Pediatric Annals

Treatment of Diabetes in Children: Revisited

Zvi Laron, MD

Abstract

1. Laron, Z. The Hypothalamus and the Pituitary Gland. D.W. Hubble, ed. In Paediatric Endocrinology. Oxford: Blackwell Scientific Pubi.. 1969. 35-111.

2. Karp, M., Laron, Z., and Doron, M. Insulin secretion in children with constitutional familial short stature. J. Pediat. 83 (1973). 241.

3. Laron. Z. and Karp, M., eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. Basel-New York: S. Karger AG. In press.

4. Weber, B. Glucagon Induced Insulin Secretion in Diabetic Children. Z. Laron and M. Karp, eds. in The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. BaselNew York: S. Karger AG. In press.

5. Laron, Z., Karp, M., and Frankel, JJ. A study of the rehabilitation of juvenile and adolescent diabetics in the Central region of Israel. Petach Tikva. (1972). 202.

6. Sussman. K. E., ed. Juvenile-Type Diabetes and Its Complications. Springfield: Charles C Thomas. 1971, 484.

7. Pardo, V., Perez-Stable. E., Alzamora. D. B., and Cleveland, W. W. Incidence and significance of muscle capillary basal lamina thickness in juvenile diabetes. Amer. J. Path. 68 (1972), 67.

8. Rosenbloom, A. L., D rash, A., and Guthrie, R. A., eds. Chemical diabetes mellitus in childhood. Metabolism 22 (1973). 209-422.

9. Travis. L. B., Lorentz, W. B.. and Carvajal, HF. Diabetes Mellitus. S.S. Geliis and BM. Kagan, eds. In Current Pediatric Therapy, Volume 6. Philadelphia-London-Toronto: W. B. Saunders. Co., 1973. 329.

10. Ritterman, I., Doron, M., Karp, M., and Laron, Z. Plasma insulin reserve in juvenile diabetes and subsequent treatment. Harefuah. In press.

11. Bradley, RF. Diabetic Ketoacidosis and Coma. A. Marble. P. White, R. F. Bradley, and L. P. Krall, eds. In Joslin's Diabetes Mellitus. Eleventh Edition. Philadelphia: Lea & Febiger, 1971, 361.

12. Laron. Z., Karp. M., Franke!, J.J., Amir, S., and Nitzan, D. Clinic and counselling center for juvenile diabetics. The Family Physician 2 (1972), 39.

13. Traisman, H. S. Management of Juvenile Diabetes Mellitus. St. Louis: The CV. Mosby Co., 1971. 56.

14. Laron, Z.. ed. Habilitation and Rehabilitation of Juvenile Diabetics. Leiden: H. E. Stente rt Kroese N. V., 1970.

15. Amir, S. and Laron, Z. Family to Family Guidance. Z. Laron, ed. In Habilitation and Rehabilitation of Juvenile Diabetics. Leiden: H. E. Stenfert Kroese NV. , 1970, 178.

16. Teuscher. A. Insulin Impurities as a Cause of Lipodystrophy in Diabetes Mellitus. Z. Laron and M. Karp, eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics. Volume 12. Basel-New York: S. Karger AG. In press.

17. Sterky, G. Physical fitness and training in juvenile diabetics. Z. Laron, ed. Habilitation and Rehabilitation of Juvenile Diabetics. Leiden: H. E. Stenfert Kroese, N. V., 1970, 115.

18. Laron, Z., Karp, M., Pertzelan. A., and Kauli. R. Insulin, growth and growth hormone. Israel J. Med. Sci. 8 (1972). 440.

19. Etzwiller, D.D. Developing a regional program to help patients with diabetes. J. Amer. Diet. Assoc. 52 (1968), 394.

20. Gill, R. Lack of Patient Motivation in the Treatment of the Juvenile Diabetic. Z. Laron and M. Karp, eds. In The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. Basel-New York: S. Karger AG. In press.

21. Baker, L., Minuchin, S., Milman, L., Liebman, R., and Todd, T. Psychosomatic Aspects of Juvenile Diabetes Mellitus. Z. Laron and M. Karp, eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. BaselNew York: S. Karger AG. In press.

22. Frankel, J.J. Juvenile Diabetes. The Look from Within. Z. Laron and M. Karp. eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. Basel-New York: S.…

No accurate figures are available for the incidence of diabetes mellitus in childhood and adolescence(JDM) - that is, from birth to 18 years of age. With a few possible exceptions, there is no compulsory registration of diabetes mellitus. It is estimated that diabetes occurs in about one out of 1,000 to 2,000 children below 15 years of age. It also is estimated that there are 100,000 to 150,000 children with diabetes in the United States and 1 to 1.5 million in the world. As the incidence of diabetes increases around puberty, the number of children up to age 18 years with the disease certainly swells well over two million. In about 2.4 per cent of these children the onset of the disease is before the age of two years.

It is noteworthy that there is an increase in JDM in developing countries; this is probably due to urbanization, rising standards of living, and changes in nutritional habits. Despite these impressive figures and the fact that diabetes mellitus is the most common pediatric endocrinologie disease, it is not accorded the attention it warrants, either by pediatricians or by diabetologists (see Tables 1 and 2). Pediatric endocrinologists would appear to be more interested in diseases of the adrenals and thyroid glands and, recently, in diseases of the pituitary gland.

Diabetes in childhood presents many problems, not only for the child and his or her family, but for the physician and society as well. In general, the services needed to cope with these problems are available to only a very few of those who require them.

DEFINITION

What is diabetes? The definition of "lack of endogenous insulin" - as measured by radioimmunoassay - does not seem to be fully conclusive; there are several other conditions in which there is a low insulin response to either arginine or glucose stimulation, such as chronic growth hormone deficiency1 or some forms of constitutional growth retardation.2

Table

TABLE 1IS JUVENILE DIABETES NOT AN IMPORTANT ENDOCRINE DISEASE?

TABLE 1

IS JUVENILE DIABETES NOT AN IMPORTANT ENDOCRINE DISEASE?

On the other hand, there are many conditions in childhood, such as the Prader-Willi syndrome, gonadal dysgenesis, ataxia telangiectasia, mucoviscidosis, Down's syndrome, lipodystrophy, and others, in which there is glucose intolerance accompanied by increased plasma immunoreactive insulin.3 Do these children have diabetes? Adults with the same laboratory findings are said to have at least latent diabetes, meaning that they have a genetic predisposition for the disease that may develop into overt diabetes when one or more environmental factors (such as infectious disease, obesity, or psychological stress) become active.

Chemical diabetes is a stage in which there is an inability of the body to handle a glucose load, resulting in glucose intolerance. This is accompanied by hyperinsulinism or a delayed peak of insulin or both. This stage is either reversible to latent diabetes or may proceed to overt diabetes, with ultimate exhaustion of the pancreatic beta cells resulting in lack of insulin response. Contrary to previous belief, these stages seem to exist in many children (see below) and resemble the glucose intolerance encountered in the syndromes listed above.

From the above information it would seem that diabetes is a syndrome, rather than a single disease entity, which is characterized by deficiency of insulin activity and not by the quantity of measurable immu noreactive insulin. Recent findings stress this point: in children who have no insulin response to glucose (and would thus be classified as typical juveniletype diabetics) there is a rise in plasma immunoreactive insulin (IRI) upon the administration of intravenous glucagon.4

HEREDITY

The exact mode of inheritance of diabetes mellitus is not known but it is probably polygenic. We have found the incidence of diabetes to be twice as frequent in the families of 100 diabetic children as in a matched control group.5 When both parents have diabetes, overt diabetes is found in about eight per cent of their children but presumably many more, perhaps 30 per cent, will develop diabetes later in life.

It is important to recognize potential or early diabetes as early as possible to attempt to prevent development of overt disease and the numerous neurologic and vascular complications6 that may develop with it (such as vascular disturbances) and that appear to be related to the duration of the disease. Newly diagnosed diabetic children have normal capillary basement membrane thickness.7

The glucose tolerance test, which measures both glucose and insulin response, is the most practical tool available today for the discovery of early diabetes.8 This test makes it possible to recognize glucose intolerance, hypo- or hyperinsulinism, and a delayed insulin response. These abnormalities may appear not only in the children of diabetic parents and in the sibs of diabetic children but also may appear in an array of conditions, some of which have been enumerated. It would therefore be wise to test any child "at risk." Puberty, with its increased hormonal activities, may aggravate diabetes or a prediabetic condition. Depending upon the circumstances, testing should be repeated at intervals; when an abnormality has been established, the interval between tests should not exceed six months.

Table

TABLE 2HOW IMPORTANT IS JUVENILE DIABETES TO DIABETOLOGISTS?

TABLE 2

HOW IMPORTANT IS JUVENILE DIABETES TO DIABETOLOGISTS?

If a patient is suspected of having diabetes or even if a patient already has symptoms such as weight loss, increased thirst, polyuria, weakness, etc., it is not sufficient (as is often customary) to ascertain that the patient has glycosuria with or without ketonuria and a higher than normal blood glucose in order to institute insulin therapy.' Our approach in such a case is as follows (see Table 3). A 7V2-year-old girl was referred to us because of typical clinical signs of diabetes - weight loss, polydipsia, and glycosuria. She had ketonuria but her general condition was good. After an oral glucose tolerance test (OGTT) was performed, she was sent home until next morning with dietary instructions. The patient's high blood sugar values are shown in Table 3. Next day an arginine test was performed, and insulin treatment was started. Two days later she returned to school.

Other physicians would have hospitalized the child for at least several days and perhaps weeks and would have tried to balance her diabetes under artificial conditions. The hospitalization itself would have frightened the patient because it would prove the seriousness of the disease and would have disrupted her and her family's normal life.

Table

TABLE 3ORAL GLUCOSE TOLERANCE TEST AND ARGININE STIMULATION TEST IN S.R. 7 8/12 YEAR-OLD GIRL WITH DIABETES MELLITUS

TABLE 3

ORAL GLUCOSE TOLERANCE TEST AND ARGININE STIMULATION TEST IN S.R. 7 8/12 YEAR-OLD GIRL WITH DIABETES MELLITUS

The measurement of endogenous insulin in addition to blood glucose during an oral glucose load is very helpful in deciding upon the therapeutic scheme.

Figure 1 shows the glucose tolerance tests of three groups of diabetic children without insulin therapy, as compared to healthy controls.10 We see three degrees of glucose intolerance. Group III had the highest glucose levels and subsequently required insulin therapy. Group I was on oral therapy for one year or more, and Group II was in clinical remission after dietary therapy alone.

Figure 2 illustrates the insulin response during the same test. It is interesting to see that Group III, which required insulin injections due to its high blood glucose and clinical state (weight loss, polyuria, weakness and ketosis) had almost no insulin reserve. These patients had almost no insulin reserve because upon I.V. glucagon injection they still show some endogenous insulin. Group II, in remission, has somewhat more insulin with a typical delayed response, and Group I, even after one year of oral therapy, has an appreciable insulin reserve.

Figure 1. Oral glucose tolerance test in three groups of diabetic children.

Figure 1. Oral glucose tolerance test in three groups of diabetic children.

In order to obtain additional information on the patients to whom we decided not to give insulin immediately, we performed a daily sugar curve after a few days on a low carbohydrate diet. Blood sugar usually is measured before meals at 7:30 a.m., noon, and 6:00 p.m. If values are below 200 mg. per cent, an attempt is made to use diet or oral agents. The aim is to maintain a blood sugar concentration of below 150 mg. per cent, with very little or no urinary sugar.

The importance of these testings, done on an ambulatory basis, is illustrated again in Figure 3, which demonstrates variations in glucose tolerance but little changes in insulin in a 13year-old girl on diet and/ or oral therapy.

These examples prove that not all diabetics in the pediatric age group require insulin immediately. This group is a minority at present, but early detection of cases at risk and in the early stages of disease will increase their number. Postponement of injection diminishes the psychological impact of having diabetes or of having a child with diabetes and avoids the problem of hypoglycemia. Even if this postponement is a short period, it permits the patient and his or her family to adjust to the new and threatening condition.

In many places patients are referred for treatment in serious condition and have marked ketoacidosis, dehydration, and even coma. The treatment of this condition is covered amply in textbooks9'11 and will not be dealt with here. The fact that we have not seen such patients for the last 10 years may serve as evidence that a well developed educational program for the general population and medical personnel leads to early recognition of the disease and early institution of therapeutic measures. We have found that the regular facilities available in a hospital are not sufficient to implement this kind of educational program. We therefore have established a Counselling Center for Juvenile Diabetics.12 Because of the psychological impact of diabetes, psychologists and social workers are an integral part of our team. At referral, the patient (if old enough) and the parents are given an explanation of the disease and are told why some testing is necessary before deciding upon which treatment should be given. If the general condition of the patient is satisfactory and he or she does not require intensive care, we explain that there is no danger in keeping the child at home.

The psychological shock of the parents and older patients is dealt with by the psychologist and social worker. The dietitian explains the principles of a low carbohydrate diet (usually 1,500 cal.), and the nurse teaches how to test urine three times a day for sugar and acetone using Clinitest tablets and Ketostix, 13 how to register the findings, and how to collect urine for 12-hour night and day samples.

After two to three days of ambulatory testing and urine examination at home it is decided whether insulin or an oral agent is indicated in addition to diet. Very rarely have we had to start insulin immediately upon referral. The child returns to school about three to four days after referral. The school physician, nurses, and teacher are invited to pay a visit to the center. If they do not come, a physician and social worker or psychologist visit the school, advising them how to deal with the diabetic child. It is only rarely that we have encountered families who decide to keep the disease a secret because of various motivations (often religious) and do not permit us to contact the school in the initial stage of the disease.

Figure 2. Plasma insulin response during oral glucose tolerance test in three groups of diabetic children.

Figure 2. Plasma insulin response during oral glucose tolerance test in three groups of diabetic children.

Figure 3. Changes in glucose tolerance in a 13-year-old girl with diabetes treated by diet or oral agents or both. Note the delayed insulin response.

Figure 3. Changes in glucose tolerance in a 13-year-old girl with diabetes treated by diet or oral agents or both. Note the delayed insulin response.

At the beginning of treatment the family calls one of our physicians every evening to report the urine tests - to help them adjust the insulin dose, if necessary. However, these calls become less and less frequent as the family comes to feel more and more self-sufficient. In the meantime the patients, parents or both receive more education on diabeties by participating in small group talks with the physician,6 and by guided reading in the center's library. The social worker and psychologists help with adjustment problems at home, which sometimes exist in large families of low socioeconomic classes.14 If necessary, an experienced family of the same cultural background is called in to help in a "family to family guidance" program.15 Other services consist of monthly meetings for lectures and panel discussions, when diabetics and their families are able to meet others with similar problems. Much emphasis is put on early recognition, treatment, and prevention of hypoglycemia.

We feel that this "intensive approach of comprehensive care carried out on an ambulatory basis during the initial period of the disease" has been very beneficial for the patients and their families and gratifying for us.

It is our opinion that even in those countries in which ambulatory treatment cannot be performed due to the great distances between hospital and home, or because the patient has been diagnosed late and is in need of rehydration and immediate insulin, the period of hospitalization can be made quite short.

Follow-up is performed according to need, from weekly to three-month visits. We advise urine testing three times a day by Clinitest as the best indication of degree of balance and as an aid for adjustment of the insulin dose. With young children this is done by the parents. Later the patient learns how to do the urine testing; however, we have found that during puberty there is a high degree of refusal.

With the aid of the dietitian, the diet is adjusted according to need, family habits, and ethnic customs. The principles of nutrition are taught by individual teaching using plastic models, slides, food exhibits, group discussions, a demonstration kitchen, and written material. As weighing of the food is a burdensome procedure, the patient and family are taught to make approximate calculations. We advise reduction in animal fats and use of polyunsaturated fat. Instructions alone are not helpful, unless they are implemented. Therefore, it is necessary to find out whether the patient complies and, if not, why not.

At follow-up visits the patient is seen by a physician and psychologist or physician and social worker team. The interpretation of the urine tests performed at home, the day and night quantitative glucose excretion, and the results of the blood glucose examination are later discussed together with the dietitian, and the conclusions are transmitted to the patient and his or her private physician, if the patient has one.

The patient is taught independence but it is not forced upon him or her. The patient's problems- which in most instances are also shared by others - are discussed in private meetings or in group discussions.

The child is taught to inject him- or herself with insulin as soon as possible but, if for psychological reasons the patient is not willing to do injections for some time, we do not force him or her but wait until the patient is ready. We recommend disposable syringes and 20-21 gauge needles. We discourage the use of automatic syringes, which usually lead to superficial injection, irregular absorption of the insulin, and lipodystrophy or insulin tumors. In most instances we use one injection per day - consisting of NPH or a combination of NPH plus regular insulin. At puberty some patients may require two injections a day. There is sufficient proof today that impurities in the insulin preparations are the main cause of local lipodystrophy.16 Purer insulin, such as the monocomponent preparations, should be made available to the public. Neutral insulin seems to be preferable also.

The education and counseling program, which includes genetic counseling and vocational rehabilitation, is started as soon as the diagnosis of diabetes is made; it does not await the summer camp, which may be months away.

We advise physical exercise and participation in sports activities17 with precautions such as urine testing and eating a light meal before the activity and spot tests of urine at intervals, depending upon physical strain or subjective feeling.

GROWTH AND DEVELOPMENT

A tendency for diabetic children to be taller at diagnosis has been claimed for a long time; we consider that this may be due to a hyperinsulinemic stage of prediabetes.18 This seems to be true for only some diabetic children. Longstanding diabetes slows linear growth, probably by insufficient control. Sexual and intellectual development are normal.

INFECTIONS

Diabetic children, especially those not under adequate control, are very susceptible to infections. Vaginal and urinary tract infections are most frequently seen. Intercurrent infections may upset the metabolic balance. Depending upon the necessity of intravenous therapy or other special care, a short hospitalization may sometimes be indicated. The patient can be returned home with high blood glucose and ketosis, which is easier to treat at home or while going back to school than during hospitalization.

VASCULAR AND NEUROLOGIC COMPLICATIONS

Late complications of diabetes are discussed with older patients and parents at various occasions as soon as they have overcome the first shock period. We try not to frighten them but stress that new research findings show that at diagnosis there are no vascular changes, which develop only within years, and that there is accumulating evidence that better balance postpones or prevents complications.

Our yearly routine examinations inelude urinary albumin excretion, fundi examination, neurologic checkup, and EEG and psychological tests at longer intervals. In older patients EMG, EKG, and ergometry may be indicated as well.

Figure 4. The impact of having diabetes on the juvenile patient.

Figure 4. The impact of having diabetes on the juvenile patient.

PSYCHOSOMATIC AND SOCIAL ASPECTS

There is little doubt that, once diagnosed, diabetes becomes a psychosomatic disease for the child and a cause for anxiety for the parents. The psyche and soma or organic aspect are so interrelated in diabetes that neglect in treatment of one of them obviously leads to an imbalance of the disease (Figures).

Diagnosis of diabetes causes a shock to the older child and to the parents, many of whom react with true "mourning." The child has to accept that he or she has been struck by a chronic disease, for which so far there is no permanent cure. We are against giving false statements such as "diabetes is not a disease" or "diabetes is kid's stuff."

Figure 4 shows some of the problems the young diabetic is faced with - the young diabetic has to accept that he or she is different from healthy peers because he or she has to test urine, give him- or herself injections, regulate diet, adjust insulin dose, and adjust physical activities. The diabetic has to get up earlier every morning to do all this, he or she cannot skip breakfast as many children do, and he or she still has to arrive on time at school.

The young diabetic is torn between many conflicts, such as with the family, which worries, o ver protects, or rejects him or her; some parents try to change their dietary habits to help their child. Good control of diabetes requires regular meals, which adolescents hate, and is difficult to oblige during the activities at school. At school there is ignorance as to what to do with the diabetic and how to handle his or her state. (We heard of a teacher who sent a child home "alone" because he did not feel well. He had hypoglycemia and could have fainted in the street.)

There is the problem of participation in social activities and sports; and very often this is forbidden to the child because his or her superiors do not want to take any responsibility. The young diabetic is worried about the future; in our country (in contradistinction to others) not to be accepted by the army is the worst thing that can happen to any youngster. It means that the society ostracizes him or her. This also happens when the diabetic applies for a job. Many employers, even government institutions in many countries, reject the diabetic. Until very recently the diabetic could not become a teacher in France or Argentina, a nurse in our country, etc. What about marriage. children, and complications? Many of these worries pass to the parents.

An important role in the habilitation to the disease is the education of child and parents; we have to explain and teach them what diabetes is and why they have to adjust the diet, insulin, and how to cope with various situations. It is impossible to teach the principles of nutrition or of pathophysiology of a complicated disease in a few hours or even a few days - as is done in many places where the child is hospitalized, instructed, and handed a booklet. In the first few weeks the parents and child are shocked and their ability to adequately learn everything is limited. Therefore, they need "continuing education" with modern tools, by a specialized team.19 The explanations of a busy practitioner or the wait for the next summer camp are insufficient, and permanent teaching programs available 365 days a year are an absolute necessity.

How should we explain all the limitations and regulations to the diabetic in order that he or she adheres to them? How can we teach motivation?20

The child may refuse cooperation because he or she is afraid of the emergence of the "bad me," which will lead to punishment and rejection by parents and physician. The child may distrust or fear the omnipotence of the therapist and equate conforming to loss of control. The parents often reject help because they fear to face their own problems, to acknowledge failure, and because of their carefully hidden feeling of guilt.

Figure 5. The balance of diabetes.

Figure 5. The balance of diabetes.

If there is no motivation to stick to the rules, control of diabetes will be inadequate, leading to hypoglycemic attacks or hyperglycemia and ketosis. This in turn may cause long and repeated hospitalizations, which will deeply affect the feelings of the sick patient and his or her family. The causative factor of the psyche in ketoacidosis has been proved by Dr. Baker and his group,21 who administered beta adrenergic blocking agents to hyperreacting patients in conjunction with psychotherapy.

We believe in preventive intervention - handling the psychological aspect concomitantly with the medical treatment and education of which it is an integral part. The psychologist is one of the therapeutic team, he or she sees the patient together with the physician. The psychologist calms the tension and tries to better understand the feelings of the patient and the family. This is also done by group discussions of parents and of youngsters according to age groups. By this approach we also learn what the diabetic thinks about him- or herself, about his or her therapists, and about "them" - the third not so sympathetic world.22

We cannot teach the patient responsibility of self-care if we do not consider him or her a full member of the therapeutic team. Instruction sheets and books are only aids; summer camps last only two to three weeks and are often months away, they are also not attended by all diabetic youngsters.

CONCLUSIONS

In order to adequately treat diabetes in juveniles, we need special centers where a multidisciplinary team consisting of physician, nurse, psychologist, social worker, and rehabilitation counselor plan and execute the habilitation and rehabilitation of the juvenile diabetic, the family, and surroundings.

The Israel Counselling Center for Juvenile Diabetics at the Beilinson Hospital is successfully functioning according to the above principles. It is too early to judge all our achievements, but we have not seen diabetic coma for 10 years and among 350 juvenile patients have only two with so-called true brittle diabetes. We try to explain it by our continuous comprehensive multidisciplinary therapeutic program.

BIBLIOGRAPHY

1. Laron, Z. The Hypothalamus and the Pituitary Gland. D.W. Hubble, ed. In Paediatric Endocrinology. Oxford: Blackwell Scientific Pubi.. 1969. 35-111.

2. Karp, M., Laron, Z., and Doron, M. Insulin secretion in children with constitutional familial short stature. J. Pediat. 83 (1973). 241.

3. Laron. Z. and Karp, M., eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. Basel-New York: S. Karger AG. In press.

4. Weber, B. Glucagon Induced Insulin Secretion in Diabetic Children. Z. Laron and M. Karp, eds. in The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. BaselNew York: S. Karger AG. In press.

5. Laron, Z., Karp, M., and Frankel, JJ. A study of the rehabilitation of juvenile and adolescent diabetics in the Central region of Israel. Petach Tikva. (1972). 202.

6. Sussman. K. E., ed. Juvenile-Type Diabetes and Its Complications. Springfield: Charles C Thomas. 1971, 484.

7. Pardo, V., Perez-Stable. E., Alzamora. D. B., and Cleveland, W. W. Incidence and significance of muscle capillary basal lamina thickness in juvenile diabetes. Amer. J. Path. 68 (1972), 67.

8. Rosenbloom, A. L., D rash, A., and Guthrie, R. A., eds. Chemical diabetes mellitus in childhood. Metabolism 22 (1973). 209-422.

9. Travis. L. B., Lorentz, W. B.. and Carvajal, HF. Diabetes Mellitus. S.S. Geliis and BM. Kagan, eds. In Current Pediatric Therapy, Volume 6. Philadelphia-London-Toronto: W. B. Saunders. Co., 1973. 329.

10. Ritterman, I., Doron, M., Karp, M., and Laron, Z. Plasma insulin reserve in juvenile diabetes and subsequent treatment. Harefuah. In press.

11. Bradley, RF. Diabetic Ketoacidosis and Coma. A. Marble. P. White, R. F. Bradley, and L. P. Krall, eds. In Joslin's Diabetes Mellitus. Eleventh Edition. Philadelphia: Lea & Febiger, 1971, 361.

12. Laron. Z., Karp. M., Franke!, J.J., Amir, S., and Nitzan, D. Clinic and counselling center for juvenile diabetics. The Family Physician 2 (1972), 39.

13. Traisman, H. S. Management of Juvenile Diabetes Mellitus. St. Louis: The CV. Mosby Co., 1971. 56.

14. Laron, Z.. ed. Habilitation and Rehabilitation of Juvenile Diabetics. Leiden: H. E. Stente rt Kroese N. V., 1970.

15. Amir, S. and Laron, Z. Family to Family Guidance. Z. Laron, ed. In Habilitation and Rehabilitation of Juvenile Diabetics. Leiden: H. E. Stenfert Kroese NV. , 1970, 178.

16. Teuscher. A. Insulin Impurities as a Cause of Lipodystrophy in Diabetes Mellitus. Z. Laron and M. Karp, eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics. Volume 12. Basel-New York: S. Karger AG. In press.

17. Sterky, G. Physical fitness and training in juvenile diabetics. Z. Laron, ed. Habilitation and Rehabilitation of Juvenile Diabetics. Leiden: H. E. Stenfert Kroese, N. V., 1970, 115.

18. Laron, Z., Karp, M., Pertzelan. A., and Kauli. R. Insulin, growth and growth hormone. Israel J. Med. Sci. 8 (1972). 440.

19. Etzwiller, D.D. Developing a regional program to help patients with diabetes. J. Amer. Diet. Assoc. 52 (1968), 394.

20. Gill, R. Lack of Patient Motivation in the Treatment of the Juvenile Diabetic. Z. Laron and M. Karp, eds. In The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. Basel-New York: S. Karger AG. In press.

21. Baker, L., Minuchin, S., Milman, L., Liebman, R., and Todd, T. Psychosomatic Aspects of Juvenile Diabetes Mellitus. Z. Laron and M. Karp, eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. BaselNew York: S. Karger AG. In press.

22. Frankel, J.J. Juvenile Diabetes. The Look from Within. Z. Laron and M. Karp. eds. The Various Faces of Diabetes in Juveniles. Modern Problems in Pediatrics, Volume 12. Basel-New York: S. Karger AG. In press.

TABLE 1

IS JUVENILE DIABETES NOT AN IMPORTANT ENDOCRINE DISEASE?

TABLE 2

HOW IMPORTANT IS JUVENILE DIABETES TO DIABETOLOGISTS?

TABLE 3

ORAL GLUCOSE TOLERANCE TEST AND ARGININE STIMULATION TEST IN S.R. 7 8/12 YEAR-OLD GIRL WITH DIABETES MELLITUS

10.3928/0090-4481-19740701-08

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