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ISLET CELLS AND INSULIN
1273
scepticism whether the incidence of chronic glomerulonephritis can be significantly influenced by penicillin therapy. seems room
for
Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
BASCOM F. ANTHONY LEWIS W. WANNAMAKER.
DENOTING DIALYSIS make a plea for the abolition of the neologism SiR,-May one " renal dialysis " before this becomes too firmly established ? The blood, not the kidney, is dialysed; hence the correct term is " haanodialysis ". R.D.T. (recurrent dialysis treatment) refers to treatment by regular repeated dialysis of patients with irreversible renal failure. The term " (artificial) kidney machine " is also causing confusion, since it is used to denote both the dialysing element and the dialysing-fluid dispensing/monitoring apparatus. If "kidney machine " there must be, this should be restricted to the machinery which produces and monitors the dialysing fluid. The words " artificial kidney " should retain their original meaning and refer to the dialyser itself. Liverpool Regional Urological Centre, Sefton General Hospital, Smithdown Road, Liverpool 15.
H. J. GOLDSMITH.
ISLET CELLS AND INSULIN SIR,-Your leading article (May 27, p. 1142), and the two papers of Dr. Power and his colleagues in the same issue (pp. 1123 and 1138), invite comment on several points. Firstly (a relatively trivial but potentially confusing point) the use of the term " anti-insulins " in your leader, initially to describe the synalbumin antagonist and later to describe the passive immunisation of rats with insulin antiserum, may well result in misinterpretation. Secondly, the use of the term " insulin-like activity" (I.L.A.) requires qualification, for it is in itself a confusing term. It was introduced by Renold et al.l to describe the resultant effect produced by complex biological fluids in insulin bioassays, acknowledging the non-specificity of the methods. The specificity of these type of assays was later and improved by the use of a potent insulin antiserum,2 " " I.L.A. became subdivided into " suppressible (or typical ") and " non-suppressible " (" atypical ") i.L.A., the suppressible fraction being that which was neutralised by insulin antiserum. It seems that the suppressible fraction should represent " free " insulin that is available for reaction with the insulin antiserum and therefore measurable by the various radioimmunoassays. We have produced some evidence to suggest that this assumption is in fact correct.4 Definitive studies have confirmed our preliminary findings. Not only does suppressible I.L.A. parallel immunoassayable insulin in all physiological and pathological instances so far encountered, but in the dog it disappears immediately after pancreactectomy (unpublished data). The identity of suppressible i.L.A. thus seems to be reasonably well established. I.L.A. (or what Dr. Power presumably is Non-suppressible " to as referring i.L.A.") we consider to be a non-specific assay " blank ", on which we should like to make a few comments. The response that is being measured in all in-vitro insulin bioassays is not totally insulin dependent, inasmuch as the tissue under study has a " basal " rate of glucose metabolism that will continue in a simple salt solution in the 1.
Renold, A. E., Martin, D. B., Dagenais, Y. M., Steinke, J., Nickerson, R. J., Sheps, M. C. J. clin. Invest. 1960, 39, 1487. 2. Slater, J. D. H., Samaan, N., Fraser, R., Stillman, D. Br. med. J. 1961, i, 1712. 3. Froesch, E. R., Burgi, H., Ramseier, E. B., Bally, P., Labhart, A. J. clin. Invest. 1963, 42, 1816. 4. Sönksen, P. H., Ellis, J. P., Lowy, C., Rutherford, A., Nabarro, J. D. N. Br. med. J. 1965, ii, 209.
absence of any added insulin. We find it not altogether unexpected that the basal rate of tissue metabolism should be higher in a complex biological solution even in the absence of any insulin. There are present many intermediate metabolites, enzymes, hormones, and proteins, all of which may facilitate whether through a " nutrient " action, glucose metabolism, " " by way of a surfactant effect, or by assisting the removal of intermediate metabolites. These substances may not have the same " dose-response " characteristics as insulin.
The apparent increase in " I.L.A." found by Dr. Power on dilution of plasma implies that the dose-response effect of plasma does not parallel that of crystalline insulin in bicarbonate buffer, in such a way that the slope of the standard response is steeper than that of the " unknown ". Conclusions based on quantitation of " I.L.A." under these circumstances must be open to criticism.
It is
our finding and that of Froesch 3 that non-suppressible (not identical with Dr. Power’s " I.L.A ", since he did not use insulin-antiserum in his assay) does not rise after glucose in any clinical situation (in fact in normal subjects there is a suggestion of a fall after intravenous glucose, although this does not reach statistical significance). The mean values for non-suppressible I.L.A. were the same in patients with diabetes mellitus (56-39±25 -.units per ml., 49 samples) as in normal subjects (55-52±24-8 -cunits per ml., 42 samples) and normal dogs (53-84±9-9 -.units per ml., 10 samples); these values are again not significantly different from the limited number of samples that we have tested from patients with islet-cell tumours of the pancreas (60-24±22-85 tlunits per ml., 25 samples from 3 patients). The mean value for non-suppressible I.L.A. in depancreatised dogs was about 20% lower (40-33±14-7 j-units per ml., 27 samples from 9 dogs), the difference being highly significant (r< 0-001). It is our experience that non-suppressible I.L.A. falls by about 20% in the early postoperative period, but later rises to the prepancreatectomy level before the dogs succumb. We find it difficult to accept that Dr. Power has given sufficient evidence to support his hypothesis that " I.L.A." is a yet-undescribed hormone originating from the islet cells, and would be so provocative as to suggest that most of his
I.L.A.
results could be ascribed
to an assay
Institute of Clinical Research, Middlesex Hospital Medical School, 40 Hanson Street, London W.1.
artefact. P. H. SÖNKSEN J. P. ELLIS R. W. MARCUSON A. RUTHERFORD J. D. N. NABARRO.
INTERPRETATION OF LABORATORY TESTS SIR,-Your leading article (May 20, p. 1091) was stimulating and timely, but its recommendation of 24-hour urine collections for clinical purposes is questionable. It is correct that random specimens are not suitable for quantitative purposes, but by using the first morning urine a certain standardisation is achieved. It must be remembered that complete collection of 24-hour urine is difficult and that it cannot be taken for granted that all the urine is collected, except in metabolic wards and in trained experimental subjects. In average outpatients, and ambulatory inpatients (who make up most of the patients in many modem wards), one can hardly expect the high quality of cooperation required: and in patients in bed, errors due to hard-working nursing staff can hardly be neglected. How many patients who have by accident discarded a portion of urine can be expected to tell the nurse? How serious is the error introduced in 24-hour sampling in this way ? In the series from which normal excretions are calculated 24-hour sampling will most likely be correct, but in the average clinical situation this is fa. less likely. Before 24-hour urine collection as a routine is recommended, it seems reasonable to study this source of error; to my knowledge this has not been done. Central Laboratory, Central County Hospital, Svendborg, Denmark.
TORBEN K. WITH.
scepticism whether the incidence of chronic glomerulonephritis can be significantly influenced by penicillin therapy. seems room
for
Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
BASCOM F. ANTHONY LEWIS W. WANNAMAKER.
DENOTING DIALYSIS make a plea for the abolition of the neologism SiR,-May one " renal dialysis " before this becomes too firmly established ? The blood, not the kidney, is dialysed; hence the correct term is " haanodialysis ". R.D.T. (recurrent dialysis treatment) refers to treatment by regular repeated dialysis of patients with irreversible renal failure. The term " (artificial) kidney machine " is also causing confusion, since it is used to denote both the dialysing element and the dialysing-fluid dispensing/monitoring apparatus. If "kidney machine " there must be, this should be restricted to the machinery which produces and monitors the dialysing fluid. The words " artificial kidney " should retain their original meaning and refer to the dialyser itself. Liverpool Regional Urological Centre, Sefton General Hospital, Smithdown Road, Liverpool 15.
H. J. GOLDSMITH.
ISLET CELLS AND INSULIN SIR,-Your leading article (May 27, p. 1142), and the two papers of Dr. Power and his colleagues in the same issue (pp. 1123 and 1138), invite comment on several points. Firstly (a relatively trivial but potentially confusing point) the use of the term " anti-insulins " in your leader, initially to describe the synalbumin antagonist and later to describe the passive immunisation of rats with insulin antiserum, may well result in misinterpretation. Secondly, the use of the term " insulin-like activity" (I.L.A.) requires qualification, for it is in itself a confusing term. It was introduced by Renold et al.l to describe the resultant effect produced by complex biological fluids in insulin bioassays, acknowledging the non-specificity of the methods. The specificity of these type of assays was later and improved by the use of a potent insulin antiserum,2 " " I.L.A. became subdivided into " suppressible (or typical ") and " non-suppressible " (" atypical ") i.L.A., the suppressible fraction being that which was neutralised by insulin antiserum. It seems that the suppressible fraction should represent " free " insulin that is available for reaction with the insulin antiserum and therefore measurable by the various radioimmunoassays. We have produced some evidence to suggest that this assumption is in fact correct.4 Definitive studies have confirmed our preliminary findings. Not only does suppressible I.L.A. parallel immunoassayable insulin in all physiological and pathological instances so far encountered, but in the dog it disappears immediately after pancreactectomy (unpublished data). The identity of suppressible i.L.A. thus seems to be reasonably well established. I.L.A. (or what Dr. Power presumably is Non-suppressible " to as referring i.L.A.") we consider to be a non-specific assay " blank ", on which we should like to make a few comments. The response that is being measured in all in-vitro insulin bioassays is not totally insulin dependent, inasmuch as the tissue under study has a " basal " rate of glucose metabolism that will continue in a simple salt solution in the 1.
Renold, A. E., Martin, D. B., Dagenais, Y. M., Steinke, J., Nickerson, R. J., Sheps, M. C. J. clin. Invest. 1960, 39, 1487. 2. Slater, J. D. H., Samaan, N., Fraser, R., Stillman, D. Br. med. J. 1961, i, 1712. 3. Froesch, E. R., Burgi, H., Ramseier, E. B., Bally, P., Labhart, A. J. clin. Invest. 1963, 42, 1816. 4. Sönksen, P. H., Ellis, J. P., Lowy, C., Rutherford, A., Nabarro, J. D. N. Br. med. J. 1965, ii, 209.
absence of any added insulin. We find it not altogether unexpected that the basal rate of tissue metabolism should be higher in a complex biological solution even in the absence of any insulin. There are present many intermediate metabolites, enzymes, hormones, and proteins, all of which may facilitate whether through a " nutrient " action, glucose metabolism, " " by way of a surfactant effect, or by assisting the removal of intermediate metabolites. These substances may not have the same " dose-response " characteristics as insulin.
The apparent increase in " I.L.A." found by Dr. Power on dilution of plasma implies that the dose-response effect of plasma does not parallel that of crystalline insulin in bicarbonate buffer, in such a way that the slope of the standard response is steeper than that of the " unknown ". Conclusions based on quantitation of " I.L.A." under these circumstances must be open to criticism.
It is
our finding and that of Froesch 3 that non-suppressible (not identical with Dr. Power’s " I.L.A ", since he did not use insulin-antiserum in his assay) does not rise after glucose in any clinical situation (in fact in normal subjects there is a suggestion of a fall after intravenous glucose, although this does not reach statistical significance). The mean values for non-suppressible I.L.A. were the same in patients with diabetes mellitus (56-39±25 -.units per ml., 49 samples) as in normal subjects (55-52±24-8 -cunits per ml., 42 samples) and normal dogs (53-84±9-9 -.units per ml., 10 samples); these values are again not significantly different from the limited number of samples that we have tested from patients with islet-cell tumours of the pancreas (60-24±22-85 tlunits per ml., 25 samples from 3 patients). The mean value for non-suppressible I.L.A. in depancreatised dogs was about 20% lower (40-33±14-7 j-units per ml., 27 samples from 9 dogs), the difference being highly significant (r< 0-001). It is our experience that non-suppressible I.L.A. falls by about 20% in the early postoperative period, but later rises to the prepancreatectomy level before the dogs succumb. We find it difficult to accept that Dr. Power has given sufficient evidence to support his hypothesis that " I.L.A." is a yet-undescribed hormone originating from the islet cells, and would be so provocative as to suggest that most of his
I.L.A.
results could be ascribed
to an assay
Institute of Clinical Research, Middlesex Hospital Medical School, 40 Hanson Street, London W.1.
artefact. P. H. SÖNKSEN J. P. ELLIS R. W. MARCUSON A. RUTHERFORD J. D. N. NABARRO.
INTERPRETATION OF LABORATORY TESTS SIR,-Your leading article (May 20, p. 1091) was stimulating and timely, but its recommendation of 24-hour urine collections for clinical purposes is questionable. It is correct that random specimens are not suitable for quantitative purposes, but by using the first morning urine a certain standardisation is achieved. It must be remembered that complete collection of 24-hour urine is difficult and that it cannot be taken for granted that all the urine is collected, except in metabolic wards and in trained experimental subjects. In average outpatients, and ambulatory inpatients (who make up most of the patients in many modem wards), one can hardly expect the high quality of cooperation required: and in patients in bed, errors due to hard-working nursing staff can hardly be neglected. How many patients who have by accident discarded a portion of urine can be expected to tell the nurse? How serious is the error introduced in 24-hour sampling in this way ? In the series from which normal excretions are calculated 24-hour sampling will most likely be correct, but in the average clinical situation this is fa. less likely. Before 24-hour urine collection as a routine is recommended, it seems reasonable to study this source of error; to my knowledge this has not been done. Central Laboratory, Central County Hospital, Svendborg, Denmark.
TORBEN K. WITH.