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PROPRANOLOL AND HYPOGLYCÆMIA
164 the higher the phosphatase activity the shorter the attack, and vice versa. The final answer could be given only if in many different cases of pseudo-gout the synovial phosphatase activity were checked, preferably daily. It must be emphasised that except for the finding of a rheumatoid " nodule, the patient had never fulfilled the accepted clinical and radiological criteria of rheumatoid arthritis. 2nd Medical Department and
Consequently,
It is important to know how drugs which depress F.F.A. release act, since such drugs, if they promoted carbohydrate utilisation, would be useful rather than harmful in a variety of conditions.
"
Rheumatology Clinic, Beilinson Hospital, Petah Tiqva, Israel.
I. MACHTEY.
AND VASCULAR DISEASE SIR,-Your leading article last week (p. 87) is a timely reminder that history repeats itself and that we are back again to the days of the gouty diathesis. Gout is to the arteries what rheumatism is to the heart, said Huchard. Fothergill (1879)/ in a chapter of seventy pages on the gouty heart, described the tense pulse, hardened arteries, and hypertrophied heart of hypertension. He attributed it to a waste-laden condition of the blood, remarking that uric acid was the form in which nitrogenised waste lingered in the blood and tissues. Articular gout was not an essential component of the gouty diathesis which was defined by Balfour (1894)2 as " only a comprehensive term for all those changes in the character and composition of the blood induced by the evils of civilisation ". He also described gouty glycosuria, and today once more carbohydrate intolerance is being related to arterial disease. Plus fa change, plus c’est la même chose-the gouty diathesis and the evils of civilisation are never out of date as an explanation of arterial disease. D. EVAN BEDFORD. London W. 1.
HYPERURICÆMIA, HYPERTENSION,
PROPRANOLOL AND HYPOGLYCÆMIA SIR,-Dr. Abramson and his colleagues3 and Dr. Kotler and his colleagues hold that the direct inhibitory action of propranolol on glucose mobilisation is probably responsible for prolonging or producing hypoglycaemia. The possible effects of the drug on insulin release and the part played by glycerol in gluconeogenesis are also considered. Might not the lowering of plasma-free-fatty-acids (F.F.A.),’ also observed, facilitate the uptake of glucose by the tissues, and so account in part for the lower blood-glucose found ? Among other 3-blocking agents, of propranolol, has been found to pronethalol, the forerunner lower F.F.A. at rest 6 and during exercise7Eaton et a1.8 claimed that at rest only prolonged depression of F.F.A. would decrease the metabolism of endogenous tissue lipid in peripheral tissues, and so allow an increase in carbohydrate metabolism. However, in the studies of Dr. Abramson and his colleagues, and Dr. Kotler and his colleagues, as was suggested for 9 the pronethalol exercise study,’ an index of the change in rate of glucose utilisation is required before it is permissible to distinguish between a block in hepatic output or increased peripheral uptake as being responsible for the lower bloodsugar. Such an index may be provided by the estimation of
respiratory exchange
and
respiratory quotient (R.Q.).
Fothergill, J. M. The Heart and its Diseases with their Treatment, including the Gouty Heart. 2nd edition. 1879. 2. Balfour, G. W. The Senile Heart. 1894 3. Abramson, E. A., Arky, R. A., Woeber, K. A. Lancet, 1966, ii, 1386. 4. Kotler, M. N., Berman, L., Rubenstein, A. H. ibid. p. 1389. 5. Randle, P. J., Garland, P. B., Hales, C. N., Newsholme, E. A. ibid. 1.
1963, i, 785.
Steinberg, D , Nestel, P. J., Buskirk, E. R., Thompson, R. H. J. clin. Invest. 1964, 43, 167. 7. Muir, G. G., Chamberlain, D. A., Pedoe, D. T. Lancet, 1964, ii, 930. 8. Eaton, R. P., Steinberg, D., Thompson, R. H. J. clin Invest. 1965, 44,
6.
247. 9.
Jenkins, D. J. A. Lancet, 1964, ii, 1184.
F.F.A.-suppressing action of nicotinic acid (N.A.) and the accompanying changes in metabolism have been extensively investigated in normal subjects.1o-13 The major actions and side-effects of N.A. are similar to those ascribed to propranolol. The depression of F.F.A. was found to be accompanied by an increase in R.Q. In a trial 14 on four obese subjects with mild diabetes and four juvenile diabetics (all untreated) repeated doses of N.A. lowered F.F.A. and blood-glucose during a 3-hour experimental period. The fall in blood-glucose was much more striking in the juvenile diabetics and this coincided with lower initial levels of F.F.A. and with the more rapid fall in F.F.A. after N.A. administration. I give here similar results in a treated overweight maturity-onset diabetic patient, who fasted for 3B/2 hours before the experiment, as follows: The
Here the hypotensive action was observed, though the cutaneous flushing, also noted with &bgr;-blocking agents, occurred only on
first dosage. In other circumstances in of
result
doses
raising
an increase in plasma F.F.A. may blood-sugar. Such a situation arises when given which are inadequate to maintain the
the
N.A. are
F.F.A. release. The F.F.A. then rises above prelevels. Failure to recognise " escape " and " overshoot " responses in F.F.A. release has hampered understanding of the effects of N.A. in the treatment of diabetes. Such responses may provide the reason why hypoglyceemia does not follow prolonged treatment with N.A.
block
on
treatment
The effect that excessive F.F.A. release may have in raising the blood-sugar was brought out in a study on a male maturityonset diabetic of normal weight. His plasma F.F.A. was already low (180 Af per ml., 3 hours after the last meal) and N.A. produced no consistent lowering of the blood-sugar. The F.F.A. was, if anything, higher. On the penultimate day when N.A. was taken he received 200 mg. per hour. It seems that during the next night, while N.A. was not being taken, the overshoot response with excessive F.F.A. release occurred unchecked. In the morning there was severe ketonuria which was not lessened by treatment with 100 mg. N.A. 1/2-hourly for 10 hours. At this time the plasma F.F.A. was 1750 fly per ml. and the blood-sugar 412 mg. per 100 ml. Thus the raised F.F.A. was associated with raised blood-sugar and exacerbation of the diabetic state. It therefore seems that the blood-glucose level and the rate of metabolism of carbohydrate are associated with changes in the F.F.A. level. If
"
"
escape
with excessive
F.F.A.
release does
not occur
with
propranolol (and this has not so far been reported) one might conclude from experience with N.A. that the pretreatment F.F.A. level will be of importance in determining whether hypoglycaemia will occur. When the F.F.A. is high there will be less danger of hypoglycaemia. The overweight patient should therefore be safer
to treat
than those who
are
normal
or
underweight. I should like to thank Dr. T. D. R. Hockaday for permission his patients, and for much helpful advice he has given.
M
study
University Laboratory of Physiology, Oxford. 10. 11.
DAVID
J. A. JENKINS.
Carlson, L. A., Orö, L. Acta med. scand. 1962, 172, 641. Carlson, L. A., Havel, R. J., Ekelund, L., Holmgren, A. Metaboasw. 1963, 12, 837. 12. Havel, R. J., Carlson, L. A., Ekelund, L., Holmgren, A. ibid 1964. 13, 1402. 13. Jenkins, D. J. A. Lancet, 1965, i, 1307. 14. Carlson, L. A., Östman J. Diabetologica, 1966, 2, 127.
Consequently,
It is important to know how drugs which depress F.F.A. release act, since such drugs, if they promoted carbohydrate utilisation, would be useful rather than harmful in a variety of conditions.
"
Rheumatology Clinic, Beilinson Hospital, Petah Tiqva, Israel.
I. MACHTEY.
AND VASCULAR DISEASE SIR,-Your leading article last week (p. 87) is a timely reminder that history repeats itself and that we are back again to the days of the gouty diathesis. Gout is to the arteries what rheumatism is to the heart, said Huchard. Fothergill (1879)/ in a chapter of seventy pages on the gouty heart, described the tense pulse, hardened arteries, and hypertrophied heart of hypertension. He attributed it to a waste-laden condition of the blood, remarking that uric acid was the form in which nitrogenised waste lingered in the blood and tissues. Articular gout was not an essential component of the gouty diathesis which was defined by Balfour (1894)2 as " only a comprehensive term for all those changes in the character and composition of the blood induced by the evils of civilisation ". He also described gouty glycosuria, and today once more carbohydrate intolerance is being related to arterial disease. Plus fa change, plus c’est la même chose-the gouty diathesis and the evils of civilisation are never out of date as an explanation of arterial disease. D. EVAN BEDFORD. London W. 1.
HYPERURICÆMIA, HYPERTENSION,
PROPRANOLOL AND HYPOGLYCÆMIA SIR,-Dr. Abramson and his colleagues3 and Dr. Kotler and his colleagues hold that the direct inhibitory action of propranolol on glucose mobilisation is probably responsible for prolonging or producing hypoglycaemia. The possible effects of the drug on insulin release and the part played by glycerol in gluconeogenesis are also considered. Might not the lowering of plasma-free-fatty-acids (F.F.A.),’ also observed, facilitate the uptake of glucose by the tissues, and so account in part for the lower blood-glucose found ? Among other 3-blocking agents, of propranolol, has been found to pronethalol, the forerunner lower F.F.A. at rest 6 and during exercise7Eaton et a1.8 claimed that at rest only prolonged depression of F.F.A. would decrease the metabolism of endogenous tissue lipid in peripheral tissues, and so allow an increase in carbohydrate metabolism. However, in the studies of Dr. Abramson and his colleagues, and Dr. Kotler and his colleagues, as was suggested for 9 the pronethalol exercise study,’ an index of the change in rate of glucose utilisation is required before it is permissible to distinguish between a block in hepatic output or increased peripheral uptake as being responsible for the lower bloodsugar. Such an index may be provided by the estimation of
respiratory exchange
and
respiratory quotient (R.Q.).
Fothergill, J. M. The Heart and its Diseases with their Treatment, including the Gouty Heart. 2nd edition. 1879. 2. Balfour, G. W. The Senile Heart. 1894 3. Abramson, E. A., Arky, R. A., Woeber, K. A. Lancet, 1966, ii, 1386. 4. Kotler, M. N., Berman, L., Rubenstein, A. H. ibid. p. 1389. 5. Randle, P. J., Garland, P. B., Hales, C. N., Newsholme, E. A. ibid. 1.
1963, i, 785.
Steinberg, D , Nestel, P. J., Buskirk, E. R., Thompson, R. H. J. clin. Invest. 1964, 43, 167. 7. Muir, G. G., Chamberlain, D. A., Pedoe, D. T. Lancet, 1964, ii, 930. 8. Eaton, R. P., Steinberg, D., Thompson, R. H. J. clin Invest. 1965, 44,
6.
247. 9.
Jenkins, D. J. A. Lancet, 1964, ii, 1184.
F.F.A.-suppressing action of nicotinic acid (N.A.) and the accompanying changes in metabolism have been extensively investigated in normal subjects.1o-13 The major actions and side-effects of N.A. are similar to those ascribed to propranolol. The depression of F.F.A. was found to be accompanied by an increase in R.Q. In a trial 14 on four obese subjects with mild diabetes and four juvenile diabetics (all untreated) repeated doses of N.A. lowered F.F.A. and blood-glucose during a 3-hour experimental period. The fall in blood-glucose was much more striking in the juvenile diabetics and this coincided with lower initial levels of F.F.A. and with the more rapid fall in F.F.A. after N.A. administration. I give here similar results in a treated overweight maturity-onset diabetic patient, who fasted for 3B/2 hours before the experiment, as follows: The
Here the hypotensive action was observed, though the cutaneous flushing, also noted with &bgr;-blocking agents, occurred only on
first dosage. In other circumstances in of
result
doses
raising
an increase in plasma F.F.A. may blood-sugar. Such a situation arises when given which are inadequate to maintain the
the
N.A. are
F.F.A. release. The F.F.A. then rises above prelevels. Failure to recognise " escape " and " overshoot " responses in F.F.A. release has hampered understanding of the effects of N.A. in the treatment of diabetes. Such responses may provide the reason why hypoglyceemia does not follow prolonged treatment with N.A.
block
on
treatment
The effect that excessive F.F.A. release may have in raising the blood-sugar was brought out in a study on a male maturityonset diabetic of normal weight. His plasma F.F.A. was already low (180 Af per ml., 3 hours after the last meal) and N.A. produced no consistent lowering of the blood-sugar. The F.F.A. was, if anything, higher. On the penultimate day when N.A. was taken he received 200 mg. per hour. It seems that during the next night, while N.A. was not being taken, the overshoot response with excessive F.F.A. release occurred unchecked. In the morning there was severe ketonuria which was not lessened by treatment with 100 mg. N.A. 1/2-hourly for 10 hours. At this time the plasma F.F.A. was 1750 fly per ml. and the blood-sugar 412 mg. per 100 ml. Thus the raised F.F.A. was associated with raised blood-sugar and exacerbation of the diabetic state. It therefore seems that the blood-glucose level and the rate of metabolism of carbohydrate are associated with changes in the F.F.A. level. If
"
"
escape
with excessive
F.F.A.
release does
not occur
with
propranolol (and this has not so far been reported) one might conclude from experience with N.A. that the pretreatment F.F.A. level will be of importance in determining whether hypoglycaemia will occur. When the F.F.A. is high there will be less danger of hypoglycaemia. The overweight patient should therefore be safer
to treat
than those who
are
normal
or
underweight. I should like to thank Dr. T. D. R. Hockaday for permission his patients, and for much helpful advice he has given.
M
study
University Laboratory of Physiology, Oxford. 10. 11.
DAVID
J. A. JENKINS.
Carlson, L. A., Orö, L. Acta med. scand. 1962, 172, 641. Carlson, L. A., Havel, R. J., Ekelund, L., Holmgren, A. Metaboasw. 1963, 12, 837. 12. Havel, R. J., Carlson, L. A., Ekelund, L., Holmgren, A. ibid 1964. 13, 1402. 13. Jenkins, D. J. A. Lancet, 1965, i, 1307. 14. Carlson, L. A., Östman J. Diabetologica, 1966, 2, 127.