileum in response to food intakex. It can delay gastric emptying, which further decreases appetite, inhibiting release of glucagon as mentioned above, and may improve insulin sensitivity by stimulating lipogenesis and glycogenesis.
GIP, gastric inhibitory peptide or glucose-dependent insulinotropic peptide, is secreted by the K cell of the proximal gut. It can be stimulated by fatty acids and amino acids to delay the emptying of the stomach and stimulate insulin secretion. But GIP does not affect gastric emptying or satiety.
GLP-1 and GIP both activate adenylate cyclase to act on Î² cells in pancreatic islets, which further activates glucose-dependent insulin secretion. Studies have shown that after a Roux-en-Y gastric bypass surgery, GLP-1 levels increase significantly. However, for participants in the control who have had same degree of weight loss by dieting rather than through RYGB, GLP-1 levels do not increase. This fact further indicates that incretin secretion is induced by the surgery itself and not caused by weight loss. Another study has shown that GLP-1 levels remained elevated for over a year in patients having RYGB. Regarding the elevation in GLP-1 levels, we can infer that bypass surgery, along with the anatomical restriction of the stomach, decreases one's appetite, leading to weight loss. We can also infer that insulin levels will increase, which leads to the direct improvement of diabetes mellitus. In contrast with the GLP-1, GIP and the effect on GIP level change has not been studied thoroughly, and the outcomes remain inconsistent in different studies: some studies show elevation in GIP level while other studies do not.
The main reason why incretin levels increase after RYGB is still unknown. Two hypotheses have been offered to explain the observation. The "hindgut hypothesis", or the lower intestinal hypothesis, suggests that the direct nutrient transport (under circumstances of RYGB) to the intestine without entering the stomach stimulate secretion of GLP-1 and GIP. The other is "foregut exclusion hypothesis", or the upper intestinal hypothesis,, suggests that passage of food via the duodenum and proximal intestine may stimulate secretion of unknown "anti-incretin factors" aiming to prevent hypoglycemia. While, anti-incretin factors inhibit incretin activity and insulin secretion, which further induces type 2 diabetes mellitus. The process of RYGB includes not only gastric but also duodenal and proximal intestinal bypass and may reduce the production of anti-incretin factor.
The role of peptide YY
Peptide YY is secreted by the L cell in response to food intake ,and it may be produced by certain neurons in the brainstem. It functions through neuropeptide Y receptors (NPY receptor), which are a class of G-protein coupled receptors in the central and peripheral nervous systemthat can be activated by not only neuropeptide Y but also by peptide YY and pancreatic polypeptides. Its function is gastric motility inhibition, and slowing gastric emptying, reducing one's appetite, as well as reducing water andelectrolyte absorption in the colon. Inferring from the functions described above, PYY may increase satiety and efficacy of food digestion.
Studies have shown a significant increase in PYY after RYGB,. The increase may result from the direct nutrient delivery to the distal ileum, and stimulate L cells to secrete peptide YY. The large increase may give rise to decreased appetite.
The role of leptin
Leptin, being an adipocyte-derived hormone, is responsible for signal transduction from the adipocyte to the hypothalamus. Leptin levels increase when fat is accumulated in the body, and it further acts on receptors of hypothalamus, also called CD295, causing neuropeptide Y to decrease in the ventromedial thalamus and inhibiting one's appetite,. Thus, the decrease in leptin may lead to uncontrolled food intake and, therefore, obesity. Studies have also shown that low leptin concentration is found in weight-losing patients with gastrointestinal cancer and in patients with chronic obstructive pulmonary disease as a negative feedback to gain weight. But paradoxically, significant decrease in plasma leptin was observed in patients soon after gastric bypass surgery, even though their BMI is still in morbidly obese range,, which is in contrast to the previous knowledge that plasma leptin represents body adipocytes. We can only hypothesize that there must be some unknown mechanisms that decrease plasma leptin after gastric bypass surgery and lead to further improvement in leptin sensitivity to leptin receptor.
The role of insulin
Insulin is secreted by Î² cells in islets of Langerhans in the pancreas. It can decrease plasma glucose by causing cells in muscle, liver, and adipose tissue to take up glucose from the blood. But inconsequently, plasma insulin in patients after RYGB decreases dramatically, within a few days, indicating that the decreased insulin is not related to weight loss. A study indicates that the loss of insulin resistance measured by IVGTT plays an important role in insulin decrease. Though not clearly known, it is hypothesized that surgical stress may be the reason for decreased insulin tolerance since another abdominal surgery leads to insulin tolerance decrease as well. Nevertheless, the main reason remains unknown.
From the data reviewed above, several hormones in the human body change after gastric bypass surgery, causing not only weight loss, but also resolution of type 2 diabetes. But the detailed molecular mechanism is still unknown. From the currently reported studies, consequence is inconsistent: after RYGB, certain hormone levels increase in some studies, while decreasing in others. The inconsistent results may be due to the small sample sizes. We suggest larger sample groups and longer follow-ups be implemented to get a more exact consequence. In addition, detailed signal pathways in those hormones should be studied because they may be an underlying cause of the cure for type 2 diabetes. For the nutrition disorder, physicians should not only be aware of perioperative complications and symptoms that develop or persist after RYGB, but should also be able to predict and manage postoperative medical and nutritional disorders. Further referral for surgical intervention or revision should be taken into consideration if needed.