GASTROENTEROLOGY 64: 217-222, 1973 Copyright 1973 by The Williams & Wilkins Co. Vol. 64, No.2 Printed in U.S.A. EFFECT OF VAGOTOMY AND PYLOROPLASTY: THE ORAL GLUCOSE TOLERANCE TEST W, H, HALL, M,D" L. L, SANDERS, M,D" AND R C, READ, M,D, Departments of Medicine and Surgery, University of Arkansas Medical Center, and Veterans Administration Hospital, Little Rock, Arkansas Fourteen patients undergoing vagotomy and pyloroplasty for duodenal ulcer disease were studied with oral glucose tolerance tests before and 4 to 8 weeks after surgery. Although none had a history of diabetes or glycosuria, 6 were chemically diabetic preoperatively. Results showed that glucose levels were higher postoperatively than preoperatively at 30 and 60 min after glucose ingestion. Glucose levels at 120 min, however, were significantly lower than those preoperatively. Five diabetics with elevated 2-hr glucose values preoperatively had normal 2-hr values postoperatively. The data suggested that the 2-hr value in the oral glucose tolerance test after vagotomy and pyloroplasty will underdiagnose the diabetic state. Symptoms suggestive of postprandial hypoglycemia occur frequently after vagotomy.l Studies of the effect of vagotomy on glucose tolerance have been confined to intravenously administered glucose 2 or to postvagotomy studies alone. 3 Because the gastric emptying of hypertonic glucose solutions is known to be accelerated by vagotomy,4 we have studied oral glucose tolerance with accompanying levels of insulin in 14 patients with duodenal ulcer before and after vagotomy and pyloroplasty. Methods Veterans hospitalized on the Surgical Service awaiting surgery for duodenal ulcer were subjects. They ranged in age from 27 to 65 years with a mean and median of 50.8 and 55.2 years, respectively. None had a history of known diabetes mellitus or glycosuria. Mean values for height and weight were 69.7 inches and 154.± 23 lb (± 1 SD). Each was given a 3-hour oral glucose tolerance test using 100 g of glucose Received June 8, 1972. Accepted September 26, 1972. Address requests for reprints to: Dr. William H, Hall, Gastroenterology Section (111H), Department of Medicine, Veterans Administration Hospital, 921 NE 13th Street, Oklahoma City, Oklahoma 73104. This work was supported by Veterans Administration Research Funds as Project 7701-2. 217 (Dextol) after at least 2 days of regular hospital or bland diet often divided into frequent feedings. Glucose tolerance was determined in the m()l:jling immediately after lo-hr fasts. Postoperative studies were done between 4 and 8 weeks after the vagotomy and pyloroplasty on an outpatient basis. Mean body weight ± 1 SD was 149 ± 14 lb. Vagotomies were truncal and abdominal, and pyloroplasties were of the Finney or Heinicke-Mikulicz type. Serum glucose was determined on an Auto Analyzer (6-60) and serum insulins were determined by a modification of the radioimmunoassay method of Herbert. 5 Significant differences were determined by the sign test. 6 Results The alteration in the oral glucose tolerance curve imparted by vagotomy and pyloroplasty consisted of two essential features: (1) a rapid climb of glucose to a significantly higher level at 30 min and a higher peak at 60 min, and (2) a more rapid descent in glucose levels from the peak at 1 hr to the 2-hr level. Preoperatively, the fasting plasma glucose averaged 92.1 mg per 100 ml, rose to a peak of 215.1, and fell to a mean of 107.8 mg per 100 ml 3 hr after ingestion. The rellatively high mean level of plasma glucose at 2 hr, 170 mg per 100 ml, reflected the
218 HALL ET AL. Vol. 64, No.2 TABLE 1. Glucose (milligrams per 100 ml) Subject Fasting 15 min 30 min 60 min 120 min 180 min Diabetic L. C. Preoperative......,'. 80 95 160 195 215 155 Postoperative......,.. 105 155 250 295 145 80 W.J. Preoperative....... 90 135 200 225 160 85 Postoperative....... 135 250 260 250 76 76 C. A. Preoperative..,-... 100 200 205 285 285 205 Postoperative...,'... 90 180 230 210 80 35 N. C. Preoperative...... 120 165 245 360 300 110 Postoperative......... 110 170 285 410 365 105 M.D. Preoperative...,.. 95 115 175 225 290 185 Postoperative ".,... " 90 145 200 235 140 65 L. McC. Preoperative... 95 155 205 275 210 130 Postoperative.......,. 95 195 290 270 65 70 Mean ± so preoperative... 97 ± 13 144 ± 38 198 ± 30 261 ± 59 243 ± 57 145 ± 46 Mean ± so postoperative.. 104 ± 17 183 ± 38 253 ± 34 278 ± 71 128 ± 75 72 ± 23 Nondiabetic C. S. Preoperative.,...... 90 120 160 170 115 110 Postopera tive.......... 95 175 215 240 95 70 P. T. Preoperative...... 90 195 140 105 95 Postoperative.. ',,.... 120 270 230 60 65 W.B. Preoperative........... 85 135 90 70 55 Postoperative.......... 90 245 165 55 70 C.W. Preoperative.,........ 76 158 162 118 77 Postoperative.......... 120 270 230 60 65 R. P. B. Preoperative......... 120 185 245 250 140 85 Postoperative........ 120 245 260 55 130 P. C. Preoperative....... 100 145 200 195 100 35 Postoperative...... ", - 105 150 230 235 70 90 J. H. Preoperative....... 56 114 170 214 144 100 Postoperative..... ".. 90 125 220 350 160 80 H. H. ' Preoperative..... 93 132 185 226 132 82 Postoperative... 0 o- lio 205 275 295 75 65 Mean ± so preoperative... 87 ± 18 141 ± 32 174 ± 63 177 ± 67 114 ± 30 78 ± 22 Mean ± so postoperative... 106 ± 13 164 ± 34 246 ± 24 251 ± 54 79 ± 35 79 ± 22
Februn:ry 1973 VAGOTOMY AND ORAL GLUCOSE TOLERANCE 219 fact that 6 of the patients had glucose serum concentrations at 2 hr in the upper 3% of the population according to the nomogram of Andres 7 (table 1). We consider these patients to be diabetic. Postoperatively, the fasting plasma glucose averaged 105.4 mg per 100 ml, rose to a peak of262.5 mg per 100 ml at 60 min and fell to a mean of 100 mg per 100 ml at 2 hr after glucose ingestion (fig. 1). The relatively low level of plasma glucose at 2 hr 300 250 ~-J o 400 350 300 250 E, ' " \,, ',,, 1 / \, \, ~200, ~ ~ 150 ~ 100 50 0 I \ ---------1-50 i i, 0 15 30 60 120 180 MINUTES FIG. 1. Preoperative glucose and insulin concentrations (upper and lower ordinat es, respectively) are shown as solid dots and postvagotomy concentrations in the same patients as hollow dots. The vertical bars are 1 SD in magnitude. The time (abcissa) reflects the 3-hr oral glucose tolerance test format of the studies. The glucose data were significantly different at 15, 30, 60, and 120 min. reflected a decline of 2.66 mg per 100 ml per min postoperatively, as compared with a decline of 0.73 mg per 100 ml per min preoperatively in the 60- to 120-min period. The 2-hr blood glucose level postoperatively was lower than the preoperative level in 13 of 14 cases (P < 0.01), whereas the 15-, 30-, and 60-min levels were higher than the preoperative levels. Fasting glucose levels were not significantly changed by the operation. Notably, 5 of the 6 diabetic patients were no longer diabetic postoperatively by the 2-hr nomogram criterion (table 1). Serum insulin levels in this study were less affected by vagotomy and pyloroplasty than were glucose levels. There was an elevation of the 60-min postglucose insulin levels postoperatively. The peak insulin concentration was 255.uU per ml postoperatively compared with 165.uU per ml preoperatively (means). At 2 hr after glucose ingestion, the serum insulin level was 60.5.uU per ml postoperatively versus 126.uU per ml preoperatively (means), P < 0.01 (table 2). The time of peak glucose concentration was shifted in 6 of the subjects individually, but not in the group as a Whole (fig. 1). It was noted that 5 of these 6 subjects were diabetic according to the glucose nomogram. In the group as a whole, there was no shift in the time after glucose ingestion of peak serum insulin concentration. Discussion This study shows that in a 100-g oral glucose tolerance test performed routinely, the climb of glucose to peak levels as well as the fall in.concentration between 1 and 2 hr are greater after vagotomy and pyloroplasty than before. The fall was attributed to higher 1-hr values and to lower 2-hr values. The latter finding is of interest because of its widespread use as a criterion for detecting diabetes mellitus. This study suggests that other criteria than 2-hr postglucose or 2-hr postprandial glucose levels are necessary for the diagnosis of diabetes mellitus after vagotomy and pyloroplasty. It is possible that the changes shown in
220 HALL ETAL. Vol. 64, No.2 TABLE 2. Insulin (microunits per milliliter) Subject Fasting 15 min 30 min 60 min 120 min 180 min Diabetic L. C. Preoperative....... <10 <10 18 48 72 62 Postoperative.... "... <10 27 97 108 48 <10 W.J. Preoperative........ <10 <10 35 42 69 <10 Postoperative........ <10 110 103 385 28 <.10 C.A. Preoperative......,'.. <10 37 20 83 175 81 Postoperative....... <10 39 66 205 97 <10 N. C. Preoperative........ <10 26 59 151 206 24 Postoperative,," "... <10 18 69 148 160 32 M.D. Preoperative........ <10 12 12 28 39 29 Postoperative...... <10 <10 72 69 143 <10 L. McC. Preoperative ". 0 <10 12 20 88 62 15 Postoperative.. -...... <10 71 233 487 38 <10 Mean ± SD preoperative.. " <10-- 18 ± 11 27 ± 17 73 ± 15 104 ± 69 37 ± 28 Mean ± SD postoperative <10-- 46 ± 38 107 ± 64 234 ± 166 85 ± 56 14 ± 9 Nondiabetic C. S. Preoperative....... <10 28 93 257 47 37 Postoperative.....,. <10 125 178 410 20 14 P.T. Preoperative ".... <10 79 72 42 <10 Postoperative... <10 80 12 <10 <10 W.B. Preoperative....... " <10 163 83 26 <10 Postoperative.. "... <10 82 101 <10 <10 C. W. Preoperative......,. <10 <10 <10 <10 <10 Postoperative......... <10 70 151 <10 <10 R. P. B. Preoperative... -, <10 110 190 385 170 13 Postoperative......... <10 121 650 41 58 P. C. Preoperative '". "..., <10 30 114 205 74 <10 Postoperative........ <10 30 49 345 <10 <10 J. H. Preoperative...... ",. <10 172 335 600 522 330 Postoperative......... <10 73 104 375 177 23 H.H. Preoperative......... <10 66 115 250 250 52 Postoperative........ <10 19 45 126 14 Mean ± SD preoperative.'.. <10-- 81 ± 61 137 ± 104 234 ± 193 143 ± 173 59 ± 111 Mean ± SD postoperative.. <10-- 62 ± 48 91 ± 43 271 ± 211 40 ± 62 19 ± 15
Februmy 1973 VAGOTOMY AND ORAL GLUCOSE TOLERANCE 221 figure 1 are due largely to the effects of one or more hormones. Among the contenders would be included glucagon, secretin, gastrin, and epinephrine. Pancreatic glucagon might brake or limit the rapid fall of glucose between 60 and 120 min. However, the diabetic subjects were essentially normal in respect to this decline whereas diabetics have been found to have higher glucagon levels than normal after oral glucose loads. 8 It is conceivable that vagotomy reduces a-cell elaboration of glucagon more in diabetics than in normal subjects. Secretin increased released insulin. 9 Although insulin concentrations were higher after vagotomy at 60 min, this difference was not statistically significant, and it seems unlikely that either the rapid fall of glucose from 60 to 120 min or the more rapid climb from ingestion to 60 min can be attributed to an alteration in secretin metabolism. Gastrin affects electrolyte and glucose transport in the small bowel, 10 but it seems unlikely that its effects on glucose transport would account for the observed effects after vagotomy and pyloroplasty. 11 One can speculate that epinephrine might be released during the oral glucose tolerance test and regulate the glucose decline. However, physical signs suggestive of epinephrine release after feeding appear to be more prominent after vagotomy.1 We found no measurements of epinephrine in this setting. Thus, it is not easy to invoke known humoral factors in the production of the abrupt glucose peak observed in figure 1. On the other hand, it is reasonable to speculate that rapid gastric emptying of glucose contributed to the abrupt peak of serum glucose observed. With a 10% glucose meal, an average of 77% was found to be emptied from the stomach in 30 min postvagotomy as compared with 35% in a similar period before vagotomy.4 Our postvagotomy glucose curves resemble somewhat the curves of hyperthyroid subjects, and it is interesting that alteration of their glucose curves by treatment was accompanied by slowing of gastric emptying. 12 Although the rise of serum glucose was faster postoperatively, the time of peak glucose concentration was made earlier in only 6 individual subjects, (L. C., W. J., C. A., M. D., L. Mc, and C. W.). Five of these were diabetic. Diabetic subjects were found to empty some meals more slowly than normal subjects. 13 The time of peak insulin concentration was earlier after the operation in only 3 subjects, (L. C., W. J., and C. A) all diabetic. These facts suggest that vagotomy had an exaggerated effect on the gastric emptying of hypertonic glucose in the diabetic subjects, or alternatively, that these subjects emptied glucose loads more slowly than did normal subjects preoperatively. In spite of the fact that diabetics characteristically have a later than normal peak in serum insulin concentration in the oral glucose tolerance test,14 the gastric emptying of hypertonic glucose meals in diabetics has received little study. REFERENCES 1. Goligher JC, Pulvertaft CN, Irvin TT: Five- to eight-year results of truncal vagotomy and pyloroplasty for duodenal ulcer. Br Med J 1:7-13, 1972 2. Nelson NC, Guzzetta DR, Kinder JL: The effect of vagotomy on glucose tolerance. Am Surg 34: 26-30, 1968 3. Linquette M, Fourlinnie JC, Lagache G: Study of blood sugar and insulin after vagotomy and pyloroplasty in man. Ann Endocrinol (Paris) 30:96-102, 1969 4. Hall WH, Read RC: Effect of vagotomy on gastric emptying. Am J Dig Dis 15:1047-1053, 1970 5. Herbert V, Lau KS, Gottlieb CW: Coated charcoal immunoassay of insulin. J Clin Endocrinol 25:1375-1384,1965 6. Goldstein A: Biostatistics: An Introductory Text. New York, Macmillan, 1961, p 61 FF 7. Andres R: Diabetes and aging. Hosp Pract 2:63-68, 1967 8. Muller A, Faloona GR, Aquilar-Parada E, et al: Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein digestion. N Engl J Med 283: 109-U5, 1970 9. Dupre J, Curtis JD, Unger RM, et al: Effects of secretin, pancreozymin, or gastrin on the response of the endocrine pancreas to administration of glucose or arginine in man. J Clin Invest 48:745-757,1968
222 HALL ETAL. Vol. 64, No.2 10. Bynum TE, Jacobson ED, Johnson LR: Gastrin inhibition of intestinal absorption in dogs. Gastroenterology 61:858-862, 1971 11. McGuigan JE, Trudeau WL: Serum gastrin: Effect of vagotomy with pyloroplasty or with antrectomy. N Engl J Med 286:184-188, 1972 12. Holdsworth CD, Bessen GM: Influence of gastric emptying rate and of insulin response on oral glucose tolerance test in thyroid disease. Lancet 2:700-702, 1968 13. Aylett P: Gastric emptying and secretion in patients with diabetes mellitus. Gut 6:262-265, 1965 14. Yalow RS, Berson SA: Immunoassay of endogenous plasma insulin in man. J' Clin Invest 39: 1157-1175,1960