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URINARY ALBUMIN EXCRETION IN THE OFFSPRING OF CONJUGAL DIABETICS
487 RESULTS OF COAGULATION STUDIES
*
Operation.
A 16-year-old boy was known to have transposition of -the great vessels, and had a shunt constructed between the inferior vena cava and left atrium at age 4. He was now admitted for corrective surgery. There was no history of unusual bleeding or bruising. Coagulation studies are shown in the accompanying table. Starting on day 2, E.A.C.A., 4 g. initially and then 1 g. hourly, was given by mouth. At 11 P.M. on day 3, the E.A.C.A. was changed to a constant intravenous infusion, so that he continued to receive 1 g. an hour. Blood was drawn at 8.30 A.M. on day 4 for coagulation studies, and the operation was started at 10.30 A.M. Because the coagulation studies also showed deterioration, the operation was discontinued. Beginning four hours after surgery, the patient lost approximately 700 ml. of blood from the closed incision. E.A.C.A. was continued intravenously for the next 5 days. At reoperation on day 9 no unusual bleeding was encountered, and the surgical reconstruction was completed uneventfully. Initial coagulation studies demonstrated decreased levels of factor v and fibrinogen, and marked shortening of the -euglobulin lysis-time. The excessive fibrinolysis in this patient was quite resistant to treatment with E.A.C.A. Immediately before and during the first operation, fibrinogen and plasminogen levels fell, and the euglobulin lysistimes became progressively shorter, despite the fact that the
patient was receiving E.A.C.A. Postoperatively, however, 1fibrinogen levels increased, indicating that fibrinolysis was now controlled. Heparin was employed only during the second operation as part of the routine for open-heart surgery. A decrease in the platelet-count after open-heart bypass surgery is commonly observed. Our experience with this patient supports the contention of Gralnickl4 that increased fibrinolysis in patients with cyanotic congenital heart-disease undergoing surgery is primary and should be managed with E.A.C.A. Northwestern UniversityMcGaw Medical Center,
Chicago, Illinois 60611, U.S.A.
DAVID GREEN.
URINARY ALBUMIN EXCRETION IN THE OFFSPRING OF CONJUGAL DIABETICS
SIR,-Dr. Soeldner and his co-workers (July 31, p. 239) report that the urinary albumin-excretion rate was the same in 96 offspring of two diabetic parents as in controls, and conclude that diabetic glomerulosclerosis is a consequence rather than a forerunner of the clinical disease. I doubt if they are justified in doing so. A previous study 1,2 showed a prevalence of diabetes of less than 5% among 656 offspring of conjugal diabetics, and gave grounds for thinking that no more than a quarter would ever develop 1. 2.
t Heparin in sample.
t Reoperation.
Cooke, A. M., Fitzgerald, M. G., Malins, J., Pyke, D. A. Br. med. J. 1966, ii, 674. Pyke, D. A. Postgrad. med. J. 1970, 46, 604.
the disease. Probably, therefore, only a minority of the persons studied by Dr. Soeldner and his co-workers are destined to become diabetic. The results from these individuals could have been diluted by those from the rest, leading to a false-negative conclusion. The authors use the term " genetic prediabetics " to describe the individuals in question, and point out that in Britain the term " potential diabetics " would be applied. This seems to imply that the two terms are similar, which they are not. A potential diabetic is a person at above-average risk of developing diabetes; a genetic prediabetic is a person destined, because of his genetic make-up, to develop diabetes. Such a person is unidentifiable. Even the identical twin of a diabetic is not certain to become diabetic. 3,4 This argument is not mere pedantry. Studies such as that of Dr. Soeldner and his co-workers may reveal less than their authors claim because they deal not with those certain to develop diabetes but with groups of persons most of whom never will. Diabetic Department, King’s College Hospital, London S.E.5.
D. A. PYKE.
The Boston and London workers received copies of this letter, and replies from Dr. Soeldner and Dr. Jarrett follow.-ED. L. SIR,-Dr. Pyke emphasises one of the problems of studies focused upon pre-" disease " states. Our last paragraph also points to this. It should be noted that one of the study groups of offspring of two diabetic parents (the diabetes-prone impaired-tolerance group) constituted 50% of the offspring of conjugal diabetics. No significant elevations of urinary albumin concentrations or urine albumin excretion-rates could be shown in this group of offspring with mild diabetes. Perhaps if this group with impaired tolerance is admitted to have " mild asymptomatic diabetes ", which conceivably could have been present for a long period of time before the repetitive glucose-tolerance tests, some significant increase of urinary albumin excretion should be apparent. Since it does not, one can only conclude that diabetic glomerulosclerosis does not precede the onset of carbohydrate intolerance. The prevalence of diabetes in persons with high genetic risk can only be truly shown by lifetime follow-up. In addition to the studies quoted by Dr. Pyke, evidence from this laboratory has indicated that chemical diabetes can be detected by repeated glucose-tolerance testing in 55-92% of the offspring of two diabetic parents, whereas only 9% show overt diabetes.5 This group from this Pyke, D. A., Cassar, J., Todd, J., Taylor, K. W. Br. med. J. 1970, iv, 649. 4. Malins, J., Cassar, J., Pyke, D. A. Diabetes, 1970, 19, 878. 5. Kahn, C. B., Soeldner, J. S., Gleason, R. E., Rojas, L., CameriniDavalos, R. A., Marble, A. New Engl. J. Med. 1969, 281, 343.
3.
488 same
laboratory
was
also
employed
for the urine albumin
studies. What perhaps is
more disturbing to me is the disbetween the crepancy frequency of chemical diabetes between many studies focused upon genetic prediabetic groups (offspring conjugal diabetics and monozygotic twins J. 2-66
Elliott P. Joslin Research Laboratory, Harvard Medical School, Boston, Mass. 02215, U.S.A.
J. STUART SOELDNER.
SIR,-Dr. Pyke at the end of his letter disclaims pedantry, having clearly demonstrated it in the earlier paragraphs. He must know that there are problems in transatlantic authorship-as Bernard Shaw said " we are two great nations divided by a common language ". In any case, we did not assume that the group under study were all going to develop diabetes, only that their higher risk was due to genetic factors. Dr. Pyke is no doubt aware that there is currently a passionate debate over the hypothesis that tissue and possibly functional changes precede the onset of overt carbohydrate intolerance or diabetes ". Our study does not settle the debate, but can be used, with others, as evidence against the hypothesis. "
Department of Medicine, Guy’s Hospital Medical School, London S.E.1.
R.
J. JARRETT.
DIABETES MELLITUS IN PIMA INDIANS
SIR,-Dr. Keen and Dr. Jarrett (Aug. 14, p. 379) raise important points concerning the natural history of diabetes mellitus and its complications in general, and its occurrence among the Pima Indians in particular.l1 Although the frequency of diabetes among the Pima is indeed extraordinary, we have no reason to believe that the metabolic abnormality is any different from diabetes mellitus in other populations. 12,13 In addition to retinopathy, the Pima Indian diabetics manifest the same specific nephropathy, the same type of peripheral vascular disease, the same complications of pregnancy, and occasional typical ketoacidosis. They do, however, in common with other American Indian populations, appear to have less coronary heart-disease than Caucasians. We feel that the weight of evidence clearly leads to the conclusion that the disease is the same as in other populations and hence infer that the metabolic abnormality is characteristic of diabetes mellitus in general. A crucial issue concerns the extent to which the un-
equivocal bimodality in glucose-tolerance distributions, seen among the Pima, may be generalised to other populations. We have previously shown that the generalisation can be applied to the Asiatic (Tongaat) Indians of South Africa, and have suggested that bimodality might also be apparent if a sufficiently large sample of older persons in the U.S. White population were tested and analysed in the same way.14 Overt bimodality, however, is unlikely to
8. 9. 10. 11.
Gottlieb, M. S., Root, H. F. Diabetes, 1968, 17, 693. Joslin, E. P., Root, H., White, P., Marble, A. Treatment of Diabetes Mellitus; p. 49. Philadelphia, 1959. Then Berg, H. J. Am. med. Ass. 1939, 112, 1091. Then Berg, H. Z. ges. Neurol. Psychiat. 1939, 165, 278. Harvald, B., Hauge, M. Acta med. scand. 1963, 173, 459. Bennett, P. H., Burch, T. A., Miller, M. Lancet, July 17, 1971,
12.
p. 125. Miller, M., Bennett, P. H., Burch, T. A. in Biomedical Challenges;
6. 7.
p. 89. 1968.
Pan American Health
Organisation, Washington, D.C.,
Bennett, P. H., Miller, M., Burch, T. A., Ballintine, LeCompte, P. M. in Reports on Oral Diabetes Therapy; Amsterdam, 1971. 14. Steinberg, A. G., Rushforth, N. B., Bennett, P. H., Burch, Miller, M. in Pathogenesis of Diabetes Mellitus (edited Cerasi and R. Luft); p. 237. Stockholm, 1970. 13.
E.
J., p. 20.
T.
A.,
by
E.
be apparent in glucose-tolerance distributions if the prevalence of diabetes is relatively low, if those with already recognised diabetes are not tested and included in the distribution, and if the sample size is too small. The asymmetrical glucose-tolerance distributions, showing increasing degrees of skewing in the older age-groups seen in various populations, are compatible with the general " bimodal hypothesis ", since, if the hyperglycsemic component were relatively small, its presence would be obscured by the upper tail of the normal component. Indeed, when plotted on a log-log scale in an attempt to detect heterogeneity, the frequency distribution from the Bedford random sample demonstrated bimodality, 15 although, of course, the untransformed data did not. The differences between mean glucose levels in the Pima Indians, after removal of the hyperglycaemic component, and in Bedford may have several explanations, none of which bear directly on the validity of the bimodal hypothesis. The Pima are more obese than the Bedford subjects, and it seems likely that the first component of the glucose-tolerance distribution, especially in the younger age-groups, will contain many subjects who will later develop hyperglycasmia, and are, therefore, prediabetic. The somewhat higher mean glucose levels found in the Pima could be attributable to one or both of these factors, since both obese and prediabetic subjects show higher than normal mean glucose levels,16 or to other differences, such as the different glucose load used. There is no doubt that the Tongaat Indians, following a 50 g. oral-glucose load, have two-hour first-component mean glucose levels lower than the Pima, yet the frequency distributions conform to the general bimodal hypothesis.14 Dr. Keen and Dr. Jarrett suggest, however, that the high prevalence of diabetes in the older Pima Indians, with a diminishing prevalence in the younger age-groups, may be attributable to a cohort effect, associated with a diabetogenic insult of diminishing importance with time in the Piman environment. While possibly true this is speculative, and the prevalence curve, although of a different order of magnitude to that described in non-south-western American Indian populations, has a configuration similar to those elsewhere. The definitive explanation will be found by prospective study of the population, but on the basis of our prospective study at its present stage we suspect that the " age activation " hypothesis is more likely to be correct. RETINOPATHY
AND
2-HOUR
PLASMA-GLUCOSE
INDIANS AGED
35-74 YEARS
LEVEL
IN
PIMA
13
The
relationship of retinopathy to glucose intolerance probably not a simple one of degree of glucose intolerance. As the Bedford data indicate, and as is confirmed by Pima Indian data (see table), retinopathy is relatively rare in subjects with two-hour glucose-tolerance levels below 200 mg. per 100 ml., and is found mainly in subjects with is
glucose levels in excess of 250 analyse the groups that show the
mg. per 100 ml. most
If
we
convincing evidence
of diabetes at the time of survey, both the Bedford and the Pima data show that retinopathy is no more common in subjects with glucose levels in excess of 330 or 400 mg. per 100 ml., respectively, than in the groups with levels 15. 16.
Butterfield, W. J. H. in Diabetes (edited by J. Ostman); p. 653. Amsterdam, 1969. Fajans, S. S., Conn, J. W. in On the Nature and Treatment of Diabetes (edited by B. S. Leibel and G. A. Wrenshall); p. 641. Amsterdam, 1965.
*
Operation.
A 16-year-old boy was known to have transposition of -the great vessels, and had a shunt constructed between the inferior vena cava and left atrium at age 4. He was now admitted for corrective surgery. There was no history of unusual bleeding or bruising. Coagulation studies are shown in the accompanying table. Starting on day 2, E.A.C.A., 4 g. initially and then 1 g. hourly, was given by mouth. At 11 P.M. on day 3, the E.A.C.A. was changed to a constant intravenous infusion, so that he continued to receive 1 g. an hour. Blood was drawn at 8.30 A.M. on day 4 for coagulation studies, and the operation was started at 10.30 A.M. Because the coagulation studies also showed deterioration, the operation was discontinued. Beginning four hours after surgery, the patient lost approximately 700 ml. of blood from the closed incision. E.A.C.A. was continued intravenously for the next 5 days. At reoperation on day 9 no unusual bleeding was encountered, and the surgical reconstruction was completed uneventfully. Initial coagulation studies demonstrated decreased levels of factor v and fibrinogen, and marked shortening of the -euglobulin lysis-time. The excessive fibrinolysis in this patient was quite resistant to treatment with E.A.C.A. Immediately before and during the first operation, fibrinogen and plasminogen levels fell, and the euglobulin lysistimes became progressively shorter, despite the fact that the
patient was receiving E.A.C.A. Postoperatively, however, 1fibrinogen levels increased, indicating that fibrinolysis was now controlled. Heparin was employed only during the second operation as part of the routine for open-heart surgery. A decrease in the platelet-count after open-heart bypass surgery is commonly observed. Our experience with this patient supports the contention of Gralnickl4 that increased fibrinolysis in patients with cyanotic congenital heart-disease undergoing surgery is primary and should be managed with E.A.C.A. Northwestern UniversityMcGaw Medical Center,
Chicago, Illinois 60611, U.S.A.
DAVID GREEN.
URINARY ALBUMIN EXCRETION IN THE OFFSPRING OF CONJUGAL DIABETICS
SIR,-Dr. Soeldner and his co-workers (July 31, p. 239) report that the urinary albumin-excretion rate was the same in 96 offspring of two diabetic parents as in controls, and conclude that diabetic glomerulosclerosis is a consequence rather than a forerunner of the clinical disease. I doubt if they are justified in doing so. A previous study 1,2 showed a prevalence of diabetes of less than 5% among 656 offspring of conjugal diabetics, and gave grounds for thinking that no more than a quarter would ever develop 1. 2.
t Heparin in sample.
t Reoperation.
Cooke, A. M., Fitzgerald, M. G., Malins, J., Pyke, D. A. Br. med. J. 1966, ii, 674. Pyke, D. A. Postgrad. med. J. 1970, 46, 604.
the disease. Probably, therefore, only a minority of the persons studied by Dr. Soeldner and his co-workers are destined to become diabetic. The results from these individuals could have been diluted by those from the rest, leading to a false-negative conclusion. The authors use the term " genetic prediabetics " to describe the individuals in question, and point out that in Britain the term " potential diabetics " would be applied. This seems to imply that the two terms are similar, which they are not. A potential diabetic is a person at above-average risk of developing diabetes; a genetic prediabetic is a person destined, because of his genetic make-up, to develop diabetes. Such a person is unidentifiable. Even the identical twin of a diabetic is not certain to become diabetic. 3,4 This argument is not mere pedantry. Studies such as that of Dr. Soeldner and his co-workers may reveal less than their authors claim because they deal not with those certain to develop diabetes but with groups of persons most of whom never will. Diabetic Department, King’s College Hospital, London S.E.5.
D. A. PYKE.
The Boston and London workers received copies of this letter, and replies from Dr. Soeldner and Dr. Jarrett follow.-ED. L. SIR,-Dr. Pyke emphasises one of the problems of studies focused upon pre-" disease " states. Our last paragraph also points to this. It should be noted that one of the study groups of offspring of two diabetic parents (the diabetes-prone impaired-tolerance group) constituted 50% of the offspring of conjugal diabetics. No significant elevations of urinary albumin concentrations or urine albumin excretion-rates could be shown in this group of offspring with mild diabetes. Perhaps if this group with impaired tolerance is admitted to have " mild asymptomatic diabetes ", which conceivably could have been present for a long period of time before the repetitive glucose-tolerance tests, some significant increase of urinary albumin excretion should be apparent. Since it does not, one can only conclude that diabetic glomerulosclerosis does not precede the onset of carbohydrate intolerance. The prevalence of diabetes in persons with high genetic risk can only be truly shown by lifetime follow-up. In addition to the studies quoted by Dr. Pyke, evidence from this laboratory has indicated that chemical diabetes can be detected by repeated glucose-tolerance testing in 55-92% of the offspring of two diabetic parents, whereas only 9% show overt diabetes.5 This group from this Pyke, D. A., Cassar, J., Todd, J., Taylor, K. W. Br. med. J. 1970, iv, 649. 4. Malins, J., Cassar, J., Pyke, D. A. Diabetes, 1970, 19, 878. 5. Kahn, C. B., Soeldner, J. S., Gleason, R. E., Rojas, L., CameriniDavalos, R. A., Marble, A. New Engl. J. Med. 1969, 281, 343.
3.
488 same
laboratory
was
also
employed
for the urine albumin
studies. What perhaps is
more disturbing to me is the disbetween the crepancy frequency of chemical diabetes between many studies focused upon genetic prediabetic groups (offspring conjugal diabetics and monozygotic twins J. 2-66
Elliott P. Joslin Research Laboratory, Harvard Medical School, Boston, Mass. 02215, U.S.A.
J. STUART SOELDNER.
SIR,-Dr. Pyke at the end of his letter disclaims pedantry, having clearly demonstrated it in the earlier paragraphs. He must know that there are problems in transatlantic authorship-as Bernard Shaw said " we are two great nations divided by a common language ". In any case, we did not assume that the group under study were all going to develop diabetes, only that their higher risk was due to genetic factors. Dr. Pyke is no doubt aware that there is currently a passionate debate over the hypothesis that tissue and possibly functional changes precede the onset of overt carbohydrate intolerance or diabetes ". Our study does not settle the debate, but can be used, with others, as evidence against the hypothesis. "
Department of Medicine, Guy’s Hospital Medical School, London S.E.1.
R.
J. JARRETT.
DIABETES MELLITUS IN PIMA INDIANS
SIR,-Dr. Keen and Dr. Jarrett (Aug. 14, p. 379) raise important points concerning the natural history of diabetes mellitus and its complications in general, and its occurrence among the Pima Indians in particular.l1 Although the frequency of diabetes among the Pima is indeed extraordinary, we have no reason to believe that the metabolic abnormality is any different from diabetes mellitus in other populations. 12,13 In addition to retinopathy, the Pima Indian diabetics manifest the same specific nephropathy, the same type of peripheral vascular disease, the same complications of pregnancy, and occasional typical ketoacidosis. They do, however, in common with other American Indian populations, appear to have less coronary heart-disease than Caucasians. We feel that the weight of evidence clearly leads to the conclusion that the disease is the same as in other populations and hence infer that the metabolic abnormality is characteristic of diabetes mellitus in general. A crucial issue concerns the extent to which the un-
equivocal bimodality in glucose-tolerance distributions, seen among the Pima, may be generalised to other populations. We have previously shown that the generalisation can be applied to the Asiatic (Tongaat) Indians of South Africa, and have suggested that bimodality might also be apparent if a sufficiently large sample of older persons in the U.S. White population were tested and analysed in the same way.14 Overt bimodality, however, is unlikely to
8. 9. 10. 11.
Gottlieb, M. S., Root, H. F. Diabetes, 1968, 17, 693. Joslin, E. P., Root, H., White, P., Marble, A. Treatment of Diabetes Mellitus; p. 49. Philadelphia, 1959. Then Berg, H. J. Am. med. Ass. 1939, 112, 1091. Then Berg, H. Z. ges. Neurol. Psychiat. 1939, 165, 278. Harvald, B., Hauge, M. Acta med. scand. 1963, 173, 459. Bennett, P. H., Burch, T. A., Miller, M. Lancet, July 17, 1971,
12.
p. 125. Miller, M., Bennett, P. H., Burch, T. A. in Biomedical Challenges;
6. 7.
p. 89. 1968.
Pan American Health
Organisation, Washington, D.C.,
Bennett, P. H., Miller, M., Burch, T. A., Ballintine, LeCompte, P. M. in Reports on Oral Diabetes Therapy; Amsterdam, 1971. 14. Steinberg, A. G., Rushforth, N. B., Bennett, P. H., Burch, Miller, M. in Pathogenesis of Diabetes Mellitus (edited Cerasi and R. Luft); p. 237. Stockholm, 1970. 13.
E.
J., p. 20.
T.
A.,
by
E.
be apparent in glucose-tolerance distributions if the prevalence of diabetes is relatively low, if those with already recognised diabetes are not tested and included in the distribution, and if the sample size is too small. The asymmetrical glucose-tolerance distributions, showing increasing degrees of skewing in the older age-groups seen in various populations, are compatible with the general " bimodal hypothesis ", since, if the hyperglycsemic component were relatively small, its presence would be obscured by the upper tail of the normal component. Indeed, when plotted on a log-log scale in an attempt to detect heterogeneity, the frequency distribution from the Bedford random sample demonstrated bimodality, 15 although, of course, the untransformed data did not. The differences between mean glucose levels in the Pima Indians, after removal of the hyperglycaemic component, and in Bedford may have several explanations, none of which bear directly on the validity of the bimodal hypothesis. The Pima are more obese than the Bedford subjects, and it seems likely that the first component of the glucose-tolerance distribution, especially in the younger age-groups, will contain many subjects who will later develop hyperglycasmia, and are, therefore, prediabetic. The somewhat higher mean glucose levels found in the Pima could be attributable to one or both of these factors, since both obese and prediabetic subjects show higher than normal mean glucose levels,16 or to other differences, such as the different glucose load used. There is no doubt that the Tongaat Indians, following a 50 g. oral-glucose load, have two-hour first-component mean glucose levels lower than the Pima, yet the frequency distributions conform to the general bimodal hypothesis.14 Dr. Keen and Dr. Jarrett suggest, however, that the high prevalence of diabetes in the older Pima Indians, with a diminishing prevalence in the younger age-groups, may be attributable to a cohort effect, associated with a diabetogenic insult of diminishing importance with time in the Piman environment. While possibly true this is speculative, and the prevalence curve, although of a different order of magnitude to that described in non-south-western American Indian populations, has a configuration similar to those elsewhere. The definitive explanation will be found by prospective study of the population, but on the basis of our prospective study at its present stage we suspect that the " age activation " hypothesis is more likely to be correct. RETINOPATHY
AND
2-HOUR
PLASMA-GLUCOSE
INDIANS AGED
35-74 YEARS
LEVEL
IN
PIMA
13
The
relationship of retinopathy to glucose intolerance probably not a simple one of degree of glucose intolerance. As the Bedford data indicate, and as is confirmed by Pima Indian data (see table), retinopathy is relatively rare in subjects with two-hour glucose-tolerance levels below 200 mg. per 100 ml., and is found mainly in subjects with is
glucose levels in excess of 250 analyse the groups that show the
mg. per 100 ml. most
If
we
convincing evidence
of diabetes at the time of survey, both the Bedford and the Pima data show that retinopathy is no more common in subjects with glucose levels in excess of 330 or 400 mg. per 100 ml., respectively, than in the groups with levels 15. 16.
Butterfield, W. J. H. in Diabetes (edited by J. Ostman); p. 653. Amsterdam, 1969. Fajans, S. S., Conn, J. W. in On the Nature and Treatment of Diabetes (edited by B. S. Leibel and G. A. Wrenshall); p. 641. Amsterdam, 1965.