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Gila Monster’s Guide to Surgery for Obesity and Diabetes
SURGICAL PERSPECTIVE
Gila Monster’s Guide to Surgery for Obesity and Diabetes Edward E Mason, MD, PhD, FACS Obesity gives rise to type 2 diabetes mellitus, which usually responds to surgical operations that cause ingested glucose to reach the lower small bowel before it is absorbed. Glucose in the distal ileum stimulates secretion of glucagonlike peptide-1 (GLP-1), which decreases both gastric emptying and intestinal transit (brake hormone), and improves insulin receptor function (incretin). GLP-1 has other functions that are beneficial in treatment of both obesity and type 2 diabetes. Regulation of glucose absorption and availability to all cells in the body appears to have been an early requirement for survival. The Gila monster secretes exendrin 4, which chemically looks like a Darwinian antecedent of human GLP-1, and has most of the same beneficial effects on obesity and type 2 diabetes. Heloderma suspectum is found in the southwestern United States along the Gila River. The Gila monster carries exendrin 4 in salivary sacs under the jaw, along with a poison that kills any small animal it is about to digest. The hormone exendrin 4 is provided at the beginning of each meal mixed in the food. Humans also provide GLP-1 at the beginning of a meal, but the system that evolved is more complex. According to Brener and colleagues,1 the volume of stomach contents regulates an initial gush of fluid from the stomach in normalweight humans after a glucose meal. Brener showed that receptors in the duodenum measure the concentration of glucose and regulate subsequent squirts of stomach fluid. Squirts and gushes are Brenner’s words, but emphasize a forceful discharge. This is consistent with a concept of duodenal overflow, which explains how glucose absorption can be regulated by secretion of GLP-1 in the distal ileum. After the initial gush, subsequent stomach squirts are regulated by the duodenum and pylorus to maintain an optimum rate of glucose entering the small bowel.
The duodenal/pyloric regulatory system for gastric emptying has a safety component in the lower end of the small bowel. GLP-1 was called the brake hormone when it was first discovered because it stimulates the pyloric muscle to stop stomach emptying, and to slow intestinal transit. Stopping stomach emptying, after a calibrating gush, allows the duodenum to analyze glucose concentration and restore the optimum emptying rate. The small bowel requires fluid that has been diluted in the duodenum to approximate the concentration of body fluids. There are osmoreceptors in the duodenum but in neither stomach nor small bowel, beyond the ligament of Treitz. If an overflow sample of the fluid from the first stomach squirt is too concentrated and enters the jejunum, it acts like an osmotic cathartic. As a result of the overflow, any glucose or fat present in the hyperosmotic, calibratingsquirt reaches the distal small bowel and colon and stimulates the secretion of GLP-1. There are also glucose receptors in the duodenum that determine the concentration of glucose and regulate gastric emptying. According to Brener, if a quantity of highly concentrated glucose is ingested during the meal, a new calibrating-squirt of stomach contents occurs. As a result, GLP-1 secretion is again stimulated and the duodenum again adjusts the rate of stomach emptying to maintain the optimum concentration of glucose in the small bowel. Brener concluded that frequent eating and drinking could drive more calories through the system than would be calculated from the closed system. Schirra and colleagues2 studied gastric emptying and release of incretin hormones after glucose ingestion in normal-weight male patients. They compared 50-g and 100-g oral glucose stimulation of rise in plasma GLP-1 and gastric inhibitory polypeptide. Both reached a peak level at 20 minutes. Gastric inhibitory polypeptide rose to the same height regardless of the dose, and GLP-1 was twice as high with the 100-g meal. This is consistent with a duodenal-overflow hypothesis for stimulation of GLP-1 secretion. The decline in plasma levels of GLP-1 paralleled the decline in glucose entering the duodenum. The findings suggested a threshold of calorie delivery into the duodenum, which must be exceeded to stimulate release of GLP-1. That is because the oral intake increases gastric volume, which stimulates a volume controlled gush. When the glucose is infused into the duodenum, there is no gastric gush and no overflow of a sample of the concentrated
Competing Interests Declared: Dr Mason purchased and owned stock in Anylin Pharmaceuticals, Inc, three years ago; this stock is held in irrevocable Family Trusts. Dr Mason declares he has no competing interests. Received August 24, 2007; Revised October 4, 2007; Accepted October 24, 2007. From the Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA. Correspondence address: Edward E Mason, MD, Department of Surgery, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242-1009.
© 2008 by the American College of Surgeons Published by Elsevier Inc.
357
ISSN 1072-7515/08/$34.00 doi:10.1016/j.jamcollsurg.2007.10.011
358
Mason
Gila Monster’s Guide to Surgery for Obesity and Diabetes
fluid into the jejunum. There is no catharsis of a sample of the concentrated glucose solution to the distal small bowel. We have described here the normal system for control of gastric emptying of glucose. In obese patients with type 2 diabetes, this system fails and glucose does not reach the distal ileum. Ranganath and colleagues3 compared meals of glucose and fat in lean and obese women and it was only the glucose that caused a marked elevation of plasma GLP-1, because the higher osmolality induced rapid intestinal transit. There was minimal rise in plasma GLP-1 after the glucose meal in the obese, or after the fat meal in either lean or obese subjects. Näslund and colleagues4 confirmed the observation of Ranganath and colleagues that GLP-1 secretion is no longer stimulated after a meal in obese humans. A normal rise did occur, when studied by Näslund and colleagues 9 months after intestinal bypass. There were very high fasting and postcibal GLP-1 plasma levels after 20 years. Valverde and colleague5 showed no response of plasma GLP-1 levels in the morbidly obese to an oral glucose meal before an operation, but a fourfold rise 1 month after biliopancreatic bypass. Peak elevation of plasma GLP-1 was seen at 60 minutes 1 month after the operation. After 3 months, the rise peaked at 30 minutes after the meal, which is what was observed again at 6 months. These observations support the conclusion that the cause of type 2 diabetes in obese patients is a failure of the antroduodenal-pyloric control of gastric emptying to expose the distal ileum to samples of hyperosmotic, glucose stomach contents. Any operation that bypasses the malfunctioning system causes glucose to reach the distal small bowel and stimulate secretion of GLP-1. What is not known and needs study is how obesity causes failure of the gastric emptying control system to send samples of hypertonic glucose into the jejunum and then to the distal ileum. Failure of stimulation of secretion of GLP-1 is the cause of type 2 diabetes in obese patients. Cells require insulin for uptake and use of glucose and insulin receptors. Insulin is not enough to treat diabetes in obese patients with type 2 diabetes. An incretin (GLP-1) is needed. Briefly, an incretin is a hormone secreted in the digestive tract that stimulates insulin production and secretion and increases insulin receptor function. Because of the effect on insulin receptors, the overall result is a reduction in plasma insulin concentration. Edwards and colleagues6 showed that infusion of exendrin 4 reduces energy intake in healthy volunteers. It reduces gastric emptying and, as suggested by Edwards, “may be a potential treatment particularly likely to benefit obese patients with type 2 diabetes.” There are two types of diabetes mellitus that were at one time called insulin-dependent diabetes and noninsulindependent or adult onset diabetes. The names were then
J Am Coll Surg
changed to type 1 and type 2 diabetes mellitus, respectively. Type 1 diabetes responds to insulin. Weight loss is an effective treatment for type 2 diabetes, but most patients are unable to lose weight and sustain that lower weight. Many obese patients are cured of type 2 diabetes when operations, such as Roux-en-Y gastric bypass, are performed, which cause glucose to reach the lower end of the small bowel where the GLP-1⫺secreting L cells are located.7 Type 2 diabetes could now be called incretin-dependent diabetes instead of noninsulin-dependent diabetes. Restriction operations improve type 2 diabetes by forcing a reduction in caloric intake and by weight reduction. All operations that allow ingested glucose to dump directly into the small bowel without dilution with duodenal juices, to approximate the concentration of body fluids, result in rapid transit of glucose to the distal small bowel. Melissas and colleagues8 questioned whether sleeve resection was a restriction operation because they found that gastric emptying is increased. If it is not a restriction procedure then does it act like a bypass operation? Analysis of plasma GLP-1 would answer that important question. Duodenal-jejunal bypass is another operation that cures incretin-dependent diabetes. It is a Roux-en-Y type of operation that bypasses duodenum and jejunum instead of most of the stomach, duodenum, and jejunum. The reason both of these operations cause glucose to reach the distal small bowel is that they bypass the malfunctioning antropyloric-duodenal control of gastric emptying. When the stomach empties directly into the jejunum, even though the pylorus is present, the duodenum has been bypassed. This suggests that the defect that causes failure of transmission of hypertonic glucose contents to the jejunum might be in the duodenum. But first, plasma GLP-1 response to duodenal-jejunal bypass must be shown. The key question, raised by the new paradigm, is whether an operation causes glucose to reach the distal ileum. Rapid transit of hyperosmotic contents or shortened functioning small bowel, or a combination of both, explain GLP-1 secretion. GLP-1 has been synthesized and used to study the treatment of type 2 diabetes, but it must be given in a continuous IV fluid because of the 90-second half-life. Dipeptidyl peptidase 4 in the blood destroys GLP-1. Exenatide, the synthesized Gila monster hormone, is not destroyed by dipeptidyl peptidase 4 in humans and is given by injection twice daily. Exenatide is marketed as a treatment for type 2 diabetes, but it also causes weight loss by slowing gastric emptying and intestinal transit, and as a satiety-producing hormone.9 There are now available medications that block dipeptidyl peptidase 4, which provides a longer half-life for endogenous GLP-1. These blocking agents can be given by mouth. A great deal is known about the action of these
Vol. 206, No. 2, February 2008
Mason
closely related incretins, but we are waiting for the needed clinical data to allow approval for use of exenatide alone in the treatment of type 2 diabetes and in the treatment of obesity. In 1981, Koopmans and Sclafani10 studied an operation in small animals in which they moved the distal small bowel to a position near the duodenum so that when the animal ate, the food would immediately pass through that transposed segment of distal ileum. They were interested in determining why intestinal bypass caused weight loss. They observed that the animals lost weight after “ileal transposition,” even though there was no bypass of any part of the digestive tract. This was the beginning of the discovery that some of the weight loss after bypass operations for obesity could be a result of stimulation of secretion of a hormone that was produced in the distal ileum. In 1999, Mason suggested that ileal transposition might be used as a treatment for type 2 diabetes and obesity.11 Strader observed decreased body weight accompanied by increased GLP-1 and PYY-3-36 secretion in rats after ileal transposition.12 There was no malabsorption. Improved insulin sensitivity was demonstrated. More recently, it has been reported that hyperinsulinemic hypoglycemia developed in occasional patients with gastric bypass. A few of these patients have been treated by removal of much of the pancreas.13,14 The original diagnosis of nesidioblastosis in the patients of Service and colleagues13 could not be substantiated when the microscopic slides were reviewed.15 This does not resolve the functional abnormality of symptomatic hypoglycemia. Some patients with hypoglycemia can be managed with a low-carbohydrate diet.16 These reports have raised concern about the effect of uncontrolled and excessive stimulation of GLP-1 secretion from transposition of the distal ileum. The desired effect should result from GLP-1 mimetics, which could be provided in a required dose and discontinued without need for reversal of an operation or removal of pancreatic tissue. We need now to determine how much of the weight loss after operations that stimulate GLP-1 secretion is a result of hormone effect. The satiety effects of exendrin 4 can help many patients eat less even without an operation. If needed after a restriction operation, GLP-1 mimetics can provide the added help that conversion to a bypass operation would provide. There are other reasons for offering restriction operations.17 For many patients, a bypass operation might be the only effective and life-saving treatment. Pories and colleagues18 called attention to the efficacy of gastric bypass in the treatment of type 2 diabetes. A surgical operation for type 2 diabetes is indicated only if medication fails. According to the new paradigm, medication should be a GLP-1 mimetic because it is GLP-1 that is stimulated by gastric
Gila Monster’s Guide to Surgery for Obesity and Diabetes
359
bypass and other bypass operations. The choice of medication, like the choice of operation, and combinations of medication and operation, awaits the reports of ongoing and future studies. In summary, this new paradigm for surgical treatment of obesity and diabetes places the focus on control of stomach emptying and rate of intestinal transit of glucose. GLP-1 secretion is the key. Samples of concentrated glucose containing gastric contents fail to reach the jejunum and the distal ileum in the severely obese. This is the cause of type 2 diabetes that needs correction. The mechanism of this failure with increasing obesity needs study of the antropyloric-duodenal GLP-1 control of gastric emptying. Bypass operations restore stimulation of secretion of GLP-1 by exposing the distal ileum to glucose, but with loss of the controls of gastric emptying that prevent overstimulation. With weight loss, normal function of normal anatomy should return. Courses of exendrin 4 therapy could be a way of reducing weight and treating incretin-dependent diabetes. Such treatment could provide an alternative to operations that disrupt the antro-pyloric-duodenal GLP-1 control of gastric emptying of glucose. The Gila monster has provided us with a 200-millionyear-old incretin/brake hormone that prevents and treats incretin-dependent diabetes. It appears to be the antecedent to GLP-1. This new paradigm for treatment of obesity and type 2 diabetes comes at a time when there is an increasing number of candidates for surgical treatment. Our goal now as metabolic obesity surgeons is to make optimum use of the knowledge and medication that Heloderma suspectum has provided.This old lizard might have more to teach us.
REFERENCES 1. Brener W, Hendrix TR, Mchugh PR. Regulation of the gastric emptying of glucose. Gastroenterology 1983;85:76–82. 2. Schirra J, Katschinski M, Weidmann C, et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 1996;97:92–103. 3. Ranganath LR, Beety JM, Morgan LM, et al. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996;38:916– 919. 4. Näslund E, Backman L, Holst JJ, et al. Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg 1998;8:253–260. 5. Valverde I, Puente J, Martin-Duce A, et al. Changes in glucagonlike peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded gastroplasty in obese subjects. Obes Surg 2005;15: 387–397. 6. Edwards CM, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 2001;281:E155– E161. 7. Mason EE. The mechanisms of surgical treatment of type-2 diabetes. Obes Surg 2005;15:459–461.
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Gila Monster’s Guide to Surgery for Obesity and Diabetes
8. Melissas J, Koukouraki S, Askoxylakis J, et al. Sleeve gastrectomy—a restrictive procedure? Obes Surg 2007;17:57–62. 9. Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515–520. 10. Koopmans HS, Sclafani A. Control of body weight by lower gut signals. Int J Obes 1981;5:491–495. 11. Mason, EE. Ileal transposition and enteroglucagon/GLP-1 in obesity (and diabetic?) surgery. Review of the literature. Obes Surg 1999;9:223–228. 12. Strader, AD, Vahl TP, Jandacek RJ, et al. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab 2004;288:E447–E453. 13. Service GJ, Thompson GB, Service J, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 2005;353:249–254.
J Am Coll Surg
14. Patti ME, McMahon G, Mun EC, et al. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia 2005;48:2236–2240 Epub 2005 Sep 30. 15. Meier JJ, Galasso R, Butler AE, et al. Hyperinsulinemic hypoglycemia after gastric bypass is not accompanied by islet hyperplasia or increased beta-cell mass. Diabetes Care 2006;29:1554– 1559. 16. Bantle JP, Ikramuddin S, Kellogg TA, Buchwald H. Hyperinsulinemic hypoglycemia developing late after gastric bypass. Obes Surg 2007;17:592–594. 17. Mason EE. Development and future of gastroplasties for morbid obesity. Arch Surg 2003;138:361–366. 18. Pories WJ, Swanson MS, MacDonald KG Jr, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995;222: 339–352.
Gila Monster’s Guide to Surgery for Obesity and Diabetes Edward E Mason, MD, PhD, FACS Obesity gives rise to type 2 diabetes mellitus, which usually responds to surgical operations that cause ingested glucose to reach the lower small bowel before it is absorbed. Glucose in the distal ileum stimulates secretion of glucagonlike peptide-1 (GLP-1), which decreases both gastric emptying and intestinal transit (brake hormone), and improves insulin receptor function (incretin). GLP-1 has other functions that are beneficial in treatment of both obesity and type 2 diabetes. Regulation of glucose absorption and availability to all cells in the body appears to have been an early requirement for survival. The Gila monster secretes exendrin 4, which chemically looks like a Darwinian antecedent of human GLP-1, and has most of the same beneficial effects on obesity and type 2 diabetes. Heloderma suspectum is found in the southwestern United States along the Gila River. The Gila monster carries exendrin 4 in salivary sacs under the jaw, along with a poison that kills any small animal it is about to digest. The hormone exendrin 4 is provided at the beginning of each meal mixed in the food. Humans also provide GLP-1 at the beginning of a meal, but the system that evolved is more complex. According to Brener and colleagues,1 the volume of stomach contents regulates an initial gush of fluid from the stomach in normalweight humans after a glucose meal. Brener showed that receptors in the duodenum measure the concentration of glucose and regulate subsequent squirts of stomach fluid. Squirts and gushes are Brenner’s words, but emphasize a forceful discharge. This is consistent with a concept of duodenal overflow, which explains how glucose absorption can be regulated by secretion of GLP-1 in the distal ileum. After the initial gush, subsequent stomach squirts are regulated by the duodenum and pylorus to maintain an optimum rate of glucose entering the small bowel.
The duodenal/pyloric regulatory system for gastric emptying has a safety component in the lower end of the small bowel. GLP-1 was called the brake hormone when it was first discovered because it stimulates the pyloric muscle to stop stomach emptying, and to slow intestinal transit. Stopping stomach emptying, after a calibrating gush, allows the duodenum to analyze glucose concentration and restore the optimum emptying rate. The small bowel requires fluid that has been diluted in the duodenum to approximate the concentration of body fluids. There are osmoreceptors in the duodenum but in neither stomach nor small bowel, beyond the ligament of Treitz. If an overflow sample of the fluid from the first stomach squirt is too concentrated and enters the jejunum, it acts like an osmotic cathartic. As a result of the overflow, any glucose or fat present in the hyperosmotic, calibratingsquirt reaches the distal small bowel and colon and stimulates the secretion of GLP-1. There are also glucose receptors in the duodenum that determine the concentration of glucose and regulate gastric emptying. According to Brener, if a quantity of highly concentrated glucose is ingested during the meal, a new calibrating-squirt of stomach contents occurs. As a result, GLP-1 secretion is again stimulated and the duodenum again adjusts the rate of stomach emptying to maintain the optimum concentration of glucose in the small bowel. Brener concluded that frequent eating and drinking could drive more calories through the system than would be calculated from the closed system. Schirra and colleagues2 studied gastric emptying and release of incretin hormones after glucose ingestion in normal-weight male patients. They compared 50-g and 100-g oral glucose stimulation of rise in plasma GLP-1 and gastric inhibitory polypeptide. Both reached a peak level at 20 minutes. Gastric inhibitory polypeptide rose to the same height regardless of the dose, and GLP-1 was twice as high with the 100-g meal. This is consistent with a duodenal-overflow hypothesis for stimulation of GLP-1 secretion. The decline in plasma levels of GLP-1 paralleled the decline in glucose entering the duodenum. The findings suggested a threshold of calorie delivery into the duodenum, which must be exceeded to stimulate release of GLP-1. That is because the oral intake increases gastric volume, which stimulates a volume controlled gush. When the glucose is infused into the duodenum, there is no gastric gush and no overflow of a sample of the concentrated
Competing Interests Declared: Dr Mason purchased and owned stock in Anylin Pharmaceuticals, Inc, three years ago; this stock is held in irrevocable Family Trusts. Dr Mason declares he has no competing interests. Received August 24, 2007; Revised October 4, 2007; Accepted October 24, 2007. From the Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA. Correspondence address: Edward E Mason, MD, Department of Surgery, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242-1009.
© 2008 by the American College of Surgeons Published by Elsevier Inc.
357
ISSN 1072-7515/08/$34.00 doi:10.1016/j.jamcollsurg.2007.10.011
358
Mason
Gila Monster’s Guide to Surgery for Obesity and Diabetes
fluid into the jejunum. There is no catharsis of a sample of the concentrated glucose solution to the distal small bowel. We have described here the normal system for control of gastric emptying of glucose. In obese patients with type 2 diabetes, this system fails and glucose does not reach the distal ileum. Ranganath and colleagues3 compared meals of glucose and fat in lean and obese women and it was only the glucose that caused a marked elevation of plasma GLP-1, because the higher osmolality induced rapid intestinal transit. There was minimal rise in plasma GLP-1 after the glucose meal in the obese, or after the fat meal in either lean or obese subjects. Näslund and colleagues4 confirmed the observation of Ranganath and colleagues that GLP-1 secretion is no longer stimulated after a meal in obese humans. A normal rise did occur, when studied by Näslund and colleagues 9 months after intestinal bypass. There were very high fasting and postcibal GLP-1 plasma levels after 20 years. Valverde and colleague5 showed no response of plasma GLP-1 levels in the morbidly obese to an oral glucose meal before an operation, but a fourfold rise 1 month after biliopancreatic bypass. Peak elevation of plasma GLP-1 was seen at 60 minutes 1 month after the operation. After 3 months, the rise peaked at 30 minutes after the meal, which is what was observed again at 6 months. These observations support the conclusion that the cause of type 2 diabetes in obese patients is a failure of the antroduodenal-pyloric control of gastric emptying to expose the distal ileum to samples of hyperosmotic, glucose stomach contents. Any operation that bypasses the malfunctioning system causes glucose to reach the distal small bowel and stimulate secretion of GLP-1. What is not known and needs study is how obesity causes failure of the gastric emptying control system to send samples of hypertonic glucose into the jejunum and then to the distal ileum. Failure of stimulation of secretion of GLP-1 is the cause of type 2 diabetes in obese patients. Cells require insulin for uptake and use of glucose and insulin receptors. Insulin is not enough to treat diabetes in obese patients with type 2 diabetes. An incretin (GLP-1) is needed. Briefly, an incretin is a hormone secreted in the digestive tract that stimulates insulin production and secretion and increases insulin receptor function. Because of the effect on insulin receptors, the overall result is a reduction in plasma insulin concentration. Edwards and colleagues6 showed that infusion of exendrin 4 reduces energy intake in healthy volunteers. It reduces gastric emptying and, as suggested by Edwards, “may be a potential treatment particularly likely to benefit obese patients with type 2 diabetes.” There are two types of diabetes mellitus that were at one time called insulin-dependent diabetes and noninsulindependent or adult onset diabetes. The names were then
J Am Coll Surg
changed to type 1 and type 2 diabetes mellitus, respectively. Type 1 diabetes responds to insulin. Weight loss is an effective treatment for type 2 diabetes, but most patients are unable to lose weight and sustain that lower weight. Many obese patients are cured of type 2 diabetes when operations, such as Roux-en-Y gastric bypass, are performed, which cause glucose to reach the lower end of the small bowel where the GLP-1⫺secreting L cells are located.7 Type 2 diabetes could now be called incretin-dependent diabetes instead of noninsulin-dependent diabetes. Restriction operations improve type 2 diabetes by forcing a reduction in caloric intake and by weight reduction. All operations that allow ingested glucose to dump directly into the small bowel without dilution with duodenal juices, to approximate the concentration of body fluids, result in rapid transit of glucose to the distal small bowel. Melissas and colleagues8 questioned whether sleeve resection was a restriction operation because they found that gastric emptying is increased. If it is not a restriction procedure then does it act like a bypass operation? Analysis of plasma GLP-1 would answer that important question. Duodenal-jejunal bypass is another operation that cures incretin-dependent diabetes. It is a Roux-en-Y type of operation that bypasses duodenum and jejunum instead of most of the stomach, duodenum, and jejunum. The reason both of these operations cause glucose to reach the distal small bowel is that they bypass the malfunctioning antropyloric-duodenal control of gastric emptying. When the stomach empties directly into the jejunum, even though the pylorus is present, the duodenum has been bypassed. This suggests that the defect that causes failure of transmission of hypertonic glucose contents to the jejunum might be in the duodenum. But first, plasma GLP-1 response to duodenal-jejunal bypass must be shown. The key question, raised by the new paradigm, is whether an operation causes glucose to reach the distal ileum. Rapid transit of hyperosmotic contents or shortened functioning small bowel, or a combination of both, explain GLP-1 secretion. GLP-1 has been synthesized and used to study the treatment of type 2 diabetes, but it must be given in a continuous IV fluid because of the 90-second half-life. Dipeptidyl peptidase 4 in the blood destroys GLP-1. Exenatide, the synthesized Gila monster hormone, is not destroyed by dipeptidyl peptidase 4 in humans and is given by injection twice daily. Exenatide is marketed as a treatment for type 2 diabetes, but it also causes weight loss by slowing gastric emptying and intestinal transit, and as a satiety-producing hormone.9 There are now available medications that block dipeptidyl peptidase 4, which provides a longer half-life for endogenous GLP-1. These blocking agents can be given by mouth. A great deal is known about the action of these
Vol. 206, No. 2, February 2008
Mason
closely related incretins, but we are waiting for the needed clinical data to allow approval for use of exenatide alone in the treatment of type 2 diabetes and in the treatment of obesity. In 1981, Koopmans and Sclafani10 studied an operation in small animals in which they moved the distal small bowel to a position near the duodenum so that when the animal ate, the food would immediately pass through that transposed segment of distal ileum. They were interested in determining why intestinal bypass caused weight loss. They observed that the animals lost weight after “ileal transposition,” even though there was no bypass of any part of the digestive tract. This was the beginning of the discovery that some of the weight loss after bypass operations for obesity could be a result of stimulation of secretion of a hormone that was produced in the distal ileum. In 1999, Mason suggested that ileal transposition might be used as a treatment for type 2 diabetes and obesity.11 Strader observed decreased body weight accompanied by increased GLP-1 and PYY-3-36 secretion in rats after ileal transposition.12 There was no malabsorption. Improved insulin sensitivity was demonstrated. More recently, it has been reported that hyperinsulinemic hypoglycemia developed in occasional patients with gastric bypass. A few of these patients have been treated by removal of much of the pancreas.13,14 The original diagnosis of nesidioblastosis in the patients of Service and colleagues13 could not be substantiated when the microscopic slides were reviewed.15 This does not resolve the functional abnormality of symptomatic hypoglycemia. Some patients with hypoglycemia can be managed with a low-carbohydrate diet.16 These reports have raised concern about the effect of uncontrolled and excessive stimulation of GLP-1 secretion from transposition of the distal ileum. The desired effect should result from GLP-1 mimetics, which could be provided in a required dose and discontinued without need for reversal of an operation or removal of pancreatic tissue. We need now to determine how much of the weight loss after operations that stimulate GLP-1 secretion is a result of hormone effect. The satiety effects of exendrin 4 can help many patients eat less even without an operation. If needed after a restriction operation, GLP-1 mimetics can provide the added help that conversion to a bypass operation would provide. There are other reasons for offering restriction operations.17 For many patients, a bypass operation might be the only effective and life-saving treatment. Pories and colleagues18 called attention to the efficacy of gastric bypass in the treatment of type 2 diabetes. A surgical operation for type 2 diabetes is indicated only if medication fails. According to the new paradigm, medication should be a GLP-1 mimetic because it is GLP-1 that is stimulated by gastric
Gila Monster’s Guide to Surgery for Obesity and Diabetes
359
bypass and other bypass operations. The choice of medication, like the choice of operation, and combinations of medication and operation, awaits the reports of ongoing and future studies. In summary, this new paradigm for surgical treatment of obesity and diabetes places the focus on control of stomach emptying and rate of intestinal transit of glucose. GLP-1 secretion is the key. Samples of concentrated glucose containing gastric contents fail to reach the jejunum and the distal ileum in the severely obese. This is the cause of type 2 diabetes that needs correction. The mechanism of this failure with increasing obesity needs study of the antropyloric-duodenal GLP-1 control of gastric emptying. Bypass operations restore stimulation of secretion of GLP-1 by exposing the distal ileum to glucose, but with loss of the controls of gastric emptying that prevent overstimulation. With weight loss, normal function of normal anatomy should return. Courses of exendrin 4 therapy could be a way of reducing weight and treating incretin-dependent diabetes. Such treatment could provide an alternative to operations that disrupt the antro-pyloric-duodenal GLP-1 control of gastric emptying of glucose. The Gila monster has provided us with a 200-millionyear-old incretin/brake hormone that prevents and treats incretin-dependent diabetes. It appears to be the antecedent to GLP-1. This new paradigm for treatment of obesity and type 2 diabetes comes at a time when there is an increasing number of candidates for surgical treatment. Our goal now as metabolic obesity surgeons is to make optimum use of the knowledge and medication that Heloderma suspectum has provided.This old lizard might have more to teach us.
REFERENCES 1. Brener W, Hendrix TR, Mchugh PR. Regulation of the gastric emptying of glucose. Gastroenterology 1983;85:76–82. 2. Schirra J, Katschinski M, Weidmann C, et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 1996;97:92–103. 3. Ranganath LR, Beety JM, Morgan LM, et al. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996;38:916– 919. 4. Näslund E, Backman L, Holst JJ, et al. Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg 1998;8:253–260. 5. Valverde I, Puente J, Martin-Duce A, et al. Changes in glucagonlike peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded gastroplasty in obese subjects. Obes Surg 2005;15: 387–397. 6. Edwards CM, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 2001;281:E155– E161. 7. Mason EE. The mechanisms of surgical treatment of type-2 diabetes. Obes Surg 2005;15:459–461.
360
Mason
Gila Monster’s Guide to Surgery for Obesity and Diabetes
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J Am Coll Surg
14. Patti ME, McMahon G, Mun EC, et al. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia 2005;48:2236–2240 Epub 2005 Sep 30. 15. Meier JJ, Galasso R, Butler AE, et al. Hyperinsulinemic hypoglycemia after gastric bypass is not accompanied by islet hyperplasia or increased beta-cell mass. Diabetes Care 2006;29:1554– 1559. 16. Bantle JP, Ikramuddin S, Kellogg TA, Buchwald H. Hyperinsulinemic hypoglycemia developing late after gastric bypass. Obes Surg 2007;17:592–594. 17. Mason EE. Development and future of gastroplasties for morbid obesity. Arch Surg 2003;138:361–366. 18. Pories WJ, Swanson MS, MacDonald KG Jr, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995;222: 339–352.