Diabetes mellitus in children

DIABETES

MELLITUS IN CHILDREN

REVIEW OF 500 CASES HENnY J. J0~N, M.D., F.A.C.P. CLEVELAND~ O i-IIO

H E diabetes seen in children m a y be considered to be a " p u r e " f o r m of the by the degenerative changes which p l a y a large p a r t in the development of diabetes in older persons. Hence it is instructive to analyze the results in y o u n g patients after twenty-six y e a r s ' experience with insulin treatment. The series of 500 cases reported here has been observed over a twenty-seveny e a r period, so a few of tl~em antedate the " i n s u l i n e r a . " Some of these patients I have observed eontinual]y over m a n y years. [ have traced as m a n y of the others as possible through correspondence with them or their families. I have no recent r e p o r t on 136, or 27.2 per cent. Of the 364 patients traced, 303 are living and sixty-one are dead ; i. e., 83.2 per cent of those traced are living and 16.7 per cent are dead.

T disease, since it is uncomplicated

INCIDENCE

The 500 cases of diabetes occurring in patients in the first of life were observed in a total series of 6,000 diabetic patients r e p o r t i n g elsewhere). Thus, the incidence of patients under 20 is 8.3 per cent. Fig. 1 shows the incidence by decades in the total

two decades (which I am years of age series.

Age.--Diabetes mellitus m a y occur in a child at any age. In this series there were two children who were less t h a n one year old when the disease appeared. Sehwartzman and associates ~ collected f r o m the literature and reviewed fifty-seven cases of diabetes me]litus in infants less than a y e a r old. I n the present series there were 263 instances in which the onset of diabetes occurred in the first decade and 237 in the second decade. Fig. 2 shows the incidence by years. This seems to indicate that the m a j o r i t y of cases of juvenile diabetes occur between the ages of 4 and 12 years. This finding m a y not be of statistical significance, but, owing ~o the r a p i d rate of growth during this period, it m a y be we]l to look for evidence in other series on this point. Sex.--The sex distribution in this series of diabetic children was practically equal, as is true of other reported series (Table I ) . There were 255 .(51 per cent) boys and 245 (49 per cent) gir]s. This finding is in definite contrast to the sex incidence of diabetes general]y, as shown by m y total series of 6,000 eases; among these patients of all age groups, the incidence in ma]es was 43.3 per cent and in females 56.7 per cent. 723

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IV

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Fig. 1.--Age incidence (by decades) N o . o~ CA ~s

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in 6,000 c a s e s of d i a b e t e s

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:Fig. 2 . - - A g e of d e v e l o p m e n t o f d i a b e t e s in 500 c h i l d r e n .

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/8

19

2--0

725

JOHN: DIABETES B'[ELLITUS IN CHILDREN TABLE I.

SEX INCIDENCE OF DIABETES IN CHILDREN PEP~ C E N T

AUTHOR

Driesel and Wagner,2 Pirqueta Joslia and White4 Sundby5 Total TABLE

lI.

NUMBER

xN[ALE

152 5,321 750 159 6,382

52 51 50A: 51 50.9

rl?HE I-IEREDITAI~y

CASES :No history obtained History obtained Gentile Jewish Hereditary history of diabetes Gentile

.FAC'I'OR IN 500 I)IABETIC

I 73 427

18

4.4

135

23.4 26.4 3.7 33.5 4.2 4,9 0.23 2.2

1

Combined hereditary and familial history of diabetes Gentile Jewish

27.1 15

Jewish

~HILDREN

89.2 10.8

101

19

48 49 49.6 49 49.1

100

116

Familial history of diabetes Gentile

FEMALE

PEN CENT

381 46

Jewish

I

(o:f (of (of (of

total group) Gentile group) total group) Jewish group)

(of (of (of (of

total group) Gentile group} total group) Jewish group)

(of (of (of (of

total group) Gentile group) total group) Jewish group)

31.5 119 16

27.6 31.3 3.9 35.5

ETIOLOGIC FACTORS The two f a c t o r s of p r i m e i m p o r t a n c e i n tile e t i o l o g y of d i a b e t e s in c h i h t r e n are heredity and infection.

He,redity.--In the 500 cases, no h i s t o r y r e g a r d i n g h e r e d i t a r y or f a m i l i a l d i a b e t e s was r e c o r d e d in s e v e n t y - t h r e e instances. Of t h e 427 eases in w h i c h the h i s t o r y was e x p l i c i t in r e g a r d to t h i s f a c t o r , t h e r e was d i a b e t e s in the h e r e d i t a r y b a c k g r o u n d in 116. T h e r e was a f a m i l i a l h i s t o r y in a n a d d i t i o n M n i n e t e e n cases (Table II). The h e r e d i t a r y f a c t o r was a p p r o x i m a t e l y e q u a l in t h e b o y s a n d tile girls. The p e r c e n t a g e of J e w i s h c h i l d r e n in w h o m h e r e d i t a r y influences were p r e s e n t was s o m e w h a t higher t h a n t h a t of t h e g r o u p as a whole. O f the 427 c h i l d r e n , f o r t y - s i x were ,Jewish a n d t h e r e was a h e r e d i t a r y or f a m i l i a l hist o r y of d i a b e t e s i n s i x t e e n of these, or 35.5 p e r c e n t (as c o n t r a s t e d w i t h 3].5 p e r cent f o r the e n t i r e g r o u p ) . M y i m p r e s s i o n is t h a t tile influence of h e r e d i t y m a y be m o r e p r o n o u n c e d t h a n is i n d i c a t e d b y these p e r c e n t a g e figures, since it h a s been m y e x p e r i e n c e r e p e a t e d l y t h a t in c h i l d r e n whose h i s t o r y s h o w e d no d i a b e t e s in the f a m i l y a t the t i m e of onset, c o n t i n u o u s f o l l o w - u p h a s l a t e r rev e a l e d the p r e s e n c e of d i a b e t e s in some o t h e r m e m b e r of the f a m i l y . H e n c e 1 w o u l d v e n t u r e to e s t i m a t e t h e a c t u a l i n c i d e n c e of a n h e r e d i t a r y t e n d e n c y in d i a b e t i c c h i l d r e n as a b o u t 40 p e r cent. T h e i n c i d e n c e as given b y o t h e r

726

TtlE JOURNAL OF PEDIATRICS TABLE t l I .

'PILE ~E~EDITARY ~'ACTOI~ IN DIABETIC OHILDF~EN (OTf-iEE, AUTHORS) FAMILIAL AND IIEREDITARY DIABETES

Am'~OR

CASES

Friese and J a h r 6 Toverud7 Lion and Moreaus Priesel and Wagner~

IIost:~ Laddie J o s l i n and White4 S c h w a r t z m a n et al.t Collens and Grayzel~l Smyth12 TABLE I V .

TYPE OF INFECTION

Mumps Influenza Measles Dysentery Pneumonia I n t e s t i n a l toxemia Boils Tonsillitis Nephritis Glandular fever Jaundice Septic endocarditis Poliomyelitis Abscessed teeth I n f e c t i o n s (nonspecific or unknown type) measles Scarlet fever

31

T H E ]~ACTOR~ OF INPECTION IN 5 0 0 :DIABETIC CHILDREN l

TIIVIE OF ONSET OF DIABETES FOLLOWING INFECTION

I i-i0

DAYS I 11-20 I 21-30 I 31-401

5 9 2 1 1 1

1 7 1 1 1 1

2 7 2 1 4

41-50

51-60 1 5 1

2 1

UNDER I YEAR 3 2 3

NOT STATED 25 3 2 2 2 3

] 1 2 2

2

I 1 1 1

1

1

1

23 1

I 1 2

1

~astoiditis W h o o p i n g cough Chicken pox Otitis media Total

11.6 17 23 27 30 37 40 43 50 54

I0

Pyelitis German

(%)

60 47 100 108 50 35 750 28

2 27

16

] 1 1 2 1 27

1

6

2

1

1

9

10

67

TOTAL 37 33 11 6 10 3 3 4 2 3 3 1 2 1 26 2 it 5 2 4 4 1 164

authors reporting on small series varies from! 11 to 54 per cent (Table I l i ) . Joslin and White, ~ who reported a series of 750 eases, f o u n d the incidence to be 40 per cent. Infection.--Infeetions of various types play a definite role in the causation of diabetes in children, as has been a m p l y demonstrated in literature on this subject. 13 The common o b s e r v a t i o n of the onset of diabetes within ten to t h i r t y days following various childhood infections certainly furnishes presumptive evidence t h a t the infections were a factor of i m p o r t a n c e in the development of these cases. I n the present series of 500 cases, there was a history of recent infection in 164 instances (Table I V ) . In eighty-seven, the diabetes appeared within sixty days a f t e r the infection; in ten, within one year, and in sixty-seven, the exact time of onset in relation to the infection was not stated. Thirty-seven cases developed following m u m p s and thirty-three a f t e r influenza.

JOHN:

DIABETES M E L L I T U S I N

CHILDREN

727

There were twenty-six eases a f t e r infections of nonspeeifie or unknown type. Other infections which were followed b y diabetes iiz this series were measles, dysentery, pneumonia, intestinal toxemia, boils, tonsillitis, nephritis, glandular fever, infectious jaundice, septic endocarditis, poliomyelitis, abscessed teeth, pyelitis, German measles, scarlet.fever, mastoiditis, whooping cough, chicken pox, and otitis media. The time of onset and the distribution of cases following these infections are shown in Table IV. The presence of a history of recent infection in 164 eases (32.8 per cent) in this series is in keeping with the observations of other authors, some of whom report a higher percentage. Friese and J a h r 6 stated t h a t in nearly three-fourths of their series of sixty diabetic children they could demonstrate that diabetes developed shortly a f t e r an infection. Fischer 14 reported that the onset of diabetes in his series was immediately traceable to infection in a p p r o x i m a t e l y 35 per cent of the eases. L a n d a b u r e and Magdalena *'~ showed that acute infectious diseases had preceded diabetes within ninety days in 23 per cent of their cases. A d a m s ~ called attention to the fact that the incidence of diabetes mellitus increases in the fall, winter, and spring, when infections are most common. Jones ~ reported a high incidence of eases of diabetes following an influenza epidemic. I n the present series, the largest n u m b e r of eases of diabetes following a p a r t i c u l a r infection was that ,'elated to mumps. Panereatitis which occurs as a complication of parotitis has been reported frequently in the literature, and in a proportion of these eases (tiabetes is the eventual result. I have seen several such eases in adults, as well as in the children reported here. Among the authors who have r e p o r t e d eases of diabetes a f t e r parotitis are Gilhespie and ttolden, ~s Jacob, ~9 I-Iarris, ~~ and Fischer. ~4 The fact, as shown in this series, t h a t diabetes in children develops a f t e r m a n y types of infections, is a m p l y corroborated by numerous reports by other authors of the onset of diabetes following various infectious diseases. A m o n g these reports are the following: a f t e r acute colds, tonsillitis, and influenzal infections, Lierle and Porter, = W e n d t a n d Peek, a~ J o n e s ; ~ a f t e r p u r p u r a , Lefkowitsch ;~a a f t e r pyelitis, Smith ;~* after hepatitis and jaundice, Sweeney and Shirley, 25 Brems, 26 F r e u n d and Marehand ;'-'~a f t e r malaria, Rau =s and a f t e r diphtheria, tteetor, =9 Nmnerous authors have ca.lied attention to the disturbance of c a r b o h y d r a t e metabo]ism that occurs during or a f t e r encephalitis or poliomyelitis. K a s a n i n and Grabfield, 3~ in a study of seventeen eases, concluded that there was a fundementa] disturbance of sugar metabolism in epidemic eneephalifts and that this derangement persisted in patients suffering from mental sequelae of the disease. Similar conclusions have been reported by McCowan, 3~ Brugsch, Dressel, and Lewy, 32 Asehner, as K a r p l u s and Kreidl; 3. N o r d m a n n 3's reported h y p e r g l y c e m i a in poliomyelitis and Sehwartzman and associates ~ f o u n d diabetes associated with n e u r o p a t h y in six of forty-eight cases. A few authors have a t t e m p t e d to show a relationship between syphilis and diabetes, but the general coneensus is t h a t syphilitic infections are of no significance as an etiologic factor in diabetes. I n this series there was no ease in which syphilis could have been a. predisposing" factor.

728

THE IVIE,CHANISM

OF

JOURNAL

1NFECTION

OF P E D I A T R I C S IN

PRODUCTION

OF

DIABETES

The question is unanswered as to why infection preeipitates diabetes in one child and does not do so in ninety-nine others. Is it that the child who becomes afflicted with diabetes had a decreased insulinogenic reserve which was exhausted by the added strain of the infection? Is it that in the individual instance in which diabetes appears, the particular predisposing infection caused a more virulent toxemia than in the usual ease? Perhaps both of these factors, and others not yet recognized, are important. One fact that is well established is that infection affects the function of the pancreas adversely. In a diabetic child whose condition is well under control, for example, on a dosage of 20 units of insulin daily, a febrile condition may so upset the picture that the dosage must be increased to 80 units to control the hyperglycemia. Knowing that this is true in the diabetic child, it is easy to imagine a similar situation (and there is clinical and experimental evidence to support this assumption) in the nondiabetie child d u r i n g an infection. The possibilities usually considered to explain the decreased sugar tolerance during' an infection, both in diabetic and nondiabetic individuals, are: (1) reduced insulin output or a prior decreased insulinogenic reserve; (2) inability of tile l i v e r to store glycogen readily; .(3) interference with the action of insulin; (4) derangement of the mechanism of nervous control of sugar metabolism; (5) an increased output of epinephrine or of pituitary secretion which inhibits the effect of insulin. Opinions differ considerably as to which of these factors is mainly responsible, alone or in combination. I t would appear to me that interference with the action of insulin, either by toxic products or by increased secretion of suprarenal or pituitary hormones antagonistic to insulin, is the most likely probability. I f the liver damage were of prime importance, h y p e r g l y c e m i a would be encountered more f r e q u e n t l y ; f u r t h e r m o r e , in patients with m a r k e d cirrhosis of the liver there is no hyperglycemia. Labb6 and Boulin a6 in a s t u d y of nondiabetic patients during' acute infections, f o u n d alim e n t a r y glycosuria in 75 per cent. The disturbance in glucose regulation did not parallel the severity of the infection, and there was no sign of insufficiency of liver function. T h e y stated: " I t is possible t h a t recurrences of this transient disturbance of glucose ~alance create a true diabetes more f r e q u e n t l y t h a n b e l i e v e d . " L a w r e n c e '~ suggested, on the basis of e x p e r i m e n t a l and clinical evidence, that toxins and infections antagonize insulin action by the stinmlation of the t h y r o i d and suprarenal glands. A c o n t r a r y opinion has been stated by F u k u d a and !tabashi; :'8 they believe that hyperglycemia during infection in febrile diseases is caused by the action of bacterial toxins on the central control mechanism and not by p e r i p h e r a l action on the suprarenals and on the liver. Although m a n y questions remain as to the mechanism of the influence of infection on development of the diabetic state, the evidence, both clinical and experimental, that the c a r b o h y d r a t e metabolism is disturbed d u r i n g infections is quite conclusive. A typical report is that of Williams and Dick, ~9 who studied the carbohydrate metabolism in ]08 patients with infections such as scarlet fever, diphtheria, pneumonia, influenza, measles, erysipelas, encephalitis, mumps,

JOHN:

DIABETES

~[ELLITUS

IN

CHILDREN

729

epidemic meningitis, poliomyelitis, and acute tonsillitis, and in twenty-nine rabbits and three dogs in which infections were produced experimentally. Temp o r a r y glyeosuria occurred in 41 per cent of the animals, in six animals this
D U R I N G ACUTE: 1 N F E , C T [ O N S

The two cases which follow illustrate the importance of adequate protection of the diabetic child during' i n t e r e u r r e n t infeetions. CASE 1.--Fig. 3 shows the course of the diabetes and the treatment required for its control in a patient who eontraeted the disease at the age of 8 years. With adequate treatment, the diabetic condition improved sufficiently t h a t all insulin eould be discontinued. He presented a normal fasting', noon, and evening blood sugar and was sugar-free on diet alone on repeated examinations. Then he contracted measles, l i e lived in a small town and his physician did not appreciate the change in the glueose metabolism caused b y the infection and did not reinstate insulin during this period. W h e n I saw him a few weeks later, the blood sugar had inereased to almost 500 rag. per cent and he displayed signs of severe acidosis. Insulin had to be reinstated, and in large doses, and now, nearly eighteen years later, he is still required to take large quantities of insulin because of the inadequate ma.nagement of the diabetes during the aeute infection. This apparently caused permanent damage which is irreversible. CASE 2 . - - I n this instanee (Fig. 4), the infection and its subsequent aggravation of the diabetes were properly considered and managed. This boy was 71/2 years old in 1936 when he first developed diabetes. At the beginning, the blood sugar was high morning, noon, and light, and insulin, bad to be increased up to 50 units daily. A f t e r a month and one-half, all insulin could be discontinued for a period of three months, during' which the three antecibal blood sugars were normal. After this, insulin had to be resumed, and in 1938, at the age of 91~ years, he was taking 10 to 18 units of insulin and 12 to 15 units of protamine zinc insulin a day. At that time he had mumps. W i t h inereased insulin dosage (to 40 units), there was only slight elevation of the blood sugar. Afterward, the dosage was reduced to 30 units. Six years later he had a seeond attack of mumps. B y this time his diabetes had inereased in severity (possibly owing to dietary indiscretion) and he was taking' 150 units of insulin daily. However, the onset of the infection required only a minimal increase in the insulin dosage. The blood sugar d u r i n g the infection and two years later showed reasonable control of the diabetie condition, since two out of three detemuinations were at or near the normal level.

730

THE

JOURNAL

OF

PEDIATRICS '3o

tT.d foo

'3z

'31

Ioo

J

IT!/

I

IZO

tv

I

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III

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Fig.

3.--Effect

of

infection

(measles]

on

the

diabetic

status

in

a

boy,

aged

$ years.

JOHN:

DIABETES MELLITUS IN

X{ XII ~ 17 (B Iq 2 0 ~1 2R I5 24 20 26" 4 ~

CHILDREN

731

/11 I g Yl" VII /l( X XII I Ill IV g~ glf X II ,V g[/ lq Ill 12 J O -~ ~ XO 27 ~ 0 I(-~ I I J I0 ~" If 1~ ~ 4 14 g5 I~l ~ q l$ ~ 0 17 ~9

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F i g . 4 . - - E f f e c t of i n f e c t i o n ( m u m p s ) on t h e d i a b e t i c s t a t u s in a child, a g e d 9J~ yea.rs, w h e n c o u n t e r a c t e d .by a d e q u a t e l y i n c r e a s e d i n s u l i n d o s a g e . CONTRAST

O'B ~ ETIOLOGIC

FACTORS

IN

ADULTS

AND

CHILDRE,I'~

As already stated, heredity and infection a p p a r e n t l y are the most important etiologic factors in juvenile diabetes; whereas in older patients obesity and degenerative diseases obviously play a p r e d o m i n a n t role. This is clearly shown in the ensuing discussion of glucose tolerance tests, obesity, circulatory disorders, and h y p e r t h y r o i d i s m in groups of children alld of adults. Glucose Tot~'a, ncc Tests in Children cbnd Adults in Various A[fections.-In 1934, I published a series of 192 gh.leose tolerance tests 4~ p e r f o r m e d on patients u n d e r 20 years of age. Some of these tests were made for diagnostic reasons, others p u r e l y for scientific information. I t seems pertinent here to re~ capitulate the results of this study, which are shown in Table V. I n this group of juvenile individuals, 81.7 per cent showed normal glucose toleranee curves, whereas in a group of 1,535 adults subjected to a similar study, normal curves were obtained in only 61.5 per cent. Fig. 5 shows graphically the trend of norreal and diabetic curves of glucose to]erance according to age in the total series of 1,727 eases. This chart corroborates the information shown in Fig. 1 on the age incidence of diabetes. The findings in r e g a r d to the increased incidence of

732

THE JOURNAL TABLE V,

CLINICAL

OF PEDIATRICS

GLUCOSE TOLERANCETESTS IN 192 CHILDREN

CONDITION

Obesity tIypcrthyroidism :Hypothyroidism Hypopituitarism and dwarfism Glyeosuria Hyperglycemia Arthritis and rheumatic disease :Eye a f f e c t i o n s Neuropathies Ityperpituitarism Raynaud's disease Tuberculosis Skin diseases Olyeosuria of pregnancy Cholelithiasis Hypogonadism Duodenal ulcer Normal Total

. GLUCOSE TOLERANCE NOR1Vs 1 DIABETIC 12 2 14 3 10 40 4 35 ]7 1 5 4 19 3 6 ] ] 1 1 3 4 1 1 1 1 2 157 35

-

PEg CENT NORIv[AL I DIABETIC 86 14 82 18 100 91 9 67 33 100 56 44 87 13 85 15 50 50 100 100 100 100 100 100 100 100 82 18

TOTAL !I'ESTS 14 17 10 44 52 1 9 22 7 2 J ?, 4 1 1 ] J 2 192

DECADE

IO0

9o 80

70

Go 50 40 5o 2o

___~IAI3

ETIC ~t3RVE,G

io 0

17,~ 7 GLUCObE TOLER. TEST5

]s'ig. 5 . - - I n c i d e n c e of a b n o r m a l ( h y p e r g l y c e m i c ) c u r v e s in 1,727 g l u c o s e t o l e r a n c e t e s t s , s h o w i n g t h e i n c r e a s e w i t h e a c h s u c c e s s i v e deea.de of life.

JOHN:

DIABFTES

I~[ELI~ITUS I N

CHILDREN

733

diabetes with age suggest that this condition is largely a degenerative disease resulting from various affections, endocrine disturbances, infeetions, arteriosclerosis, and senescence. The contrast in the ineidenee of diabetic-type glucose tolerance curves in adults and children is quite striking. I n patients with obesity and h y p e r t h y roidism, for instance, there were a b o u t three times as m a n y diabetic curves in adults as in children. In the presence of glyeosuria, rheumatism, and hypopituitarism, the incidence of diabetic curves was about the same in tile 'two groups. I n rheumatic conditions and chronie infections both groups showed a high incidence of abnormal eurves. These differences a p p a r e n t l y reflect functional differences between the child and the adult. The child a p p a r e n t l y is a better physiologic unit than the adu]t who has been subject to r e p e a t e d infections, functional stresses and strains, and dietary abuses, and thus has exhausted much of his initial insulinogenic reserve. A n y i n t e r c u r r e n t s t r a i n imposed on such a background produces greater damage t h a n when the physiologic baekground is intact. Heredity a~d Infectio.n.---As has already been pointed out, heredity a n d infection seem to be the most i m p o r t a n t etiologic factors in diabetes in children. As shown in Table II, there was a history of h e r e d i t a r y or familial diabetes in 31.5 per eent of this group of children, whereas in a series of 6,000 eases, ineluding both adults and children, the incidence of the h e r e d i t a r y factor was 19.13. This indicates t h a t heredity is a much more i m p o r t a n t factor in juvenile diabetes than it is in adults with the disease. The same is true of infection, although the actual role of infection is more difficult to assess in adults. The appearance of diabetes following an acute infection is by no means r a r e in adults, though a history of this type is nmeh less frequently encountered than is the case with ehildren. I n adults who have had repeated acute or chronic infections it is difficult or impossible to say how much of the general physiologic breakdown which f o r m s the background for the development of diabetes is attributable to this cause. T h a t it is not negligible is suggested by the f a c t that the incidence of abnormal glucose tolerance curves is much higher, both in adults and children, in patients with rheumatic conditions or chronic infections t h a n it is among patients in general. Obes#,y.--Obesity is not the p r o m i n e n t f a c t o r in the causation of diabetes in children that it is in adults, although even in v e r y young patients it cannot be completely ignored. Fig. 6 shows the percentage incidence of abnormal, or hyperglycemic, g h e o s e tolerance curves in adults and in children with obesity. Not all of these patients have or will have f r a n k diabetes, but the abnormal carbohydrate metabolism represents a warning signal that the d~sease m a y develop if the obesity remains uncontrolled. This is corroborated by tl~e strikingly similar incidence of a history of obesity in diabetic patients. In a series of 2,970 diabetic patients of all ages in whom this factor was determined definitely, it was found that 33.9 per cent were and always had been of normal weight, or at most no more than 10 p e r cent above normal. Conversely, 66.1 per cent were or had been at some time 11 to 220 per cent overweight. Anders and

734

TIIE

JOURNAL

OF PEDIATRICS

Jameson 4~ reported a series of 1,306 eases of obesity in which they found that 119, or 9.1 per eent were diabetic. Since the incidence of diabetes in the general population is, at most, no more than 2 per cent, this represents a greatly increased incidence (approximately five times the usual) in the obese. Fortunately, because degenerative influences have not been at work over a sufi%iently long period in clfildren, overweight does not have tlhe same coincidence with diabetes that it has in adults. Nevertheless, in 1920, l~Iouriquand ~2 called attention to the fact that obesity or a familial history of obesity cannot be ignored in considering the problem of juvenile diabetes, t~Ie warned that incipient diabetes might be detected in children of the obese, the diabetic, and also arthritie and gouty parents. He stated that near]y all of his patients with early inherited obesity developed diabetes before the age of 40 years, but that when obesity did not deve]op until later in life; only 50 per cent became diabetic, in contrast to this inherited type of obesity, only 15 per cent of patients with acquired obesity developed diabetes.

A D u LT5 ~I.,.ACK

I~, T H E

CH

NUP1B~R 1oo

OF .DIABETIC

L DT:~E N G.T. ~ u R v E 8

T~T~,

l:i'ig". 6 . - - I n c i d e n c e of abnormal (hyperglycemic) curves in glucose tolerance tients, showing that the percentage is much higher in aduIts than

tests on obese in children.

pa-

Despite the relative r a r i t y of obesity in diabetic children, it is nevertheless wise from the clinical standpoint to look upon the overweight child with suspicion and to assess carefully the carbohydrate metabolism in such individuals. The treatment of obesity in children depends, of course, on the underlying cause, which is often glandular. The problem of the prevention or control of obesity in children presents a fertile field for investigation in pediatrics and perhaps might prove to be significant from the standpoint of public health in pointing the way toward understanding' and control of degenerative diseases later in life. A~rterioscIerosis.--In children, arteriosclerosis does not precede diabetes as it often does in older individuals, and for that reason cannot be considered as an etiologic factor in juvenile diabetes. Pearl Zeek 4~ searched-the medical literature for the past 100 years and found but, ninety-eight cases of juvenile

JOHN:

DIABETES MELLITUS

IN

CHILDREN

735

arteriosclerosis, excluding those resulting from syphilitic infections, and, so far as could be determined, none of these children with arteriosclerosis had diabetes. Although arteriosclerosis is not an etiologic factor in diabetes in children, it is a complication of this condition. A f t e r children have had diabetes ten years or more, arteriosclerosis begins to a p p e a r in a large proportion of cases. The literature brings out more evidence of this with each passing year. White 4'~ reported a series of 220 cases of juvenile diabetes in which the incidence of vascular disease in those who had had diabetes twenty years or more was 92 per cent. The vascular changes in young diabetics lead to diabetic retinitis with hemorrhages and intereapillary glomerulosclerosis, both of which are extremely serious conditions. I am not in a position to give statistical data on the incidence of arteriosclerosis in this series of children, since this requires systematic, periodic, roentgeno]ogic study. I s t a r t e d such a survey, but when I entered p r i v a t e practice it h a d to be a b a n d o n e d because of the cost to the patient, t t o w e v e r , in the p a t i e n t s t h a t I have followed consistently over a period of years, at least 50 per cent have developed arteriosclerosis and m a n y of t h e m h a v e h a d the more serious sequelae, such as blindness and renal failure.

Hypert,hy,ro~dism.--Some years ago I analyzed 9,000 cases of hyperthyroidism 4~ and found t h a t 38.6 per cent of these had glycosuria and 6.88 p e r cent had nonphysiologie hyperglycemia (either fasting or two and one-half hours or more a f t e r meals). The patients with hyperglycemia were closely watched and protective t r e a t m e n t with insulin was administered. Despite this, 186 of the 620 patients remained p e r m a n e n t l y diabetic. This represented an incidence of diabetes in the 9,000 cases of 2.1 per cent. W i t h o u t the protection afforded by diet and insulin during the hyperthyroidism, I believe the incidence of permanent diabetes in this group would have been much higher. I n the case of children, abnormal (diabetic-type) glucose tolerance curves occur only about one-fourth as f r e q u e n t l y in hyperthyroidism. ~~ A p p a r e n t l y the greater physiologic reserve or flexibility seen in the presence of other conditions, such as obesity, in the young, can withstand the grave metabolic derangement seen in h y p e r t h y r o i d i s m and still right itself when the acute strain has been removed. I n m y own series of children with h y p e r t h y r o i d i s m who were protected d u r i n g and a f t e r the acute stage of the disease, none developed a f r a n k a n d lasting diabetes. Itowever, two children with slight derangement of carbohydrate metabolism during the acute stage of h y p e r t h y r o i d i s m were told by the surgeon to forget about the hyperglycemia a f t e r t h y r o i d e c t o m y ; both r e t u r n e d l a t e r with f r a n k diabetes and are u n d e r t r e a t m e n t to this day. On the whole, h y p e r t h y r o i d i s m plays an insignificant p a r t in the production of diabetes in children. However, when abnormalities in carbohydrate metabolism are f o u n d in the presence of juvenile hyperthyroidism, these cannot be safely disregarded, as the two cases just cited show. I n fact, no m a t t e r what its cause, h y p e r g l y c e m i a should never be disregarded as insignificant.

SE~: M 1 F M 2 ]~ M 3 F M 4 F M 5 F M 6 F M 7 F M 8 F M 9 F M ]O P M 11 F M 12 F M 13 ~' M 14 F M 15 F M 16 }~ M 17 t,' ?r 18 F M 19 F M 20 V

AGE OF ONSET AND

6

1

]

1

1

l

25

2

1

1

l

1 2 3

1 1

1 1 4 1

3 1

1

16

1

I

1

1 1

1 1 1 1

1

1 1

1

1

5

1 1

2 2

11

1

1

l 1

l 1

2

I

1

1 1

8

1

1

2

1

1

1

1

1 I 2 ] 3 ] 4 I5 } 6 2

11

1

1

t 1 1

1

1

1

1 1 1

1

1 10

I

1

1

3

1

1

I 7 I 8

20

1

1

1

1 1 t

1

2

1

13

1

1

1

2 1 2

1

i

1

I

1 1 1

1 2

1

I 1

12

303

LIVING CHILDREN

15

1

I

2 1 1 2 1 1 1 1

1

1

6

I

2

15

J

1

1 I 1 1 ]

I 2 I

14

1

2 I

1 2

1

1

2 2

12

14

2

I

17

2

I

12

I

14

1

I

15

I 2

11

1 5

6

1

I

4

5

1

16 I 17 1181 19 ] 2 0 I 21 I 22 [ 23 ' 24 [ 25 I 26 I 27 I 28 1 1 I 1 ] I 2 1 2 1 1 2 1 1 1 1 1 1 1 2 ! 1 1 1 1 1 1 1 1 1 l 1 1 1 2 1 1 l 2 I I I 2 I l 2 I 1 I 1 ! 1 1 1 2 7 ] 2 1 1 I 1 2 1 1 3 1 1 I 1 2 1 1 ! 1 I 2 2 I I I I I l I

DURATION OF DIABETES IN YEARS

DURATION OF DIABETES IN

9 ! 10 I 11 ] 12 J 13 ! 1 4 I 15 1 1 I I 2 I I 3 1 2 3 1 1 1 I 1

TABLE V I .

0

3

3

5

]

5

8

5

15

10

10

11

10

10

9

1O

13

7

9

5

3

2

6

4

7

4

8

6

10

13

13

6

11

9

7

11

11

10

9

4

M I ~

TOTAL

9

9

N

--4

JOHN:

737

DIABETES MELLITUS IN CHILDREN ~s

Y

Of the present series o[ 500 cases, I have been able to trace fully 364 cases, or 72.8 per cent. Of these, 303, or 83.2 per cent (of those traced) are living, and sixty-one, or 16.7 percent, died during the twenty-seven-year period of the study. Of the 303 living patients, 41.25 per cent have been followed ten years or less since the onset of the diabetes, 43.23 per cent have been followed f r o m ten to twenty years, and 15.51 per cent have bee~~ observed for more t h a n twenty years. A detailed analysis of these eases, according to the age at which diabetes developed, sex, and the length o.f survival to the present, is shown in Table VI. i n considering the sixty-one deaths in this series, it must be remembered that some of these, eases date back to about two years before the use of insulin. a fact that influences the n m n b e r of deaths f r o m coma. Many of the children died in their homes in small towns, where facilities were not available for adequate treatment. Table V I I shows the causes of death in this series. I t is clear that coma r a n k s first as a cause of death in diabetic children. The second most frequent cause of death was kidney involvement which I called intereapillary glomeruloselerosis. [['his diagnosis was confirmed in some of these eases b y necropsy; in others it was based on clinical evidence of. diabetes of long duration, retinal sclerosis and hemorrhages, albuminuria, and edema. TABSF~

VII.

CAUSE

OF

CAUSE

Diabetic coma I~tercapillary glomerulosclerosis A f t e r surgery Tuberculosis Accident Uremic coma Aspiration of foreign body Pneumonia Meningitis Ruptured appendix Septicemia Unknown Total

I)EATII

IN

61

C~LDi~EN NO. CASES

31 11 5 4 3 1 1 1 1 1 1 1 61

Table VII;[ shows the length of time that these sixty-one diabetic children lived from the onset of their diabetes until death. The highest m o r t a l i t y rate was in the first y e a r of the disease. Eighteen children, or 29.5 per cent of the sixty-one who died, succumbed within a year of onset of the diabetes. I f a mother can see her child through tile first year, the immediate threat to his life caused by the diabetes is greatly lessened. The initial period of a d j u s t m e n t to the diabetic condition and its involved problems is by far the hardest f o r all concerned--the patient, the family and the physician. The commonest mistake made by the family, and even by some physicians, when a diabetic child becomes ill and cannot retain food, is to withhold food and insulin, with the result that he goes into coma.

738

Till,: J O U R N A L OF P E D I A T R I C S

~4

~4

?

m

o

9

c~

JOHN:

DIABETES MELLITUS

IN

739

CHILDREN

~1C A T I O N S

COMPI

C o m a . - - T h e most serious complication and threat to the life of the diabetic child is coma resulting f r o m acidosis. Thirty-one of the sixty-one deaths in this series were caused by this condition, representing 8.5 per cent of the 364 patients traced, or 6.2 per cent of the entire series of 500 cases. I n 1934, I reported m y studies on diabetic coma in a series of 218 dinbetie children. ~ I n this series, covering a period of fourteen years, there were fifty instances of diabetic coma (23 per cent). Thirty-one of these children were under my immediate care d u r i n g the coma; nineteen were cared for by family physicians, chiefly in small towns. Of the thirty-one patients u n d e r my care, five died; three of these were m o r i b u n d on arrival and died within one hour a f t e r admission to the hospital. One died d u r i n g the preinsulin period. Of the nineteen children cared for b y other physicians, sixteen died and three survived. Thus the total m o r t a l i t y in the group I cared for was 16.1 per cent, and if the four patients just mentioned are excluded, only 3.2 p e r cent. The mortality in the group cared for b y family physicians was 8~:.2 per cent. I t must be remembered that these results were obtained in the early years of the use of insulin at a time when physicians were not well acquainted with this d r u g and were a f r a i d to use it in large quantities. In the years since the period covered by this earlier study, coma occurred in twenty-seven children of the present series (between 1934 and 1948). Of these, twenty-three wore u n d e r m y care d u r i n g the emergency and f o u r were managed by other physicians. Of the twenty-three, only one died (Table I X ) . Two of the four children cared for elsewhere succumbed. TABLE

IX.

INCIDENCE

0F ])IABETIC

COMA

IN 500

CHILDREN

1920-1934

CASES Total diabetic children Coma Under personal care Died U n d e r c a r e o f family Died

physician

I

218 59 31 5* 19 16

*One t r e a t e d in p r e - i n s u l i n e r a ; t h r e e m o r i b u n d

1934-1948

PERCENT

100 23 16.1 84.2

I

CASES 282 27 23 1 4 2

I

PE~CEN~

]00 9.5 4.3 50.0

on admission and died within one hour.

These figures reflect the picture in r e g a r d to diabetic coma in children during the last twenty-eight years. The results show that the quality of medical care during this emergency has improved tremendously, but still is not all it could be. The chief reasons for the failures are inadequate dosage of insulin and failure to use sodimn chloride and glucose solutions in large quantities. Failure to handle the emergency of diabetic coma adequately in the early days of insulin use was excusable; knowledge of it was incomplete, and m a n y physicians were timid in handling it. However, this excuse is no longer tenable, a n d it is significant that the two deaths in the f o u r eases handled b y other physicians in the later series occurred in one of o u r best hospitals, where ali the facilities for adequate t r e a t m e n t w e r e available. One of the reasons for in-

740

Tile

,JOURNAL ()I~ PEDIATRICS

efficient treatment in a hospital is delay in getting the laboratory reports. The results of determination of blood sugar should be available in thirty minutes, for the test requires only twenty minutes. Blood sugar determinations on a patient in diabetic coma should take precedence over routine laboratory work, for the regulation of the insulin dosage in these cases is literally a matter of life or death. A patient in coma should never be left to the care of assistants or studeuts. The physician responsible should take personal charge of the case and show his assistants how to proceed resolutely in the emergency, on the basis of confidence resulting from much experience. Intercapiltary Glomerulosclerosis.--The diagnosis of intereapillary glomerulosclerosis in this series was based largely on clinical evidence, although this was confirmed by necropsy in a few cases, ttenderson and associates ~7 performed post-mortem studies in a large series of diabetic patients with glomeruloselerosis accounting for 19 per cent of the deaths. In correlating their pathologic findings with clinical data, they suggested that a presumptive diagnosis of g]omeruloselerosis should be based on the following factors: (1) diabetes of long standing, (2) albuminuria, (3) hypertension, (4) renal insufficiency, and (5) mixed vascular and diabetic retinopathy. Glomeruloselerosis is but rarely associated only with diabetes and albuminuria, aceording to these authors. Using these criteria, the evidence justified the diagnosis of intereapillary glomeruloselerosis in eleven of the sixty-one deaths in this series (18 per cent of the deaths; 3 pet' cent of the 364: eases traced). The optimistic attitude that prevailed for nearly two decades after the introduction of insulin concerning the treatment of the diabetic child has, in recent years, been tempered considerably by the disconcerting reports regarding the incidence of arteriosclerosis and its serious complications in young diabetics who have had the disease ten years or longer. The future for these patients looks considerably less bright than it did ten years ago. White and Waskow 44 reported 220 juvenile diabetics who had survived twenty years or more since the onset of the disease. Of this group, 203, or 92 pet' cent, had vascular disease. Two had had a cerebral vascular accident; seven had eoronary insufficiency; forty showed albuminuria; fifty-five had hypertension; seventy had calcified arteries; seventy-five had retinal hemorrhages; eighty-five had retinal arteriosclerosis, and six had retinitis proliferans. These authors also reported: "Since 1940 every diabetic child in our clinic who has survived fifteen years of diabetes and has come to autopsy has shown this lesion (intereapiIlary glomerulosclerosis), with or without pyelonephritis." Dolger 48 reported that of 200 patients subjected to regular periodic examinations, 50 per cent showed albuminuria at the time that retinopathy developed. In a group of sixteen patients who developed diabetes before the age of 10 years and in thirty-nine who developed diabetes between the ages of 10 and 20 years, all of whom had had diabetes for twenty-five years, Dolger found retinitis with hemorrhages in all. Although I have not been able to follow personally all of the patients in this series by regular periodic examinations, I do have data on the incidence of a/buminuria in a g'ro~p of eighty-three patients who have contim,~ed under my

JOHN:

DIABETES M E L L I T U S IN

741

CHILDREN

personal care over a period of years. Twenty-six (31.3 per cent) of these show albuminuria, and fifty-seven (68.7 per cent) do not. The incidence of albuminuria relative to the duration of the diabetes is shown in Table X. The interesting thing here is that the percentage incidence of albuminuria did not increase appreciably with longer duration of the diabetes, a finding somewhat at variance with the reports of others. TABLE DUlgATION 0Y DIABETES IN YEARS 10 10 16 21

or to to to

Total

less 15 20 25

X,

2~-PPEARANCE

OF ALBUMINUIr

1N EIGH'PY-TJIIIEE

~ CASES

])IABETIC

~HILDEEN

. ALBUMINURIA CASES ] PE~ CENT

NO ALBUMINUP~IA CASES I PER CENT

31 31 18 3

9 11 6 O

29 35.4 33.3

22 20 12 3

71 64.6 66.7 100.0

83

26

31.3

57

68.7

Other Complications.--Diabefie coma and glomerulosclerosis accounted for slightly u n d e r 70 per cent of the sixty-one deaths in the present series. The other deaths resulted from surgical operation, some type of infection, or accident. Diabetes represents an additional risk in ease of surgery, but if the diabetic status is carefully watched and m a n a g e d during the emergency, with p r o p e r regnlation of the insulin dosage according to tlhe indications, the results are general]y satisfactory. The five deaths after operation in this series are largely accounted for by the fact that the surgery was performed in small hospitals where adequate facilities for emergency management of the diabetes were lacking. There is a]so the possibility that two of these patients actually had diabetic coma, rather than the acute appendicitis for which operations were performed. Since the onset of diabetic coma is marked by nausea and vomiting, this diagnostic mistake is not rare among physicians without great experience in treatment of diabetes. The importance of thorough study of the carbohydrate metabolism and its fluctuations during any intereurrent infection has already been stressed. I f these sudden changes are not properly controlled, infection may be a precipitating cause of diabetic coma. In any infection in a diabetic child, there is danger of a permanent decrease in the insulinogenic reserve unless adequate protection is given at such a time. SUMIV[ARY

The present study reports an analysis of 500 cases of juvenile diabetes (onset of the disease during the first two decades of life) in a total series of 6,000 diabetics observed during a period of twenty-seven years. Thus the incidence of diabetes in patients 20 years of age or less was 8.3 per cent. The sex distribution in the 500 cases of diabetes in children was practically equal, with 255 (51 per cent) boys and 245 (49 per cent) girls. H e r e d i t y and infection are evidently the prime ctioIogie factors in the development of juvenile diabetes. In this series there was an hereditary or familial history of diabetes in 31.5 per cent, with the incidence in forty-six Jewish children of the group somewhat higher, i. e., 35.5 per cent. Infections,

742

THE

JOURNAL

OF

PEDIATRICS

principally the acute exanthemata, play a considerable role in precipitating the onset of diabetes. In this group of 500 eases, there was a history of antecedent infection in 164. In the majority of these, the diabetes appeared within two months after the infection. A comparison of glucose tolerance tests in adults and children and of the histories of diabetic patients in the two age groups shows the increasing importance of obesity, endocrine disturbances, and degenerative ehanges, particularly arteriosclerosis, in the causation of disturbances in carbohydrate metabolism and in the development of diabetes, with advancing age. Of this series of 500 juvenile diabetics, 364 were traced to the present time. Of these, 303, or 83.2 per cent are living, and sixty-one (16.7 per tent) are dead. Of the 303 living' patients, 41.25 per cent have been followed for ten years or less since the onset of the diabetes, 43.23 per cent have been observed from ten to twenty years, and 1.5.51 per eent have had the disease more than twenty years. Diabetie coma was the principal cause of death in this series, accounting' for thirty-one of the sixty-one deaths. Only six of these thirty-one patients were under my immediate care at the time of death; of these six, one was treated in the preinsulin era and three were moribund and died within one hour after admission to the hospital. The others were under the care of their family physicians, mostly in small towns, at the time of the emergency. The second most important cause of death was intereapillary glomeruloselerosis, whieh brought death to eleven of the sixty-one patients. The other deaths occurred a f t e r infections, surgical operations, or accidents. Deaths in these sixty-one patients occurred from within less than a year to twenty-four years after onset of the diabetes. The largest number died within the first year, i. e., eighteen of the sixty-one (29.5 per cent). Thirty-seven of the deaths oceurred in males and twenty-four in females. As shown by the mortality figures, diabetic coma is the most serious complieation threatening the child with diabetes. According to the records in this series, as experience has been gained by physicians and as the training of younger physicians in the handling of emergencies has improved, the incidence of diabetie eoma has become eonsiderabJy less than in the first decade after insulin was discovered. In this series, there were 218 patients seen from ]920 to 1934, and of these, fifty are known to have had diabetie coma (23 per eent). In the period 1934 to 1948, twenty-seven patients (9.5 per cent) had diabetic coma. Of the seventy-seven patients with this eomp]ieation, fifty-four were under my personal care at the time of the emergency, with a total of six deaths. Twenty-three patients reeeived t}eatment :for the diabetic coma by their family physicians, and in this group there were eighteen deaths. The optimism concerning the fate of diabetic children which represented the general eoncensus in the years immediately following the discovery of insulin has been modified considerably in reeent years by the high ineidenee of premature arterioselerotie changes in these patients, leading to retinopathy and g]omerular changes in the kidney which have led to blindness and early death ~n many instances. In this series, eJeven of the sixty-one deaths ,(18 per cent) were due to intereapillary glomerulosderosis.

JOHN:

DIABETES MELLITUS IN CHILDREN

743

In a series of eighty-three patients in this series whom I have been able to observe by regular periodic examinations over a period of years, twenty-six (31.3 per cent) show albuminuria. In this series, the incidence of albuminuria is not significantly higher in patients who have had diabetes for ten to twentyfive years than in the group who have.bad the disease less than ten years. Other authors report an increasing incidence with longer duration of diabetes. REFE.RENC]~S 1. Sehwartzman, J., Crusins, IVI., and Beirne, D . P . : Diabetes Mellitus in I n f a n t s Under One Year of Age, Am. J. Dis. Child. 74: 587-606, 1947. 2. Priesel, R., and Wagner, R.: Studien iiber das Manifestationsalter nnd die Heredit~itsverhaltnisse des kindliehen Diabetes mellltus, ~Ischr. Kinderhlk. 44: 412, 1929. 3. Pirquet, C.: Quoted by Prlesel u. Wagner, Die Zuekerkrankheit und ihre Behandlung im t(indesalter, Leipzig, 1932, Georg Thieme. 4. Joslin, E. P., and White, P.. Diabetes in Children, J. PEmA'r. 12: 255, 1938. 5. Saundby, Robt.: Lectures on Renal and U r i n a r y Diseases, Bristol, 1896, J o h n W r i g h t & Sons, Ltd. 6. Friese, R., and J a h r , J. M.: Die Klinik des Diabetes mellitus in Kindesalter, Abh. d. Kinderhlk. Berlin, 1932, S. ]s 7. Toverud, I(. U.: Norsk. Mug. f. Laegevid 88: 956, 1923. 8. Lion, G., and Moreau, C.: Diab6,te i n f a n t i l e familial, Arch. d. n%d. des E n f a n t s 12: 21-41, 1909. 9. ]lost, II. F.: Etiology and Cause of Diabetes Mellitus, Norsk. MagMa f. Laegev. 8: 169-232, 1927. 10. Ladd, W. S.: Growth of' Children w i t h Diabetes Mellitus, Am. J. Dis. Child. 32: 812, 1926. 11. Collens, W. S., and Grayze], I-L G.: M a n a g e m e n t of A m b u l a t o r y Diabetic Child, Am. J. Dis. Child 38: 275-293, 1929o 12. Smyth, F. S.: Analysis of Survey on Diabetic Children, Calif. West. Nied. 25: 629633, 1926. 13. John, It. J . : The Diabetic Child, Etiologic l%ctors, Ann. Int. 1Ked. 8: 198-213, 1934. 14. l~ischer, Alfred, ]d." Personal communication. ]5. Landabure, P. B., and Magdalena, A.: Las enfermedades infeetiosas en la etiologia de la diabetes infantil, Dia M6d. 10: 41, 1938. 16. Adams, S . F . : Seasonal Variations in Onset of Acute Diabetes, Arch. Int. Med. 37: 861-864, 1926. 17. Jones, A.: Referred to by yon Noorden, Die Zuekerkrankheit, ed. 8, Berlin, 1927, Julius Springer. t8. Gilhespie, F. B , and ]]olden, ~ . S.: Grave Diabetes MetHtus with Pulmoaary Tuberculosis Following 1Yfumps, Brit. M. J. 2: 115, 1917. 19. Jacob, H. W.: Notes on a Case of Acute Pancreatitis Complicating ~Iumps. British M. J. 1: 1532, 1900. 20. Harris, H . F . : A Case of Diabetes 1Vieliitus Quickly Following Mmnps, Boston M. & S. J. 140: 465, 2899. 21. Lierle, D. M , and :Potter, J. J.: Role of Chronic and of Subaeute Infections in Diabetic Children, Arch. Otolaryng. 14: 432-439, 1931. 22. Wendt, L. F., and Peck~ F. B.: Review of ].073 Cases of Diabetes Mellitus, Am. J. Med. Sei. 181: 52-65, ]931. 23. Lefkowitseh, C. ~I.: Diabetic P u r p u r a , Arch. Pediat. 23: 73, ]906. 24. Smith, R. P.: Diabetes in a Child Three Years of Age, Canad. M. A. Jo 17: 214-216, 1927. 25. Sweeney, J. Shirley: P a n c r e a t i t i s in Diabetes 5Vfellitus, Endocrlno]. 15: 508, 1931. 26. Brems, A.: Alimentary Hyperglycemia in Certain Infectious Disturbances, Ugeskrlft for Laeger 94: 403, 1932. 27. l~reund, tI., and 1Karchand, F.: Ueber das Verhalten des Blutzuckers im Fieber, Deutsch. Arch. f. klin. Med. 110: 120-127, 1913. 28. Rau, It.. Diabetesbehandhmg im Kindesalter, Deut. reed. Wehnsehr. 58: 171-173, 1932. 29. :Hector, F. J . : Carbohydrate Metabolism in Diphtheria, Lancet, 2: 633, 1926. 30. Kasanin, J., Grabfield, G. P. : ]~lood Sugar Curves in Epidemic Encephalitis. Arch. Int. I~ed. 37: 102-I09, 1926. 31. MeCowan, P. K.: Blood Sugar Studies in Epidemic Encephalitis, Lancet, 1: 795-844, 1926.

744

THE JOURNAl, OF PEDIATRICS

52. Brugsch, T., ])ressel, K.. and Lewy, F. H.: Beitr~ge zur Stoffweehsehteurologie. Ztschr. 2. exp. Path. u. Ther. 21: 358-379, 1920. 33. Asehner, B.: Zur Physiologie des Zwischenhirns, Wien. ]din. Wclmsehr. 25: ]042, .1912. 34. Karplus, J. P., and Kreidl, A. : Gehirn und Sympathicus, Pfliiger's Arch. f. d. ges. Physiol. Bonn 135: 406, 1910. 35. Nordmann, 3,L: Glykogenleber bei Poliomyelitis anterio b Vir'chows Arch. f. path. Anat. 263: 832-838, 1927. 36. Labb6, M., and Boulin, R.: Troubles de la glyco-r6gulacion au cours des infeetions~ Bull. et mere. Soe. M6d. d hop. de P a r i s 69: 1358-1368, 3925. 37. Lawrence, IL D.: I n h i b i t i o n of Insulin Action b y Toxem~as) B r i t i s h M. J. 2: 983-984, 1926,

38. Fukud G T., a.lld .1tabashi I~o: Hyperglycemia in Experimental Infection~ Ztschr. s d. ges. exp. Med. 76: 756, 1931. 39. Williams, J. L., and Dick, G. F.: Decreased Dextrose Tolerance in Acute Infectious Diseases, Arch. Int. Med. 1: 801-818, 1932. 40. John, ]4. J . : Glucose Tolerance Studies in Children and in Z.doleseeats, Endocrinology 18: 75~ ]934. 41. Anders, J. M., and Jamesol b :I[. L.: Adiposity and Otl~er Etiological Factors in Diabetes Mellitus. Am. J. M. Se. 170: 313-324, ]925. 42. Mouriquand, G.. Obesity in Children, Lyon m6d. 129: 883, 1920. 43. Zeek, Pearl: Juvenile Arteriosclerosis, Arch. Path. 10: 4[7-446, 1930. 44. White, P., and Waskow~ E.: Arteriosclerosis in Childhood Diabetes. Proc. Amer. Diab. Assn. 8: 141-149, .1948. 45. John, H. J . : Ten Ye'~rs Study and Follow Up of Cases of ]-Iyperthyroidism Showing Carbohydrate Metabolism Disturbances, J. A. M. A. 99: 620-627, .1932. 46. Jolm, ]4. J . : Diabetic Coma Jn Children, Amer. J. Dig. :Dis. & Nutr. 1: 569-578, 1934. 47. :Henderson~ L. L., Sprague, R. G., Wagener, II. p . : Intereapillary Glomerulosclerosis~ Am. J. Med. 3: 131-144~ .1947. 4,S Dolger, ]4.: A Clinical Evaluation of Vascular Damage in Diabetes Mellitus. Proc. Amer. ])iab. Assn. 6: 397-405~ 1946.