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GROWTH IN DIABETIC CHILDREN
Saturday
GROWTH IN DIABETIC CHILDREN Studies in Identical Twins R. B. TATTERSALL Diabetic
D. A. PYKE
Department, King’s College Hospital, London SE5 9RS An
inquiry to determine whether early-onset diabetes leads to retardation of growth and development is described. Healthy monozygotic twins are normally very similar in height and therefore provide ideal comparisons for the effect of disease on height. The adult height Summary
and age of menarche in 35 young-onset identicaltwin pairs, one or both of whom has diabetes, have been studied. In all but one of 12 pairs in which one twin developed diabetes before puberty and the other did not, the affected twin was shorter; the mean difference was 2¼ in., which is much more than would be expected by chance. In the pairs in which diabetes appeared after puberty in one or both twins there was no significant difference in height. When both twins developed diabetes before puberty, again there was no significant difference in height. In 2 pairs of girl twins in whom diabetes appeared before puberty in one but not in the other, menarche was 4 and 5 years later in the affected than in the unaffected twin, whereas in the other pairs the difference was only about 1 month. These differences were seen despite apparently satisfactory diabetic control. It is concluded that diabetes of early onset leads to retardation of growth and development, even when its treatment is adequate as judged by conventional criteria, that these criteria are inadequate, and that the control of insulin-dependent diabetes is almost always poor.
17 November 1973
Introduction IN the early days of insulin treatment gross retardation of physical and sexual development in diabetic children was common.1 With improved treatment it was expected that this failure of growth could be prevented, and " diabetic dwarfism" was said to have disappeared between 1935 and 1945 2 Nevertheless, later series have still shown retardation of the height of diabetic children diagnosed before the growth-spurt years.3-5 Interpretation of published results is difficult because it is not always clear whether the shortness of the diabetics as a group is due to a general diminution of all patients or the stunting of a few, and there is difficulty in obtaining suitable controls. Whiter in her large series from the Joslin Clinic, attempted to circumvent this difficulty by comparing the height of diabetic children with their nondiabetic siblings; she found no significant difference. We have investigated the effect of early-onset diabetes on growth and development in identical twins: since healthy twins are normally of the same height 1,8 they are ideal subjects for studies on the effect of disease on growth. Since the suggestion has also been made that there is a delay in the menarche of girls who develop diabetes before puberty,9 we have investigated the age at menarche in these twins.
Patients and Methods Our entire series consists of 96 pairs of identical twins both of whom has diabetes; a general description has already been published 1° We are concerned with 35 pairs in which the index twin developed diabetes before the age of 30. The whole series contains 49 pairs in which the index twin was diagnosed before the age of 30, but 14 one or
TABLE I-PAIRS WITH ONE TWIN DIAGNOSED BEFORE PUBERTY, THE OTHER BEING NON-DIABETIC: GROUP 1
7838
1106 included in the present study because of death inaccessibility. All the diabetic twins were on insulin and all pairs were brought up together. Monozygosity was established by clinical examination and by typing for the blood-groups ABO, CDE, MN, S, P, Lua, K, Lea, and Fya. The error in diagnosing monozygosity by this method does not exceed 3%. In most cases both members of a pair were examined, and their standing height was measured at the same time either in the clinic or in their homes. Information about previous height was obtained from hospital notes and from records kept by the parents. The age at the menarche was obtained from the twins themselves or their mothers. The exact age at which it occurred may not always have been reliable, but patients could always remember with confidence the interval between their first menstrual period and their twin’s. Assessment of diabetic control is always difficult and was complicated in this study because records of bloodsugars and urine tests for the period before puberty were often either unobtainable or inadequate. As far as possible, objective criteria were used, but we have also included our own assessment of control, taking account of how conscientiously the patients had managed their diabetes. If diabetes retards growth one might expect to see an effect in those who develop diabetes before puberty (here defined as the 13th birthday) but none, or a smaller effect, in those who do so later. We have therefore divided the twins into five groups: Diabetes Diagnosed before Puberty in One Twin but not in the Other Group 1.-7 discordant pairs in which the diabetic twin was diagnosed before puberty and the other has remained unaffected (table i). Group 2.-5 concordant pairs in which one twin developed diabetes before puberty and the other afterwards are not
or
(table 11).
Diagnosed before Puberty in Both Twins Group 3.-6 concordant pairs in which both twins developed diabetes before puberty (table ill).
Diabetes
Diabetes
Diagnosed after Puberty in One or Group 4.-10 discordant pairs in which
Both Twins the diabetic
was diagnosed after puberty and the other twin is unaffected (table iv). Group 5.-7 concordant pairs in which both twins developed diabetes after puberty (table v).
twin
Results
Height have a few records of the of the twins at the time of diagnosis of diabetes in the index twin; in other cases we have had to rely on the memory of the twins themselves or their parents. In all cases, differences in height between the twins were noted or recollected as being negligible; in no case was the difference as much as 1 in. (2’5 cm.). At the time ofexamination.-In healthy pairs the first-born twin will as often be taller than the second as vice versa (i.e., the net difference in height between identical twins is nil). Only 2% of pairs brought up together, as our twins were, differ by as much as 1-5 in. (3’75 cm.).8 In the two groups in which one twin became diabetic before puberty and the other was not diabetic (group 1) or became so only after puberty (group 2), the prepubertal diabetic twin was,shorter by an average of 2-3 in. (5’8 cm.), a highly significant difference (tables I and II). Of the 12 pairs in these groups the first (or only) diagnosed twin was shorter in 11, in 7 cases by more than 1-5 in. (3-75 cm.), and taller in none. The smallest differences were found in those pairs who had not yet reached puberty; if only the twin pairs are considered who had reached adulthood, the index twin was, on average, 3 in. (7-5 cm.) shorter. Where both twins developed diabetes before puberty (group 3), in all cases within 3 years of one another, their heights were similar, the mean difference being only 0-3 in. (0-76 cm.) (table ill). If the
At
diagnosis.-We
height
TABLE II-PAIRS WITH ONE TWIN DIAGNOSED BEFORE
PUBERTY, THE
OTHER AFTERWARDS: GROUP
TABLE III-BOTH TWINS DIAGNOSED BEFORE PUBERTY: GROUP
3
2
1107
TABLE IV-ONE DIABETIC TWIN DIAGNOSED AFTER PUBERTY, THE OTHER BEING NON-DIABETIC: GROUP 4
TABLE V-BOTH TWINS DIAGNOSED AFTER PUBERTY: GROUP
pair (18) who were still prepubertal (the twin developing diabetes at age seven being 1.5 in. shorter than the one diagnosed two years later) is excluded the adult height of the twins was almost identical, the mean difference being 0-1 in. (0.25 cm.). Where one or both twins develop diabetes after puberty (groups 4 and 5) the intrapair differences The mean difference were small (tables IV and v). of both groups was 0.2 in. (0.5 cm.) and none of the 17 pairs differed by more than 1.5 in. (3.75 cm.).
5
menarche of the diabetic girls was 4 and 5 years later than that of their unaffected twins. (The third pair in this group (no. 5, table l) have not yet reached their menarche.) All the 5 pairs of group 2 (one twin diagnosed before puberty, the other after it) were male.
Weight At diagnosis.-Obesity is seldom important in the xtiology of juvenile diabetes, and in discordant identical twins there is
Menarche The age
no
evidence that it is the
(table VI)j
the menarche is a convenient measure of development. In healthy monozygotic twins the mean intrapair difference is only 2.8 months, whereas in dizygotic twins and sisters it is over a year.12 Although numbers in this study are small there are wide differences. Where both twins developed diabetes before puberty (group 3) the interval was a month or less in 3 of the 4 pairs. In the fourth (no. 16, table vi) the interval of eighteen months is explained by one of the twins having the SteinLeventhal syndrome. The other also has oligomenorrhoea and may well be similarly affected. Where one or both twins developed diabetes after puberty (groups 4 and 5) the mean interval was 1.7 months. Thus in 10 out of 12 pairs in these three groups, the menarche was within 3 months in both Numbers are too small and memory too twins. unreliable to decide whether the menarche was delayed in those pairs both of whom developed diabetes before puberty (group 3) compared to those twins who developed it later (groups 4 and 5). The two pairs of group 1, where one twin developed diabetes before puberty and the other is still non-diabetic, provide a striking contrast. The
TABLE VI-AGE AT MENARCHE
at
Pairs 15, 26, and 28 are excluded because they could not remember any details and pair 18 because neither twin has reached the menarche.
1108 TABLE VII-DIABETIC CONTROL
(IN
THE PERIOD FROM DIAGNOSIS TO
b.d.=twiceaday.
OF TWINS DIAGNOSED BEFORE PUBERTY
PZI=Protamine-zinc insulin.
fatter twin who becomes diabetic." As far as we can tell from hospital records of the twins and from information supplied by their parents the intrapair differences in weight at the time of diagnosis in the index twin were always small. Of 29 pairs of discordant twins about whose weight at the time of diagnosis we have accurate information, 19 pairs did not differ by more than 6 lb. (2700 g.); in 4 pairs the diabetic twin was heavier, in the other 6 the non-diabetic was heavier. At the time ofexamination.-Weight is influenced more by environmental than by genetic factors,12,13 and even identical twins do not show a close intrapair correlation for weight. The weight of the twins in this series at the time of examination has little significance because of the presence of diabetes and its treatment. In groups 1 and 2 the mean intrapair differences were 3 lb. (1360 g.) and 12 lb. (5450 g.), respectively, the non-diabetic or second diagnosed twin being the heavier as well as taller. In group 3 the first diagnosed twin was heavier by 4 lb. (1820 g.). In group 4 the diabetic twin was 8 lb. (3640 g.) heavier than his non-diabetic co-twin; in group 5 the mean intrapair difference was only 1 lb.
(450 g.). Diabetic Control Table vn shows the data about control which have been able to collect. The relevant period is the time between diagnosis and puberty, which in many cases was several years before we examined the twins. Only 2 pairs were attending King’s College Hospital during this period. The lapse of time has added to the inevitable difficulty of assessing such an imprecise feature as control of diabetes. We have not assessed control of either twin in groups 3, 4, and 5, and in group 2 only of the twin who developed diabetes before puberty. As far as the data go, they show a reasonable degree of control of diabetes. None of the patients was badly controlled, except perhaps for the diabetic twin in pair 2 who was the only one of the 12 in groups 1 and 2 to have been in diabetic precoma more than once. On our assessment from the data available of the control of the twins in groups 1 and
we
PUBERTY)
(GROUPS
1 AND
2)
CHO= Carbohydrate.
we rated it as " good " in 5, " fair " in 4, and poor " in 3. Eight of the twins had been treated with a single daily injection, of whom two had been changed to soluble insulin, and four with twice-daily injections of soluble insulin from the outset. Seven were on measured carbohydrate diets and five on
2 "
free diets.
Discussion Most published series show retardation of growth of diabetic children, especially when diabetes is diagnosed before the growth-spurt years.3,4,14 However, it is not always clear from these reports whether the overall retardation was common to all diabetic children or due only to the inclusion of some very stunted individuals among diabetic children of normal height. The failure of growth in diabetic children has been attributed to poor control Other by some,4,15,16,19 and denied by others 1’>18 suggested causes are genetic factors 1,19 and poor
nutrition 20 Our results show that diabetics diagnosed before puberty consistently became shorter than their unaffected identical twins. The data we have indicate that at the time of diagnosis of diabetes in the index twin the twins were of the same height. Certainly we have no evidence that the diabetic twin was shorter when diabetes was diagnosed; it has even been suggested that diabetic children may be abnormally tall at the time of diagnosis 4>s It seems inescapable, therefore, that the differences we found were due to retardation of growth of the diabetic twin after the time of diagnosis. Many children whose growth is retarded during a severe acute illness show a "catch-up" after recovery.21 Beal14 reported a catch-up in the growth of diabetic children in their late teens, although this was not seen by others.3,22 Our results show that the diabetic twins do not catch up; their adult height is lower than that of their non-diabetic cotwins.
Some workers have
suggested that retardation of
growth of diabetic children is greater in boys than
girls .4,11,12 this
Our
study suggestion. Only
neither supports nor refutes 3 of the pairs in groups 1 and
1109 were female, but in all these the index twin was shorter, which does not suggest that girls are immune to the growth-retarding effect of early-onset diabetes. On the other hand, the mean height of the twelve female diabetic twins diagnosed before puberty who have reached adulthood was only 1-8 in. (4-5 cm.) less than that of the twelve diagnosed after it and only 0-8 in. (2 cm.) less than the 8 non-diabetic twins, whereas among the corresponding groups of males (numbering five, fourteen, and fifteen, respectively) the differences were larger, 6-3 in. (15-75 cm.) and 4-7 in. (11-75 cm.). All the twins lived together during the growthspurt period, and the general standard of nutrition, apart from carbohydrate restriction in the diabetic twin, seemed to be good and to be similar for both, so that inadequate diet alone is unlikely to account for the retardation. Retardation of growth in groups 1 and 2 was just as severe in those on free as in those on restricted diets. The twins were not of the diabetic twins one undernourished; only more before was than 10% below diagnosed puberty the expected weight for height, and so was her nondiabetic co-twin. An explanation for the retardation of growth is that twins with onset of diabetes before puberty were badly controlled. However, since as many as eleven out of twelve were shorter, it would have been remarkable if they had all been exceptionally badly controlled. Objective assessment of diabetic control is always difficult, but according to our estimates it was adequate in these twins. Certainly there was nothing to suggest that it was unusually bad. Most had made a conscientious attempt at good treatment, as judged by the number of urine tests and the regularity of clinic visits, and had avoided ketoacidosis. Only one had been in precoma more than once. We conclude that growth retardation occurs in nearly all diabetic children, including those whose standard of control would generally be accepted as
2
(nos. 2, 3, and 5)
cases
adequate. are familiar with the clinical situation of a child failing to grow who, when treattreated badly ment is improved-perhaps by starting insulinthen does so. It seems that retardation of growth and development are a more sensitive index of diabetic control than we had supposed, reflecting not merely downright bad control but even the imperfection of control which is usually regarded
We
as
acceptable. If this interpretation
is correct, we have some learn about the treatment of diabetes, generally as well as in the young. We know that really good control of blood-sugar is of crucial importance in the outcome of pregnancy in the diabetic. It now seems that the same may be true for the growth of the child diabetic. Thus, we have two easily measurable indices-fetal survival and bodily growth-by which to judge the results of treatment, and find that they are still far from good. We have accepted the lessons of the poor results of the treatment of diabetic pregnancy in the past and now attempt near-physiological control
lessons
to
of blood-sugar during pregnancy.23 Perhaps we should do the same with young diabetic children. These results show-if it still needs showing-that " " " when we speak of good " or satisfactory or even " adequate " control of insulin-dependent diabetes, When assessed by critical we are deluding ourselves. indices we see that our control is almost always poor-sometimes fairly poor, sometimes very poorbut hardly ever good. Normally blood-sugar varies by only 20-30 mg. per 100 ml. during the 24 hours. This is true of only a tiny minority of insulindependent diabetics; in most the swings are much
greater. We have
long way to go to achieve control of blood-sugar approaching the physiological, but the attempt to achieve it is worth making. However, we are doubtful whether we can greatly improve on current standards of treatment of diabetes by present methods. Perhaps the glucose sensor 24 will provide a
the solution? We thank the twins for their cooperation in this and other and many colleagues and the British Diabetic Association for referring them; Mr Geoffrey Stevens for statistical advice; and Mrs A. M. Spink for much secretarial help. R. B. T. is supported by a grant from the Nuffield Foundation. Requests for reprints should be addressed to D. A. P.
studies,
REFERENCES 1. Wagner, R., White, P., Bogan, I. K. Am. J. Dis. Child. 1942, 63, 667. 2. White, P., Graham, C. A. Joslin’s Diabetes Mellitus; p. 347. Philadelphia, 1971. 3. Knowles, H. C., Jr., Guest, G. M., Lampe, J., Kessler, M., Skillman, T. G. Diabetes, 1965, 14, 239. 4. Pond, H. Postgrad. med. J. 1970, 46, 616. 5. Evans, N., Robinson, V. P., Lister, J. Archs Dis. Childh. 1972, 47, 589. 6. White, P. Diabetes, 1960, 9, 345. 7. Newman, H. H., Freeman, F. N., Holzinger, K. J. Twins: A Study of Heredity and Environment. Chicago, 1937. 8. Shields, J. Monozygotic Twins Brought up Together and Apart. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20. 21.
London, 1962. Post, R. H., White, P. Diabetes, 1958, 7, 27. Tattersall, R. B., Pyke, D. A. Lancet, 1972, ii, 1120. Wilson, R. S. Hum. Hered. 1970, 20, 30. Tanner, J. M. Growth at Adolescence. Oxford, 1962. Osborne, R. H., De George, F. V. The Genetic Basis of Morphological Variation. Cambridge, Mass., 1959. Beal, C. K. J. Pediat. 1948, 32, 170. Jackson, R. L., Kelly, H. G. ibid. 1946, 29, 316. Bergquist, N. Acta endocr., Copenh. 1954, 15, 133. Sterky, G. Acta pœdiat. 1963, suppl. 144, p. 13. Craig, J. O. Postgrad. med. J. 1970, 46, 607. Hamne, B. Acta pœdiat. 1962, suppl. 135, p. 72. Boyd, J. D., Kantrow, A. H. Am. J. Dis. Child. 1938, 55, 460. Prader, A., Tanner, J. M., Von Harnack, G. A. J. Pediat. 1963, 62,
646. 22. Larsson, Y., Sterky, G. Acta pœdiat. 1962, suppl. 130, p. 20. 23. Essex, N. L., Pyke, D. A., Watkins, P. J., Brudenell, J. M., Gamsu, H. R. Br. med. J. 1973, iv, 89. 24. Soeldner, J. S., Chang, K. W., Hiebert, J. M., Aisenberg, S.
Diabetes, 1973, 22, suppl. 1, p. 294. "
The lower reaches of the Rhine-a water source for 6 million people-may often contain 40% of sewage effluent, and this may rise to nearly 100% in periods of low flow. The Thames, which provides two-thirds of the water supply for the Greater London area, contains about 14% of sewage effluent when flowing at an average rate. In times of drought, the water supply source for Agra, India, consists almost entirely of partially treated sewage from New Delhi, 190 km away.... The use of such rivers as sources of domestic water supply, despite the increasing
nearly
of waste they contain, creates a potential health hazard because the water withdrawn continues to be treated by conventional methods ... "-W.H.O. Chron. 1973, 27, 493.
proportions
GROWTH IN DIABETIC CHILDREN Studies in Identical Twins R. B. TATTERSALL Diabetic
D. A. PYKE
Department, King’s College Hospital, London SE5 9RS An
inquiry to determine whether early-onset diabetes leads to retardation of growth and development is described. Healthy monozygotic twins are normally very similar in height and therefore provide ideal comparisons for the effect of disease on height. The adult height Summary
and age of menarche in 35 young-onset identicaltwin pairs, one or both of whom has diabetes, have been studied. In all but one of 12 pairs in which one twin developed diabetes before puberty and the other did not, the affected twin was shorter; the mean difference was 2¼ in., which is much more than would be expected by chance. In the pairs in which diabetes appeared after puberty in one or both twins there was no significant difference in height. When both twins developed diabetes before puberty, again there was no significant difference in height. In 2 pairs of girl twins in whom diabetes appeared before puberty in one but not in the other, menarche was 4 and 5 years later in the affected than in the unaffected twin, whereas in the other pairs the difference was only about 1 month. These differences were seen despite apparently satisfactory diabetic control. It is concluded that diabetes of early onset leads to retardation of growth and development, even when its treatment is adequate as judged by conventional criteria, that these criteria are inadequate, and that the control of insulin-dependent diabetes is almost always poor.
17 November 1973
Introduction IN the early days of insulin treatment gross retardation of physical and sexual development in diabetic children was common.1 With improved treatment it was expected that this failure of growth could be prevented, and " diabetic dwarfism" was said to have disappeared between 1935 and 1945 2 Nevertheless, later series have still shown retardation of the height of diabetic children diagnosed before the growth-spurt years.3-5 Interpretation of published results is difficult because it is not always clear whether the shortness of the diabetics as a group is due to a general diminution of all patients or the stunting of a few, and there is difficulty in obtaining suitable controls. Whiter in her large series from the Joslin Clinic, attempted to circumvent this difficulty by comparing the height of diabetic children with their nondiabetic siblings; she found no significant difference. We have investigated the effect of early-onset diabetes on growth and development in identical twins: since healthy twins are normally of the same height 1,8 they are ideal subjects for studies on the effect of disease on growth. Since the suggestion has also been made that there is a delay in the menarche of girls who develop diabetes before puberty,9 we have investigated the age at menarche in these twins.
Patients and Methods Our entire series consists of 96 pairs of identical twins both of whom has diabetes; a general description has already been published 1° We are concerned with 35 pairs in which the index twin developed diabetes before the age of 30. The whole series contains 49 pairs in which the index twin was diagnosed before the age of 30, but 14 one or
TABLE I-PAIRS WITH ONE TWIN DIAGNOSED BEFORE PUBERTY, THE OTHER BEING NON-DIABETIC: GROUP 1
7838
1106 included in the present study because of death inaccessibility. All the diabetic twins were on insulin and all pairs were brought up together. Monozygosity was established by clinical examination and by typing for the blood-groups ABO, CDE, MN, S, P, Lua, K, Lea, and Fya. The error in diagnosing monozygosity by this method does not exceed 3%. In most cases both members of a pair were examined, and their standing height was measured at the same time either in the clinic or in their homes. Information about previous height was obtained from hospital notes and from records kept by the parents. The age at the menarche was obtained from the twins themselves or their mothers. The exact age at which it occurred may not always have been reliable, but patients could always remember with confidence the interval between their first menstrual period and their twin’s. Assessment of diabetic control is always difficult and was complicated in this study because records of bloodsugars and urine tests for the period before puberty were often either unobtainable or inadequate. As far as possible, objective criteria were used, but we have also included our own assessment of control, taking account of how conscientiously the patients had managed their diabetes. If diabetes retards growth one might expect to see an effect in those who develop diabetes before puberty (here defined as the 13th birthday) but none, or a smaller effect, in those who do so later. We have therefore divided the twins into five groups: Diabetes Diagnosed before Puberty in One Twin but not in the Other Group 1.-7 discordant pairs in which the diabetic twin was diagnosed before puberty and the other has remained unaffected (table i). Group 2.-5 concordant pairs in which one twin developed diabetes before puberty and the other afterwards are not
or
(table 11).
Diagnosed before Puberty in Both Twins Group 3.-6 concordant pairs in which both twins developed diabetes before puberty (table ill).
Diabetes
Diabetes
Diagnosed after Puberty in One or Group 4.-10 discordant pairs in which
Both Twins the diabetic
was diagnosed after puberty and the other twin is unaffected (table iv). Group 5.-7 concordant pairs in which both twins developed diabetes after puberty (table v).
twin
Results
Height have a few records of the of the twins at the time of diagnosis of diabetes in the index twin; in other cases we have had to rely on the memory of the twins themselves or their parents. In all cases, differences in height between the twins were noted or recollected as being negligible; in no case was the difference as much as 1 in. (2’5 cm.). At the time ofexamination.-In healthy pairs the first-born twin will as often be taller than the second as vice versa (i.e., the net difference in height between identical twins is nil). Only 2% of pairs brought up together, as our twins were, differ by as much as 1-5 in. (3’75 cm.).8 In the two groups in which one twin became diabetic before puberty and the other was not diabetic (group 1) or became so only after puberty (group 2), the prepubertal diabetic twin was,shorter by an average of 2-3 in. (5’8 cm.), a highly significant difference (tables I and II). Of the 12 pairs in these groups the first (or only) diagnosed twin was shorter in 11, in 7 cases by more than 1-5 in. (3-75 cm.), and taller in none. The smallest differences were found in those pairs who had not yet reached puberty; if only the twin pairs are considered who had reached adulthood, the index twin was, on average, 3 in. (7-5 cm.) shorter. Where both twins developed diabetes before puberty (group 3), in all cases within 3 years of one another, their heights were similar, the mean difference being only 0-3 in. (0-76 cm.) (table ill). If the
At
diagnosis.-We
height
TABLE II-PAIRS WITH ONE TWIN DIAGNOSED BEFORE
PUBERTY, THE
OTHER AFTERWARDS: GROUP
TABLE III-BOTH TWINS DIAGNOSED BEFORE PUBERTY: GROUP
3
2
1107
TABLE IV-ONE DIABETIC TWIN DIAGNOSED AFTER PUBERTY, THE OTHER BEING NON-DIABETIC: GROUP 4
TABLE V-BOTH TWINS DIAGNOSED AFTER PUBERTY: GROUP
pair (18) who were still prepubertal (the twin developing diabetes at age seven being 1.5 in. shorter than the one diagnosed two years later) is excluded the adult height of the twins was almost identical, the mean difference being 0-1 in. (0.25 cm.). Where one or both twins develop diabetes after puberty (groups 4 and 5) the intrapair differences The mean difference were small (tables IV and v). of both groups was 0.2 in. (0.5 cm.) and none of the 17 pairs differed by more than 1.5 in. (3.75 cm.).
5
menarche of the diabetic girls was 4 and 5 years later than that of their unaffected twins. (The third pair in this group (no. 5, table l) have not yet reached their menarche.) All the 5 pairs of group 2 (one twin diagnosed before puberty, the other after it) were male.
Weight At diagnosis.-Obesity is seldom important in the xtiology of juvenile diabetes, and in discordant identical twins there is
Menarche The age
no
evidence that it is the
(table VI)j
the menarche is a convenient measure of development. In healthy monozygotic twins the mean intrapair difference is only 2.8 months, whereas in dizygotic twins and sisters it is over a year.12 Although numbers in this study are small there are wide differences. Where both twins developed diabetes before puberty (group 3) the interval was a month or less in 3 of the 4 pairs. In the fourth (no. 16, table vi) the interval of eighteen months is explained by one of the twins having the SteinLeventhal syndrome. The other also has oligomenorrhoea and may well be similarly affected. Where one or both twins developed diabetes after puberty (groups 4 and 5) the mean interval was 1.7 months. Thus in 10 out of 12 pairs in these three groups, the menarche was within 3 months in both Numbers are too small and memory too twins. unreliable to decide whether the menarche was delayed in those pairs both of whom developed diabetes before puberty (group 3) compared to those twins who developed it later (groups 4 and 5). The two pairs of group 1, where one twin developed diabetes before puberty and the other is still non-diabetic, provide a striking contrast. The
TABLE VI-AGE AT MENARCHE
at
Pairs 15, 26, and 28 are excluded because they could not remember any details and pair 18 because neither twin has reached the menarche.
1108 TABLE VII-DIABETIC CONTROL
(IN
THE PERIOD FROM DIAGNOSIS TO
b.d.=twiceaday.
OF TWINS DIAGNOSED BEFORE PUBERTY
PZI=Protamine-zinc insulin.
fatter twin who becomes diabetic." As far as we can tell from hospital records of the twins and from information supplied by their parents the intrapair differences in weight at the time of diagnosis in the index twin were always small. Of 29 pairs of discordant twins about whose weight at the time of diagnosis we have accurate information, 19 pairs did not differ by more than 6 lb. (2700 g.); in 4 pairs the diabetic twin was heavier, in the other 6 the non-diabetic was heavier. At the time ofexamination.-Weight is influenced more by environmental than by genetic factors,12,13 and even identical twins do not show a close intrapair correlation for weight. The weight of the twins in this series at the time of examination has little significance because of the presence of diabetes and its treatment. In groups 1 and 2 the mean intrapair differences were 3 lb. (1360 g.) and 12 lb. (5450 g.), respectively, the non-diabetic or second diagnosed twin being the heavier as well as taller. In group 3 the first diagnosed twin was heavier by 4 lb. (1820 g.). In group 4 the diabetic twin was 8 lb. (3640 g.) heavier than his non-diabetic co-twin; in group 5 the mean intrapair difference was only 1 lb.
(450 g.). Diabetic Control Table vn shows the data about control which have been able to collect. The relevant period is the time between diagnosis and puberty, which in many cases was several years before we examined the twins. Only 2 pairs were attending King’s College Hospital during this period. The lapse of time has added to the inevitable difficulty of assessing such an imprecise feature as control of diabetes. We have not assessed control of either twin in groups 3, 4, and 5, and in group 2 only of the twin who developed diabetes before puberty. As far as the data go, they show a reasonable degree of control of diabetes. None of the patients was badly controlled, except perhaps for the diabetic twin in pair 2 who was the only one of the 12 in groups 1 and 2 to have been in diabetic precoma more than once. On our assessment from the data available of the control of the twins in groups 1 and
we
PUBERTY)
(GROUPS
1 AND
2)
CHO= Carbohydrate.
we rated it as " good " in 5, " fair " in 4, and poor " in 3. Eight of the twins had been treated with a single daily injection, of whom two had been changed to soluble insulin, and four with twice-daily injections of soluble insulin from the outset. Seven were on measured carbohydrate diets and five on
2 "
free diets.
Discussion Most published series show retardation of growth of diabetic children, especially when diabetes is diagnosed before the growth-spurt years.3,4,14 However, it is not always clear from these reports whether the overall retardation was common to all diabetic children or due only to the inclusion of some very stunted individuals among diabetic children of normal height. The failure of growth in diabetic children has been attributed to poor control Other by some,4,15,16,19 and denied by others 1’>18 suggested causes are genetic factors 1,19 and poor
nutrition 20 Our results show that diabetics diagnosed before puberty consistently became shorter than their unaffected identical twins. The data we have indicate that at the time of diagnosis of diabetes in the index twin the twins were of the same height. Certainly we have no evidence that the diabetic twin was shorter when diabetes was diagnosed; it has even been suggested that diabetic children may be abnormally tall at the time of diagnosis 4>s It seems inescapable, therefore, that the differences we found were due to retardation of growth of the diabetic twin after the time of diagnosis. Many children whose growth is retarded during a severe acute illness show a "catch-up" after recovery.21 Beal14 reported a catch-up in the growth of diabetic children in their late teens, although this was not seen by others.3,22 Our results show that the diabetic twins do not catch up; their adult height is lower than that of their non-diabetic cotwins.
Some workers have
suggested that retardation of
growth of diabetic children is greater in boys than
girls .4,11,12 this
Our
study suggestion. Only
neither supports nor refutes 3 of the pairs in groups 1 and
1109 were female, but in all these the index twin was shorter, which does not suggest that girls are immune to the growth-retarding effect of early-onset diabetes. On the other hand, the mean height of the twelve female diabetic twins diagnosed before puberty who have reached adulthood was only 1-8 in. (4-5 cm.) less than that of the twelve diagnosed after it and only 0-8 in. (2 cm.) less than the 8 non-diabetic twins, whereas among the corresponding groups of males (numbering five, fourteen, and fifteen, respectively) the differences were larger, 6-3 in. (15-75 cm.) and 4-7 in. (11-75 cm.). All the twins lived together during the growthspurt period, and the general standard of nutrition, apart from carbohydrate restriction in the diabetic twin, seemed to be good and to be similar for both, so that inadequate diet alone is unlikely to account for the retardation. Retardation of growth in groups 1 and 2 was just as severe in those on free as in those on restricted diets. The twins were not of the diabetic twins one undernourished; only more before was than 10% below diagnosed puberty the expected weight for height, and so was her nondiabetic co-twin. An explanation for the retardation of growth is that twins with onset of diabetes before puberty were badly controlled. However, since as many as eleven out of twelve were shorter, it would have been remarkable if they had all been exceptionally badly controlled. Objective assessment of diabetic control is always difficult, but according to our estimates it was adequate in these twins. Certainly there was nothing to suggest that it was unusually bad. Most had made a conscientious attempt at good treatment, as judged by the number of urine tests and the regularity of clinic visits, and had avoided ketoacidosis. Only one had been in precoma more than once. We conclude that growth retardation occurs in nearly all diabetic children, including those whose standard of control would generally be accepted as
2
(nos. 2, 3, and 5)
cases
adequate. are familiar with the clinical situation of a child failing to grow who, when treattreated badly ment is improved-perhaps by starting insulinthen does so. It seems that retardation of growth and development are a more sensitive index of diabetic control than we had supposed, reflecting not merely downright bad control but even the imperfection of control which is usually regarded
We
as
acceptable. If this interpretation
is correct, we have some learn about the treatment of diabetes, generally as well as in the young. We know that really good control of blood-sugar is of crucial importance in the outcome of pregnancy in the diabetic. It now seems that the same may be true for the growth of the child diabetic. Thus, we have two easily measurable indices-fetal survival and bodily growth-by which to judge the results of treatment, and find that they are still far from good. We have accepted the lessons of the poor results of the treatment of diabetic pregnancy in the past and now attempt near-physiological control
lessons
to
of blood-sugar during pregnancy.23 Perhaps we should do the same with young diabetic children. These results show-if it still needs showing-that " " " when we speak of good " or satisfactory or even " adequate " control of insulin-dependent diabetes, When assessed by critical we are deluding ourselves. indices we see that our control is almost always poor-sometimes fairly poor, sometimes very poorbut hardly ever good. Normally blood-sugar varies by only 20-30 mg. per 100 ml. during the 24 hours. This is true of only a tiny minority of insulindependent diabetics; in most the swings are much
greater. We have
long way to go to achieve control of blood-sugar approaching the physiological, but the attempt to achieve it is worth making. However, we are doubtful whether we can greatly improve on current standards of treatment of diabetes by present methods. Perhaps the glucose sensor 24 will provide a
the solution? We thank the twins for their cooperation in this and other and many colleagues and the British Diabetic Association for referring them; Mr Geoffrey Stevens for statistical advice; and Mrs A. M. Spink for much secretarial help. R. B. T. is supported by a grant from the Nuffield Foundation. Requests for reprints should be addressed to D. A. P.
studies,
REFERENCES 1. Wagner, R., White, P., Bogan, I. K. Am. J. Dis. Child. 1942, 63, 667. 2. White, P., Graham, C. A. Joslin’s Diabetes Mellitus; p. 347. Philadelphia, 1971. 3. Knowles, H. C., Jr., Guest, G. M., Lampe, J., Kessler, M., Skillman, T. G. Diabetes, 1965, 14, 239. 4. Pond, H. Postgrad. med. J. 1970, 46, 616. 5. Evans, N., Robinson, V. P., Lister, J. Archs Dis. Childh. 1972, 47, 589. 6. White, P. Diabetes, 1960, 9, 345. 7. Newman, H. H., Freeman, F. N., Holzinger, K. J. Twins: A Study of Heredity and Environment. Chicago, 1937. 8. Shields, J. Monozygotic Twins Brought up Together and Apart. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19. 20. 21.
London, 1962. Post, R. H., White, P. Diabetes, 1958, 7, 27. Tattersall, R. B., Pyke, D. A. Lancet, 1972, ii, 1120. Wilson, R. S. Hum. Hered. 1970, 20, 30. Tanner, J. M. Growth at Adolescence. Oxford, 1962. Osborne, R. H., De George, F. V. The Genetic Basis of Morphological Variation. Cambridge, Mass., 1959. Beal, C. K. J. Pediat. 1948, 32, 170. Jackson, R. L., Kelly, H. G. ibid. 1946, 29, 316. Bergquist, N. Acta endocr., Copenh. 1954, 15, 133. Sterky, G. Acta pœdiat. 1963, suppl. 144, p. 13. Craig, J. O. Postgrad. med. J. 1970, 46, 607. Hamne, B. Acta pœdiat. 1962, suppl. 135, p. 72. Boyd, J. D., Kantrow, A. H. Am. J. Dis. Child. 1938, 55, 460. Prader, A., Tanner, J. M., Von Harnack, G. A. J. Pediat. 1963, 62,
646. 22. Larsson, Y., Sterky, G. Acta pœdiat. 1962, suppl. 130, p. 20. 23. Essex, N. L., Pyke, D. A., Watkins, P. J., Brudenell, J. M., Gamsu, H. R. Br. med. J. 1973, iv, 89. 24. Soeldner, J. S., Chang, K. W., Hiebert, J. M., Aisenberg, S.
Diabetes, 1973, 22, suppl. 1, p. 294. "
The lower reaches of the Rhine-a water source for 6 million people-may often contain 40% of sewage effluent, and this may rise to nearly 100% in periods of low flow. The Thames, which provides two-thirds of the water supply for the Greater London area, contains about 14% of sewage effluent when flowing at an average rate. In times of drought, the water supply source for Agra, India, consists almost entirely of partially treated sewage from New Delhi, 190 km away.... The use of such rivers as sources of domestic water supply, despite the increasing
nearly
of waste they contain, creates a potential health hazard because the water withdrawn continues to be treated by conventional methods ... "-W.H.O. Chron. 1973, 27, 493.
proportions