INSULIN SENSITIVITY OF HUMAN BRAIN

822 3. It is very improbable that in all the countries concerned medical will agree on what constitutes a death from diabetes. The commonest causes of death in this disease are cardio-renalvascular lesions, and such deaths will not always be certified as due to diabetes.

practitioners

It is therefore clear that the data must be regarded with considerable suspicion, and that nothing could be regarded as firmly established on the basis of such evidence. The best way to determine whether these associations are real is by means of a prospective survey, involving the follow-’iip of a large population of diabetics over a period of years. Such an investigation is now being carried out by this fund with the cooperation of the British Diabetic Association and the Registrar General’s Office. Should these associations be confirmed, then the reasons for them and the possibility of their use in the treatment or prevention of the neoplasms concerned would be considered. It is felt that speculations on such lines would be premature until the completion of the investigation outlined. I shall be pleased to supply copies of the data used to anyone interested. Statistics Unit,

Imperial Cancer Research Fund, Lincoln’s Inn Fields,

A. J. LEA.

London W.C.2.

intravenous liquid should be given fast, but when the circulation is restored as much time as possible must be allowed for equilibration. If this is done, fits are uncommon, and there is usually a urea-induced diuresis. Acidosis, if severe as judged by the respiration, may need correction with bicarbonate or lactate, but often settles as the circulation improves. If the similar picture in diabetes is due to dehydration from glucose diuresis in a patient drinking too little water (or too much sugary " tonic fizz "), the use of 5% dextrose solution initially, as suggested by Dr. Halmos and his colleagues, may be unwise.

T. H. HUGHES-DAVIES.

INSULIN SENSITIVITY OF HUMAN BRAIN

i

SIR,-Professor Butterfield and his colleagues (March 12)

the well-known clinical observation that in f insulin-dependent diabetic patients, hypoglycxmic symptomsI bear little relation to blood-sugar levels. This feature surely ! underlines the fact that disturbances of consciousness are more closely related to the intracellular metabolism of the cerebrum than to levels of circulating metabolites. An in-vivo assessment of such metabolic activity may be made by the measurement of cerebral oxygen consumption,I which according to Kety1 has a mean value in the region of 3-3 c.cm. of oxygen per 100 g. of brain tissue per minute (i.e., 40 c.cm. per minute for a brain weighing 1200 g.) in conscious " and alert individuals. Under normal conditions the fuel for this activity is exclusively carbohydrate, since values of cerebral respiratory quotient (R.Q.) in normal man approximate to units. 1Since each mole of glucose (180 g.) requires 6 moles of oxygen (134-1 litres) for its complete oxidation, a simple calculation reveals that an expected cerebral oxygeni consumption of 40 c.cm. per minute should involve the utilisation of roughly 53 mg. per minute of glucose. This is within the range of values of glucose uptake measured by Professor Butter- í field and his colleagues, representing in terms of energy con- I sumption about 20% of the expected total base metabolism. Traditionally, the brain is said not to depend on insulin for its metabolism. In support of this view are the observations that normal cerebral glucose uptakes and R.Q.s close to unity are found even in dogs rendered ketotic by fat-feeding,3 or diabetic by pancreatectomy.4 Professor Butterfield and his colleagues demonstrate that the intravenous infusion of insulin can actually i decrease the rate of cerebral glucose-uptake in man, while [ simultaneously increasing the rate of peripheral glucose-uptake. The interpretation they offer is that the cerebral threshold for glucose falls more slowly than does the peripheral threshold in response to insulin. Perhaps an alternative explanation for their unexpected observation is that a rising level of extracellular insulin may actually tend to block the entry of glucose into cerebral tissue, while facilitating its passage across the cell membranes of peripheral tissues. Conversely, the diabetogenic growth hormone or fat-mobilising substancewhich is released from the pituitary gland during starvation, fat-feeding, or diabetic ketosis may block the entry of glucose into periperal tissues while permitting its entry into the brain. Since consciousness appears to depend on the organised and uninterrupted flow of electrons from hydrogen to oxygen within the cerebrum, any interference with this final common (aerobic) pathway is liable to lead to disturbance of consciousness pari passu with increasing concentration of hydrogen ion within the neurone. Interference with this orderly transport may result from hypoxia (acute or chronic), lack of substrate (in hyperinsulinism) or of coenzymes (in vitamin-B-deficiency state), or the presence of depressant agents of endogenous or exogenous origin. In diabetic precoma these agents include excess ketone bodies and hydrogen ions produced (anaerobically) by peripheral

draw attention

to

,

I

HYPEROSMOLAR COMA IN DIABETES

SiR,łIread with interest the

of eight cases of hyperosmolar non-ketoacidotic coma in diabetes reported by Dr. Halmos and his colleagues (March 26). I was surprised that they did not mention possible upsets in potassium metabolism in this condition. The prolonged osmotic diuresis produced by the severe glycosuria in these patients, by embarrassing potassium reabsorption in the renal tubules, may lead to hypokalxmia, especially if the process continues over several weeks. The accompanying severe dehydration might mask the hypokalsmia, so that the serum-potassium could appear normal. Treatment of these patients by rehydration and large doses of insulin will promote the movement of potassium ions from the extracellular fluid into the cells, and this will further aggravate the hypokalxmia. Hypokalsemia might well have been the cause of the sudden death of two of the patients reported, and might also have contributed to the episodes of hvuotension. Edgware General Hospital, Middlesex. J. O. HUNTER. account

SIR,-The hyperosmolar coma in diabetic patients described by Dr. Halmos and his colleagues is very like the hypernatrasmic form of gastroenteritis in infants. These patients have usually received milk during their illness. This milk, if digested but not absorbed, fills the gut with a very hyperosmotic solution which draws water from the circulation, producing a rapid fall in blood-volume with a rise in hoemoglobin and electrolyte concentration. (Some infants have a very high blood-sugar, too-perhaps because of a failure of peripheral utilisation.) Sodium levels of 180 mEq. per litre, and urea levels of 300 mg. per 100 ml. or more, are not uncommon. The traditional response to such biochemical abnormalities was to give the

child intravenous glucose in water. Unfortunately this often leads to death, for, after preliminary improvement, the sunken fontanelle bulges as water passes into the cerebrospinal space and cells more quickly than urea and electrolytes can escape, as in the postdialysis syndrome; and sudden collapse from " coning " or fits may occur. If the child survives, the kidneys may fail temporarily-perhaps because of similar passage of water into recently anoxic renal cells-and treatment becomes difficult. Later, thrombosis is common. In such patients, normal saline is hypotonic enough at first, and nothing weaker than half-normal physiological saline in glucose solution should be given intravenously. Initially

I

I I

.

Kety, S. S., Schmidt, C. F. J. clin. Invest. 1948, 27, 476. Gibbs, F. L., Lennox, W. G., Nims, L. F., Gibbs, F. A. J. biol. Chem. 1942, 144, 325. 3. Milder, A. G., Crandall, L. A. Am. J. Physiol. 1942, 137, 437. 4. Himwich, H. E., Nahum, L. H. Prov. Soc. exp. Biol. Med. 1929, 26, 496. 5. Chalmers, T. M., Pawan, G. L. S., Kekwick, A. Lancet, 1960, ii, 6. 1. 2.

823

tissues, aided and abetted by dehydration.The depressant effect of these changes in intracellular electron transport to oxygen is reflected by the finding of abnormally low rates of cerebral oxygen consumption in diabetic coma, despite the maintenance of a normal or augmented cerebral circulation carrying adequate quantities of oxygen and glucose.7 Your leading article (March 12) states that the problems which present themselves for study by the technique of differential blood-sampling devised by Professor Butterfield and his colleagues extend well beyond the boundaries of endocrinology. such boundaries, indeed, did Sherrington predict: Beyond " It is then around the cerebrum, its physiological andpsychological attributes, that the main interest of biology must ultimately tnm "

0

Canberra, Australia.

S. B. FURNASS.

SIR,-Owing to a regrettable oversight, the name of Norman Veall, B.Sc.Lond., F.Inst.P., was omitted from the list of authors of our joint article (March 12), and I should like to pay full tribute

his invaluable contribution to our investicerebral blood-flow by the method he devised with Mallett.9 Department of Medicine, Guy’s Hospital Medical School, W. J. H. BUTTERFIELD. London, S.E.1. to

gations measuring

METHOXYFLURANE AND RENAL TOXICITY

SIR,-We have noted, among postoperative patients who had

undergone major abdominal surgery, a peculiar type of renal insufficiency characterised by a striking rise of blood-urea nitrogen (B.U.N.) from normal levels, and by a large urinary output of low specific gravity. Most of these patients had associated hypernatrxmia with only a slight rise of serumpotassium, as well as clinical dehydration and mental confusion. It appeared as if there was glomerular tubular imbalance. During one month 5 of our postoperative patients showed urea retention and increased urinary output. The patients had medical and surgical complications that by themselves could have caused renal difficulty, but the renal picture was so unusual that a common denominator was sought extraneous to the patient’s disease and complications. The only common factor appeared to be that all had received methoxyflurane as an anxsthetic agent (along with pentothal, nitrous oxide, oxygen, and suxamethonium chloride). In reviewing the total anaesthetic experience at our hospital, we found that 180 patients out of 7323 had received methoxyflurane over an eight-month period. Out of the 180 patients 123 had had abdominal procedures. 20 (16%) of these 123 patients showed severe dehydration, increased urinary output, confusion, and urea retention in the postoperative period. All of them had had medical or surgical complications postoperatively. Of the 20 patients, 6 have died. Artusio 10 described 3 patients in whom he noted a high urinary output accompanied by a rising B.u.N. after methoxyflurane anaesthesia. Likewise, Paddock et al. reported renal failure in 3 patients 11; in a control study they gave methoxyflurane anxsthesia without adverse renal effects to 40 healthy male patients undergoing herniorrhaphy. North and Stephen noticed

an

increased incidence of elevation of

B.u.N.

in 170

patients receiving methoxyflurane compared with 149 patients receiving other anaesthetic agents. In their series they did not notice increased urinary output.12 Our observation suggests that methoxvflurane

mav

be

6. Nabarro, J. D. N. in Disorders of Carbohydrate Metabolism; p. 141. Royal College of Physicians of London. 1962. 7. Kety, S. S., Polis, B. D., Nadler, C. S., Schmidt, C. F. J. clin. Invest. 1948, 27, 500. 8. Sherrington, C. The Integrative Action of the Nervous System; p.390. Cambridge, 1947. 9. Mallett, B. L., Veall, N. Lancet, 1963, i, 1081. 10. Cited by Paddock et al. (see footnote 2). 11. Paddock, R. B., Parker, J. W., Guadagni, N. P. Anesthesiology, 1964, 25, 707. 12. North, W. C., Stephen, C. R. ibid. 1965, 26, 257.

nephrotoxic. Furthermore the presence of a serious medical or surgical complication following major abdominal surgery seems to be necessary for the toxicity to become manifest. Further studies

are

in progress.

Department of Surgery and Medicine, Abington Memorial Hospital, Abington, Pennsylvania, U.S.A.

PIO J. PEZZI ALFRED S. FROBESE SIGMUND R. GREENBERG.

PHYTOHÆMAGGLUTININ AND MOUSE LYMPHOCYTES

SIR,-Successful attempts to demonstrate phytohaemagglutinin (P.H.A.) stimulation of mice lymphocytes in vitro have been reported, but results have not been described in detail. Other investigators 2have failed to induce mitosis with P.H.A. We have been able to show that mouse lymphocytes responded similarly to human lymphocytes when they are exposed to P.H.A.

in vitro.

modifications, a simple technique for small of whole blood4 was used. Heparinised peripheral blood was obtained from 50 inbred stock Rockland adult mice of both sexes. Portions of each sample were incubated at 37°C in the presence ofTC 199’ (Difco), penicillin, and streptomycin, in two test-tubes (0-8 x 10 cm.). P.H.A. was added (2575 litres) to one test-tube, the other remaining as control. Cultures were harvested at different intervals (from 3 to 264 hours) without addition of colchicine. For cell count and identification air-dried preparations on clean, cold, wet microslides were made after both hypotonic and fixative treatments (3 parts methyl alcohol to 1 part glacial acetic acid). Both the supernatant and sediment of culture-tubes were analysed. Direct smears were also made from cultured cell suspension without hypotonic and fixative pretreatments. Giemsa stain was used in most instances. Blast " formation and mitotic index were estimated, scoring at least 1000 cells from each culture. In all samples tested the erythroagglutinating effect of P.H.A. could be demonstrated. After the addition of P.H.A., polymorphonuclear leucocytes disappeared rapidly, and a virtually pure lymphocytic population remained. While in control tubes no mitoses were seen and blast formation was negligible (occasional cultures displayed activity as low as 5%), in P.H.A.stimulated cultures structural changes and mitoses could be detected (only 15 samples failed to grow). At 24-48 hours blast formation (19%) and mitotic activitv (0.5%) reached the With

some

quantities

"

P.H.A.-stimulated culture of mouse peripheral blood. Blasts (left) and mitosis (right) are evident. (Giemsa stain.)

maximal degree (see accompanying figure). Impaired growth and cellular damage were evident after 72-96 hours. In an additional set of cultures, blood-samples were obtained from 20 animals previously inoculated with purified protein derivative (P.P.D.) and Freund’s complete adjuvant. Results were structurally identical; but in all cultures at 24-48 hours the proportion of blasts (average 38%) and the mitotic index (0-7%) were higher than those established for non-treated animals. 1. 2. 3. 4.

Nichols, W. W., Levan, A. Blood, 1962, 20, 106. Marshall, W. H., Roberts, K. B. Lancet, 1963, i, 773. Willard, H. G., Hoppe, I. B. H., Nettesheim, P. Proc. Soc. exp. Biol. Med. 1965, 118, 993. Arakaki, D. T., Sparkes, R. S. Cytogenetics, 1963, 2, 57.