INSULIN RESPONSES AFTER JEJUNOILEAL BYPASS SURGERY
A study of obese pattents before and after intestinal bypass surgery demonstrates the presence of an tntesttnal factor whtch stimulates insulm release in response to an oral amino acid load
Key Words insulin. jejunoileal bypass, amino acid load. insulin releasing factor
The first report of intestinal bypass surgery. published 25 years ago, focused on the metabolic complications of the procedure. l Since that time. jejunoileal bypass surgery has been performed with increasing regularity as an elective therapy for obesity which has not responded to conventional treatment.2 Some patients with intestinal bypass have an improved self esteem and productivity as the appreciation of body image changes. Although the benefits are sometimes impressive, there are numerous unpleasant side effects including oxalate stone formation, electrolyte imbalance, malnutrition and hepatic d y s f u n ~ t i o n . ~ . ~ One recent study attempted to use the bypass abnormality to define certain aspects of intestinal function as related to insulin secretion. Moxley et al. studied patients before surgery and four months after ~ u r g e r yThe . ~ patients were selected on the basis of refractoriness to conventional weight reducing therapy. Their weights averaged 243 percent of ideal weight. At surgery 32 cm of proximal jejunum was anastomosed to 13 cm of terminal ileum and the blind loop was anastomosed distally end to side with the transverse colon. The type of surgery performed is important because the metabolic alteration and degree of weight loss probably varies with the nature of the anatomical derangement. Caloric intake prior to the study was 4000 to 6000 calories per day. After the study, intake had fallen to 3000 to 4000 calories per day. Average weight loss four months after surgery was approximately 20 percent. In the first experiment, a 30 g equimolar mixture of leucine, glycine and lysine was administered orally before and four months after 110
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surgery. Postoperatively the peak levels of leucine and glycine were 55 percent and 62 percent of the preoperative levels respectively The basal insulin concentrations were low and both the absolute and relative percentage increases after the amino acid load were markedly depressed after surgery. When the amino acids were given intravenously identical levels were achieved in both groups of patients. Regardless of the initial basal insulin level, the absolute and percent increases in insulin were identical to the values achieved in patients before bypass surgery. In another experiment. a sufficient load of amino acids was given orally to achieve postoperative plasma levels of glycine and leucine which were equivalent to preoperative levels. The increase in insulin was significantly lower in the postoperative patients. The authors also showed that when a comparison was made between preoperative patients who received amino acids orally or intravenously but achieved the same plasma level of leucine. oral administration led to a significantly higher level of insulin both in absolute and relative terms. These data demonstrate that the pancreas can respond adequately to the stimulus of elevation of the plasma amino acids after bypass. It is also clear, however, that isolation of a section of the jejunum and ileum blunts the insulin response to oral stimulus with amino acids. The authors postulate that their studies demonstrate the presence of an "enteric insulinotropic factor". Although the existence of such a factor has been postulated, without such clear evidence,6 its nature is unknown. It is clear that the "insulinotropic factor" is related to amino acid stimulation since oral glucose tolerance tests give the same results in terms of insulin levels both before and after bypass.
The authors consider other possible reasons for the abnormal response. They discuss the possibility that protein-energy malnutrition consequent upon bypass surgery is the cause. Other workers have previously likened the post bypass patients to children with kwashiorkor.' The plasma amino acid patterns, low levels of plasma insulin, anemia, hypoproteinemia, fatty infiltration of the liver, hypokalemia, hypomagnesemia and hypovitaminosis occur in both situations. The malnourished person, however, has a marked diminution of insulin release in response to intravenous arginine, as well as glucose, indicating an impairment of pancreatic function.* The plasma levels of amino acids also fall to much lower levels in subjects with primary protein energy malnutrition. A further aspect of this study was not discussed by the authors. This relates to the possibility that the low levels of insulin and the blunted response to oral amino acids might in themselves contribute to some of the metabolic abnormalities. Although plasma levels of cholesterol and triglycerides fall and abnormal hyperlipoproteinemias may disappear after surgery, increased accumulation of fat in the liver in some patients and hepatic failure is the most feared complication of bypass surgery. Is impairment of protein synthesis which results from low levels of insulin implicated in the production of hepatic steatosis in the same manner as in malnourished children? Post bypass patients show alterations in food preferences and tastes. Is it possible that the effects of the operation in causing weight loss are related to factors other than the obvious malabsorption? Is the elimination of certain endocrine functions of the isolated segment of the gut relevant to these changes? This line of investigation offers the opportunity to study the function of isolated portions
of the intestine which are no longer performing their normal physiological functions in relation to the digestion and absorption of food. The intestine is an endocrine organ of established importance. It may have an undisclosed function important to the maintenance of good nutritional status. 0
1. J.H. Payne, L.T. DeWind and R.R. Commons: Metabolic Observations in Patients with Jejunocolic Shunts. Am. J . Surg. 106: 273289. 1963. 2. G.A. Bray, R.E. Barry, J.R. Benfield, P. Castelnuovo-Tedesco, E.J. Drenick and E. Passaro: Intestinal Bypass Operation As a Treatment for Obesity. Ann. lnt. Med. 85: 97-109. 1976 3. Current Status of Jejuno-Ileal Bypass for Obesity. Nutrition Reviews 32: 333336, 1974 4. Intestinal Adaptation and Hepatic Decompensation after Jejunoileal Bypass for Morbid Obesity. Nutrition Reviews 35: 4345, 1977
5. R.T. Moxley Ill. D.H. Lockwood. J.M. Amatruda. J.D. Tobin and T. Pozefsky: Loss of Insulin Response to Ingested Amino Acids after Jejunoileal Bypass Surgery for Morbid Obesity. Diabetes 27: 78-84, 1978 6. S. Raptis. H.C. Dollinger. K.E. Schroder. M. Schleyer, G. Rothenbuchner and E.F. Pfeiffer: Differences in Insulin, Growth Hormone and Pancreatic Enzyme Secretion after Intravenous and lntraduodenal Administration of Mixed Amino Acids in Man. New Engl. J . Med. 288: 11991202. 1973 7. R.T. Moxley 111, T . Pozefsky and D.H. Lockwood: Protein Nutrition and Liver Disease after Jejunoileal Bypass for Morbid Obesity. New Engl. J . Med. 290: 921-926. 1974 8. S . R . Smith. P . J Edgar. T . Pozefsky. M . K . Chhetri and T.E. Prout: Insulin Secretion and Glucose Tolerance in Adults With Protein-Calorie Malnutrition. Metabolism 24: 1073 1084. 1975
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A study of obese pattents before and after intestinal bypass surgery demonstrates the presence of an tntesttnal factor whtch stimulates insulm release in response to an oral amino acid load
Key Words insulin. jejunoileal bypass, amino acid load. insulin releasing factor
The first report of intestinal bypass surgery. published 25 years ago, focused on the metabolic complications of the procedure. l Since that time. jejunoileal bypass surgery has been performed with increasing regularity as an elective therapy for obesity which has not responded to conventional treatment.2 Some patients with intestinal bypass have an improved self esteem and productivity as the appreciation of body image changes. Although the benefits are sometimes impressive, there are numerous unpleasant side effects including oxalate stone formation, electrolyte imbalance, malnutrition and hepatic d y s f u n ~ t i o n . ~ . ~ One recent study attempted to use the bypass abnormality to define certain aspects of intestinal function as related to insulin secretion. Moxley et al. studied patients before surgery and four months after ~ u r g e r yThe . ~ patients were selected on the basis of refractoriness to conventional weight reducing therapy. Their weights averaged 243 percent of ideal weight. At surgery 32 cm of proximal jejunum was anastomosed to 13 cm of terminal ileum and the blind loop was anastomosed distally end to side with the transverse colon. The type of surgery performed is important because the metabolic alteration and degree of weight loss probably varies with the nature of the anatomical derangement. Caloric intake prior to the study was 4000 to 6000 calories per day. After the study, intake had fallen to 3000 to 4000 calories per day. Average weight loss four months after surgery was approximately 20 percent. In the first experiment, a 30 g equimolar mixture of leucine, glycine and lysine was administered orally before and four months after 110
NUTRlTlON REVlEWS / VOL. 37,NO.4 / A P R I L 1979
surgery. Postoperatively the peak levels of leucine and glycine were 55 percent and 62 percent of the preoperative levels respectively The basal insulin concentrations were low and both the absolute and relative percentage increases after the amino acid load were markedly depressed after surgery. When the amino acids were given intravenously identical levels were achieved in both groups of patients. Regardless of the initial basal insulin level, the absolute and percent increases in insulin were identical to the values achieved in patients before bypass surgery. In another experiment. a sufficient load of amino acids was given orally to achieve postoperative plasma levels of glycine and leucine which were equivalent to preoperative levels. The increase in insulin was significantly lower in the postoperative patients. The authors also showed that when a comparison was made between preoperative patients who received amino acids orally or intravenously but achieved the same plasma level of leucine. oral administration led to a significantly higher level of insulin both in absolute and relative terms. These data demonstrate that the pancreas can respond adequately to the stimulus of elevation of the plasma amino acids after bypass. It is also clear, however, that isolation of a section of the jejunum and ileum blunts the insulin response to oral stimulus with amino acids. The authors postulate that their studies demonstrate the presence of an "enteric insulinotropic factor". Although the existence of such a factor has been postulated, without such clear evidence,6 its nature is unknown. It is clear that the "insulinotropic factor" is related to amino acid stimulation since oral glucose tolerance tests give the same results in terms of insulin levels both before and after bypass.
The authors consider other possible reasons for the abnormal response. They discuss the possibility that protein-energy malnutrition consequent upon bypass surgery is the cause. Other workers have previously likened the post bypass patients to children with kwashiorkor.' The plasma amino acid patterns, low levels of plasma insulin, anemia, hypoproteinemia, fatty infiltration of the liver, hypokalemia, hypomagnesemia and hypovitaminosis occur in both situations. The malnourished person, however, has a marked diminution of insulin release in response to intravenous arginine, as well as glucose, indicating an impairment of pancreatic function.* The plasma levels of amino acids also fall to much lower levels in subjects with primary protein energy malnutrition. A further aspect of this study was not discussed by the authors. This relates to the possibility that the low levels of insulin and the blunted response to oral amino acids might in themselves contribute to some of the metabolic abnormalities. Although plasma levels of cholesterol and triglycerides fall and abnormal hyperlipoproteinemias may disappear after surgery, increased accumulation of fat in the liver in some patients and hepatic failure is the most feared complication of bypass surgery. Is impairment of protein synthesis which results from low levels of insulin implicated in the production of hepatic steatosis in the same manner as in malnourished children? Post bypass patients show alterations in food preferences and tastes. Is it possible that the effects of the operation in causing weight loss are related to factors other than the obvious malabsorption? Is the elimination of certain endocrine functions of the isolated segment of the gut relevant to these changes? This line of investigation offers the opportunity to study the function of isolated portions
of the intestine which are no longer performing their normal physiological functions in relation to the digestion and absorption of food. The intestine is an endocrine organ of established importance. It may have an undisclosed function important to the maintenance of good nutritional status. 0
1. J.H. Payne, L.T. DeWind and R.R. Commons: Metabolic Observations in Patients with Jejunocolic Shunts. Am. J . Surg. 106: 273289. 1963. 2. G.A. Bray, R.E. Barry, J.R. Benfield, P. Castelnuovo-Tedesco, E.J. Drenick and E. Passaro: Intestinal Bypass Operation As a Treatment for Obesity. Ann. lnt. Med. 85: 97-109. 1976 3. Current Status of Jejuno-Ileal Bypass for Obesity. Nutrition Reviews 32: 333336, 1974 4. Intestinal Adaptation and Hepatic Decompensation after Jejunoileal Bypass for Morbid Obesity. Nutrition Reviews 35: 4345, 1977
5. R.T. Moxley Ill. D.H. Lockwood. J.M. Amatruda. J.D. Tobin and T. Pozefsky: Loss of Insulin Response to Ingested Amino Acids after Jejunoileal Bypass Surgery for Morbid Obesity. Diabetes 27: 78-84, 1978 6. S. Raptis. H.C. Dollinger. K.E. Schroder. M. Schleyer, G. Rothenbuchner and E.F. Pfeiffer: Differences in Insulin, Growth Hormone and Pancreatic Enzyme Secretion after Intravenous and lntraduodenal Administration of Mixed Amino Acids in Man. New Engl. J . Med. 288: 11991202. 1973 7. R.T. Moxley 111, T . Pozefsky and D.H. Lockwood: Protein Nutrition and Liver Disease after Jejunoileal Bypass for Morbid Obesity. New Engl. J . Med. 290: 921-926. 1974 8. S . R . Smith. P . J Edgar. T . Pozefsky. M . K . Chhetri and T.E. Prout: Insulin Secretion and Glucose Tolerance in Adults With Protein-Calorie Malnutrition. Metabolism 24: 1073 1084. 1975
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