307
mechanisms involved in antibody synthesis and give further insight into the disease process.
should
ance, and basal and maximal
gastric-acid output, and includbarium meals and cholecystography. All had non-endocrine severe juvenile-onset obesity and had repeatedly failed to respond to conventional therapy. None had had skull trauma or neurological symptoms. Weight increases had been gradual and their body weights had stabilised; they had neither gained nor lost more than 2 kg for at least three months. None was on a diet or regular medication. They were not overtly diabetic although the oral glucose-tolerance test revealed raised blood-glucose and plasma-insulin. They had no ing
We thank Mrs Deborah de Villiers and Mrs Meiriir Jones for technical assistance and Mr M. J. Lange, F.R.C.S., Mr M. Sturridge, F.R.C.S., and Dr L. Loh for help in obtaining thymus specimens. G.K.S. is an Abbott research fellow. This work was supported by the Medical Research Council. ’
Requests for reprints should be addressed
Neurological Science, Royal NW32QG.
of
Free
to
J. N.-D., Department
Hospital,
Pond Street, London
REFERENCES
gastrointestinal complaints.
1. Castleman, B., Norris, E. H. Medicine, Baltimore, 1949, 28, 27. 2. Simpson, J. A. Brain, 1958, 81, 112. 3. Toyka, K. V., Drachman, D. B., Griffin, D. E., Pestronk, A., Winkelstein,
Methods After mobilisation of the
J. A., Fisebbeck, K. H., Kao. I. New Engl. J. Med. 1977, 296, 125. A., Pinching, A. J., Newsom-Davis, J. Neurology, Minneap. 1977, 27, 364. 5. Engel, A. G., Lambert, E. H., Howard, F. M. Mayo Clin. Proc. 1977, 52,
4. Vincent,
McIntosh, C. L. Lancet, 1977, i, 1310. 8. Nicholson, G. A., Appel, S. H. J. neurol. Sci. 1977, 34, 101. 9. Mittag, T., Kornfeld, P., Tormay, A., Woo, S. C. New Engl. J. Med. 1976, 294, 691. 10. Böyum, A. Scand. J. clin. Lab. Invest. 1968, 21, suppl. 97, 77. 11. Ito, Y., Miledi, R., Molenaar, P. C., Polak, R. L., Newsom-Davis, J., Vincent, A. in Biochemistry of Myasthenia Gravis and Muscular Dystrophy (edited by R. Marchbanks and G. Lunt), New York and London (in the press). 12. Scadding, G. K., Thomas, H. C., Havard, C. W. H. Br. med. J. 1977, i,
RESULTS
JOHN G. KRAL Department of Surgery II, University of Göteborg, Sahlgrenska Sjukhuset, Göteborg, Sweden Three women weighing 137, 133, and 135 kg underwent truncal vagotomy; after 16, 20, and 24 weeks they had lost 10, 17, and 19 kg respectively without serious side-effects. No dietary restrictions have been imposed, but they are eating less than they were preoperatively and report a total lack of hunger. Truncal vagotomy may be a useful treatment for severe obesity.
Summary
changed. Barium meals have not revealed dilatation or ulcers. Emptying is greatly delayed as shown by X-rays and studies of gastric emptying. Completeness of vagotomy has been confirmed by theHollander test which revealed less than 2 mmol HCl/h in each patient after stimulation with intravenous insulin (0-15 !.u. /kg body-weight).
INTRODUCTION
JEJUNO-ILEAL bypass is an effective treatment for gross obesity, but it cannot always be said to be associated with less morbidity than obesity itselfl.2 Several human and rat studies have shown that weight’loss after jejuno-ileostomy is due more to diminished food intake
DISCUSSION
weight reduction in these patients may be due to impaired gastric emptying8,9 creating a sensation of fullness or satiety.9,10 Drugs that inhibit gastric emptying such as phenformin cause weight reduction, but they also have primary metabolic effects. On the other hand, selective gastric vagotomy in rats with hyperphagia did not effectively overcome obesity" implying that impaired emptying alone is insufficient to cause weight The
than to increased losses in the stools.3·4 The mechanism is not known, although changes in taste for glucose and sucrose4 have been said to account for a reduced caloric intake.s Similar reductions in food and carbohydrate intake in vagotomised, but otherwise normal, rats have been reported. Vagotomy has also been shown to abolish obesity in hyperphagic rats with lesions in the ventromedial hypothalamus6 (the satiety centre), but it did not influence genetic obesity in obese Zucker rats.’
sive tests such
as
those
on
body composition, oral glucose-toler-
upper midline
weight losses to date are 19, 17, and 10 kg over 24, 20, and 16 weeks respectively. Patients have not vomited, despite the lack of a drainage procedure. They have not had diarrhoea. One had retrosternal pain while eating during the first three postoperative weeks and two complained of occasional foul-smelling eructations which were coming on with decreasing. frequency. No dietary restrictions have been imposed. All three patients say that they have a total lack of appetite, often going without food for 12-18 hours, and that their food intake now is mainly for social reasons, and not because of hunger. All have noticed changes in food preferences. The 21-year-old girl who had been unusually fond of sweets has stopped eating them. The other two patients avoid milk and fatty foods. The main complaint has been fatigue comparable to that accompanying weight reduction by conventional means. The blood-count and serum-electrolytes have not
VAGOTOMY FOR TREATMENT OF SEVERE OBESITY
Three obese women aged 21, 29, and 41, and weighing 135, 137, and 133 kg respectively, underwent vagotomy after exten-
an
The
1512. 13. Newsom-Davis, J., Vincent, A. Unpublished.
Patients
via
as high up as possible between the crura of the diaphragm into the mediastinum where about 3 cm of each trunk was resected and sent for histological verification; the hepatic branches were cut as an extra precaution. No drainage was carried out. Complete oral feeding was started by the fifth postoperative day and patients were followed up monthly after discharge.
267. 6. Kao, I., Drachman, D. B. Science, 1977, 195, 74. 7. King Engel, W., Trotter, J. L., McFarlin, D. E.,
PATIENTS AND METHODS
oesophagus
incision, the posterior and anterior vagal trunks were followed
loss. The
’
weight loss could also be due to changes in food preference, resulting in reduced carbohydrate and caloric intake, as shown in rats. This might be a contributory factor in the long-term but cannot account for all the reduction in food consumption either in rats or in our patients. Increased faecal fat excretion (even without diarrhaeal2) as seen after truncal vagotomy plus
308
patients with duodenal ulcer might also long-term weight loss; duodenal ulcer patients who have undergone vagotomy and gastroenteros13’14 tomy lose weight or become underweight. reduction be due to alterations in vagally may Weight mediated central and peripheral mechanisms for appetite regulation. Insulin levels have been considered important for the control of food intake and body weight. 15 The hyperinsulinaemia of animals with lesions in the hypothalamus precedes hyperphagia and weight gain" which in turn are abolished by vagotomy6 or by destrucpyloroplasty contribute
in
to
tion of beta cells.17 Since Russek demonstrated hepatic glucoreceptors in 1963,18 peripheral mechanisms for appetite regulation in the duodenuml9 and liver20 in normal animals have been reported. Vagotomy increases hypothalamic neuron firing induced by injection of glucose into the portal vein20 which causes anorexia in hungry animals. 18 It is not possible to equate human obesity with the animal obesity caused by hypothalamic lesions, and it is difficult to determine the relative importance of vagotomy in suppressing vagally mediated hunger, but our observations suggest that truncal vagotomy may be helpful in selected cases of severe obesity resistant to medical treatment. Even the resulting delay in gastric emptying and the diarrhoea and steatorrhoea may be
Hypothesis HYPERINSULINISM, DIABETES MELLITUS, AND RESPIRATORY DISTRESS OF THE NEWBORN: A COMMON LINK?
WILLIAM A. STUBBS*
SEONA M. STUBBS
Southampton General Hospital and Department of Obstetrics and Gyncecology, Kings College Hospital, London
Hyperinsulinism may reduce glycerol-3phosphate and dihydroxyacetone phosphate production and thus impair phospholipid synthesis and surfactant production in the lung. This mechanism could be responsible for the increased incidence of respiratory-distress syndrome in the infants of Summary
beneficial. Vagotomy for obesity, without drainage, is a procedure which deserves further investigation. REFERENCES
1. Faloon, W. N. New Engl. J. Med. 1976, 294, 159.
Benfield, J. R., Greenway, F. L., Bray, G. A., Barry, R. E., Lechago, J., Mona, J., Schedewie, H. Surg. Gynec. Obstet. 1976, 143, 401. 3. Pilkington, T. R. E., Gazet, J-C., Ang, L., Kalucy, R. S., Crisp, A. H., Day, S. Br. med. J. 1976, i, 1504. 4. Bray, G. A., Barry, R. E., Benfield, J. Castelnuovo-Tedesco, P., Rodin, J. in Hunger: Basic Mechanisms and Clinical Implications, (edited by D. Novin, W. Wyrwicka, and G. Bray); p. 431. New York, 1976. 5. Fox, K. A., Kipp, S. C., VanderWeele, A. Am. J. Physiol. 1976, 231, 1790. 6. Powley, T. L., Opsahl, C. A. ibid. 1974, 226, 25. 7. Opsahl, C. A., Powley, T. L. ibid. p. 34. 8. Wilbur, B. G., Kelly, K. A. Ann. Surg. 1973, 178, 295. 9. Aune, S. Scand. J. Gastroent. 1969, 4, 447. 10. Schachter, S., Goldman, R., Gordon, A. J. Personal. soc. Psychol. 1968, 10, 2.
91. 11.
tional Conference 1977. 12.
E. L. Abstracts 6th Internaof Food and Fluid Intake, Paris,
Sarchenko, P. E., Eng, R., Gold, R. M., Simson, on
the
Edwards, J. P., Lyndon,
P.
Physiology
J., Smith, R. B., Johnston,
D.
Gut, 1974, 15,
521. 13. Wheldon, E. J., Venables, C. W., Johnston, I. D. A. Lancet, 1970, i, 437. 14. Johnson, H. D., Khan, T. A., Srivatsa, R., Doyle, F. H., Welbourn, R. B.
Br. J. Surg. 1969, 56, 4. 15. Woods, S. C., Porte, Jr., D. in
plications, (edited by 16. 17. 18. 19. 20.
D.
Hunger: Basic Mechanisms and Clinical ImW. Wyrwicka, and G. Bray); p. 273. New
Novin,
York, 1976. Hustvedt, B. E., Lövö, A. Acta physiol. scand. 1972, 84, 29. York, D. A., Bray, G. A. Endocrinology, 1972, 90, 885.
Russek, M. Nature, 1963, 197, 79. Rezek, M., Havlicek, V., Novin, D. Am. J. Physiol. 1975, 229, 545. Schmitt, M. ibid. 1973, 225, 1089.
the lung may also use circulating glycerol to a limited extents (see accompanying figure). The lung has generally been regarded as being insensitive to the immediate effects of insulin.8 However, addition of physiological concentrations of insulin to a perfusion system increased glucose uptake by the rat lung by 30% over 4 hours.9 This effect on glucose uptake was unaltered by a tenfold increase in insulin concentration,10 although the disposal of glucose was affected. Thus, physiological concentrations of insulin increased glycerol production by 100% while glycerol production with a higher insulin dose showed no such increase." In the lungs of ketoacidotic diabetic animals, in which glucose uptake was depressed, there was a fall in glycerol production, and whilst physiological concentrations of
diabetic mothers.
respiratory-distress syndrome (R.D.S.) is of death in neonates.l,2 The precise important biochemical aetiology of this condition is uncertain, but a deficiency of surfactant production has been impliIDIOPATHIC
an
cause
cated.l-3 The major component of surfactant is phospholipid.4 Considerable attention has been paid to the investigation of phophatidylcholine synthesis, one of the main constituents of phospholipid.s However, the possible importance of glycerol-3-phosphate (glycerol-3-P) or dihydroxyacetone phosphate (D.H.A.P.), which are necessary for the biosynthesis of complex lipids,6 has been largely overlooked. In other tissues, the provision of these intermediates of glycolysis can govern the rate of lipid production6 and there is some evidence that this may also be the case in the lung.’ Glucose is probably the major source of glycerol-3-P and D.H.A.P., although *Present address:
Department of Medicine,
Smithfield, London.
St. Bartholomew’s
Hospital, West
and the possible effects of hyperinsulinism on the production of surfactant.
Glycolysis
mechanisms involved in antibody synthesis and give further insight into the disease process.
should
ance, and basal and maximal
gastric-acid output, and includbarium meals and cholecystography. All had non-endocrine severe juvenile-onset obesity and had repeatedly failed to respond to conventional therapy. None had had skull trauma or neurological symptoms. Weight increases had been gradual and their body weights had stabilised; they had neither gained nor lost more than 2 kg for at least three months. None was on a diet or regular medication. They were not overtly diabetic although the oral glucose-tolerance test revealed raised blood-glucose and plasma-insulin. They had no ing
We thank Mrs Deborah de Villiers and Mrs Meiriir Jones for technical assistance and Mr M. J. Lange, F.R.C.S., Mr M. Sturridge, F.R.C.S., and Dr L. Loh for help in obtaining thymus specimens. G.K.S. is an Abbott research fellow. This work was supported by the Medical Research Council. ’
Requests for reprints should be addressed
Neurological Science, Royal NW32QG.
of
Free
to
J. N.-D., Department
Hospital,
Pond Street, London
REFERENCES
gastrointestinal complaints.
1. Castleman, B., Norris, E. H. Medicine, Baltimore, 1949, 28, 27. 2. Simpson, J. A. Brain, 1958, 81, 112. 3. Toyka, K. V., Drachman, D. B., Griffin, D. E., Pestronk, A., Winkelstein,
Methods After mobilisation of the
J. A., Fisebbeck, K. H., Kao. I. New Engl. J. Med. 1977, 296, 125. A., Pinching, A. J., Newsom-Davis, J. Neurology, Minneap. 1977, 27, 364. 5. Engel, A. G., Lambert, E. H., Howard, F. M. Mayo Clin. Proc. 1977, 52,
4. Vincent,
McIntosh, C. L. Lancet, 1977, i, 1310. 8. Nicholson, G. A., Appel, S. H. J. neurol. Sci. 1977, 34, 101. 9. Mittag, T., Kornfeld, P., Tormay, A., Woo, S. C. New Engl. J. Med. 1976, 294, 691. 10. Böyum, A. Scand. J. clin. Lab. Invest. 1968, 21, suppl. 97, 77. 11. Ito, Y., Miledi, R., Molenaar, P. C., Polak, R. L., Newsom-Davis, J., Vincent, A. in Biochemistry of Myasthenia Gravis and Muscular Dystrophy (edited by R. Marchbanks and G. Lunt), New York and London (in the press). 12. Scadding, G. K., Thomas, H. C., Havard, C. W. H. Br. med. J. 1977, i,
RESULTS
JOHN G. KRAL Department of Surgery II, University of Göteborg, Sahlgrenska Sjukhuset, Göteborg, Sweden Three women weighing 137, 133, and 135 kg underwent truncal vagotomy; after 16, 20, and 24 weeks they had lost 10, 17, and 19 kg respectively without serious side-effects. No dietary restrictions have been imposed, but they are eating less than they were preoperatively and report a total lack of hunger. Truncal vagotomy may be a useful treatment for severe obesity.
Summary
changed. Barium meals have not revealed dilatation or ulcers. Emptying is greatly delayed as shown by X-rays and studies of gastric emptying. Completeness of vagotomy has been confirmed by theHollander test which revealed less than 2 mmol HCl/h in each patient after stimulation with intravenous insulin (0-15 !.u. /kg body-weight).
INTRODUCTION
JEJUNO-ILEAL bypass is an effective treatment for gross obesity, but it cannot always be said to be associated with less morbidity than obesity itselfl.2 Several human and rat studies have shown that weight’loss after jejuno-ileostomy is due more to diminished food intake
DISCUSSION
weight reduction in these patients may be due to impaired gastric emptying8,9 creating a sensation of fullness or satiety.9,10 Drugs that inhibit gastric emptying such as phenformin cause weight reduction, but they also have primary metabolic effects. On the other hand, selective gastric vagotomy in rats with hyperphagia did not effectively overcome obesity" implying that impaired emptying alone is insufficient to cause weight The
than to increased losses in the stools.3·4 The mechanism is not known, although changes in taste for glucose and sucrose4 have been said to account for a reduced caloric intake.s Similar reductions in food and carbohydrate intake in vagotomised, but otherwise normal, rats have been reported. Vagotomy has also been shown to abolish obesity in hyperphagic rats with lesions in the ventromedial hypothalamus6 (the satiety centre), but it did not influence genetic obesity in obese Zucker rats.’
sive tests such
as
those
on
body composition, oral glucose-toler-
upper midline
weight losses to date are 19, 17, and 10 kg over 24, 20, and 16 weeks respectively. Patients have not vomited, despite the lack of a drainage procedure. They have not had diarrhoea. One had retrosternal pain while eating during the first three postoperative weeks and two complained of occasional foul-smelling eructations which were coming on with decreasing. frequency. No dietary restrictions have been imposed. All three patients say that they have a total lack of appetite, often going without food for 12-18 hours, and that their food intake now is mainly for social reasons, and not because of hunger. All have noticed changes in food preferences. The 21-year-old girl who had been unusually fond of sweets has stopped eating them. The other two patients avoid milk and fatty foods. The main complaint has been fatigue comparable to that accompanying weight reduction by conventional means. The blood-count and serum-electrolytes have not
VAGOTOMY FOR TREATMENT OF SEVERE OBESITY
Three obese women aged 21, 29, and 41, and weighing 135, 137, and 133 kg respectively, underwent vagotomy after exten-
an
The
1512. 13. Newsom-Davis, J., Vincent, A. Unpublished.
Patients
via
as high up as possible between the crura of the diaphragm into the mediastinum where about 3 cm of each trunk was resected and sent for histological verification; the hepatic branches were cut as an extra precaution. No drainage was carried out. Complete oral feeding was started by the fifth postoperative day and patients were followed up monthly after discharge.
267. 6. Kao, I., Drachman, D. B. Science, 1977, 195, 74. 7. King Engel, W., Trotter, J. L., McFarlin, D. E.,
PATIENTS AND METHODS
oesophagus
incision, the posterior and anterior vagal trunks were followed
loss. The
’
weight loss could also be due to changes in food preference, resulting in reduced carbohydrate and caloric intake, as shown in rats. This might be a contributory factor in the long-term but cannot account for all the reduction in food consumption either in rats or in our patients. Increased faecal fat excretion (even without diarrhaeal2) as seen after truncal vagotomy plus
308
patients with duodenal ulcer might also long-term weight loss; duodenal ulcer patients who have undergone vagotomy and gastroenteros13’14 tomy lose weight or become underweight. reduction be due to alterations in vagally may Weight mediated central and peripheral mechanisms for appetite regulation. Insulin levels have been considered important for the control of food intake and body weight. 15 The hyperinsulinaemia of animals with lesions in the hypothalamus precedes hyperphagia and weight gain" which in turn are abolished by vagotomy6 or by destrucpyloroplasty contribute
in
to
tion of beta cells.17 Since Russek demonstrated hepatic glucoreceptors in 1963,18 peripheral mechanisms for appetite regulation in the duodenuml9 and liver20 in normal animals have been reported. Vagotomy increases hypothalamic neuron firing induced by injection of glucose into the portal vein20 which causes anorexia in hungry animals. 18 It is not possible to equate human obesity with the animal obesity caused by hypothalamic lesions, and it is difficult to determine the relative importance of vagotomy in suppressing vagally mediated hunger, but our observations suggest that truncal vagotomy may be helpful in selected cases of severe obesity resistant to medical treatment. Even the resulting delay in gastric emptying and the diarrhoea and steatorrhoea may be
Hypothesis HYPERINSULINISM, DIABETES MELLITUS, AND RESPIRATORY DISTRESS OF THE NEWBORN: A COMMON LINK?
WILLIAM A. STUBBS*
SEONA M. STUBBS
Southampton General Hospital and Department of Obstetrics and Gyncecology, Kings College Hospital, London
Hyperinsulinism may reduce glycerol-3phosphate and dihydroxyacetone phosphate production and thus impair phospholipid synthesis and surfactant production in the lung. This mechanism could be responsible for the increased incidence of respiratory-distress syndrome in the infants of Summary
beneficial. Vagotomy for obesity, without drainage, is a procedure which deserves further investigation. REFERENCES
1. Faloon, W. N. New Engl. J. Med. 1976, 294, 159.
Benfield, J. R., Greenway, F. L., Bray, G. A., Barry, R. E., Lechago, J., Mona, J., Schedewie, H. Surg. Gynec. Obstet. 1976, 143, 401. 3. Pilkington, T. R. E., Gazet, J-C., Ang, L., Kalucy, R. S., Crisp, A. H., Day, S. Br. med. J. 1976, i, 1504. 4. Bray, G. A., Barry, R. E., Benfield, J. Castelnuovo-Tedesco, P., Rodin, J. in Hunger: Basic Mechanisms and Clinical Implications, (edited by D. Novin, W. Wyrwicka, and G. Bray); p. 431. New York, 1976. 5. Fox, K. A., Kipp, S. C., VanderWeele, A. Am. J. Physiol. 1976, 231, 1790. 6. Powley, T. L., Opsahl, C. A. ibid. 1974, 226, 25. 7. Opsahl, C. A., Powley, T. L. ibid. p. 34. 8. Wilbur, B. G., Kelly, K. A. Ann. Surg. 1973, 178, 295. 9. Aune, S. Scand. J. Gastroent. 1969, 4, 447. 10. Schachter, S., Goldman, R., Gordon, A. J. Personal. soc. Psychol. 1968, 10, 2.
91. 11.
tional Conference 1977. 12.
E. L. Abstracts 6th Internaof Food and Fluid Intake, Paris,
Sarchenko, P. E., Eng, R., Gold, R. M., Simson, on
the
Edwards, J. P., Lyndon,
P.
Physiology
J., Smith, R. B., Johnston,
D.
Gut, 1974, 15,
521. 13. Wheldon, E. J., Venables, C. W., Johnston, I. D. A. Lancet, 1970, i, 437. 14. Johnson, H. D., Khan, T. A., Srivatsa, R., Doyle, F. H., Welbourn, R. B.
Br. J. Surg. 1969, 56, 4. 15. Woods, S. C., Porte, Jr., D. in
plications, (edited by 16. 17. 18. 19. 20.
D.
Hunger: Basic Mechanisms and Clinical ImW. Wyrwicka, and G. Bray); p. 273. New
Novin,
York, 1976. Hustvedt, B. E., Lövö, A. Acta physiol. scand. 1972, 84, 29. York, D. A., Bray, G. A. Endocrinology, 1972, 90, 885.
Russek, M. Nature, 1963, 197, 79. Rezek, M., Havlicek, V., Novin, D. Am. J. Physiol. 1975, 229, 545. Schmitt, M. ibid. 1973, 225, 1089.
the lung may also use circulating glycerol to a limited extents (see accompanying figure). The lung has generally been regarded as being insensitive to the immediate effects of insulin.8 However, addition of physiological concentrations of insulin to a perfusion system increased glucose uptake by the rat lung by 30% over 4 hours.9 This effect on glucose uptake was unaltered by a tenfold increase in insulin concentration,10 although the disposal of glucose was affected. Thus, physiological concentrations of insulin increased glycerol production by 100% while glycerol production with a higher insulin dose showed no such increase." In the lungs of ketoacidotic diabetic animals, in which glucose uptake was depressed, there was a fall in glycerol production, and whilst physiological concentrations of
diabetic mothers.
respiratory-distress syndrome (R.D.S.) is of death in neonates.l,2 The precise important biochemical aetiology of this condition is uncertain, but a deficiency of surfactant production has been impliIDIOPATHIC
an
cause
cated.l-3 The major component of surfactant is phospholipid.4 Considerable attention has been paid to the investigation of phophatidylcholine synthesis, one of the main constituents of phospholipid.s However, the possible importance of glycerol-3-phosphate (glycerol-3-P) or dihydroxyacetone phosphate (D.H.A.P.), which are necessary for the biosynthesis of complex lipids,6 has been largely overlooked. In other tissues, the provision of these intermediates of glycolysis can govern the rate of lipid production6 and there is some evidence that this may also be the case in the lung.’ Glucose is probably the major source of glycerol-3-P and D.H.A.P., although *Present address:
Department of Medicine,
Smithfield, London.
St. Bartholomew’s
Hospital, West
and the possible effects of hyperinsulinism on the production of surfactant.
Glycolysis
