Diazoxide treatment of idiopathichypoglycemia of infancy

494

October, 1967 T h e ]ournal o[ P E D I A T R I C S

Diazoxide treatment of idiopathic hypoglycemia of infancy Diazoxide has been used in the treatment of eight infants and children with severe idiopathic hypoglycemia. During periods o[ treatment ranging from 4 to 18 months, patients responded well to administration of Diazoxide even though control had previously been inadequate on corticosteroid therapy. The most [requent side effect has been hypertrichosis lanuginosa. Suppression o[ insulin response appears to be an important part of the mechanism of action of Diazoxide.

Lester Baker, M.D., Robert Kaye, M.D., Allen W. Root, M.D., and A. L. N. Prasad, Ph.D. PHILADELPHIA, PA.

D I A Z o X I D E,, * a nondiuretic benzothiadiazine, was originally introduced as an antihypertensive agent? Its potent hyperglycemic potential 2 precluded its use as a routine drug for that disease, but Drash and Wolffa suggested that this side effect could be put to good use in the treatment of idiopathic hypoglycemia of infancy, a disease for which therapy is not completely adequate. The high doses of corticosteroids required to maintain normoglycemic levels in many of these children result in significant Cushingoid-like side From the Divisions o[ Metabolism and Endocrinology of the Children's Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania, School of Medicine. Supported in part by United States Public Health Service Grants HD00444, AM-00619-09 (HD 00371-10), TGMD (5T)-IAM-05197-08. Several of these children were studied in the Clinical Research Center o[ the Children's Hospital o[ Philadelphia, supported by FRO0240, Division of Research Facilities and Resources. ~'Chernlcal name, 3-methyl-7-chloro-l,2,4-benzotMadlazine-l,l-dioxide. VoL 71, No. 4, pp. 494-505

effects, such as suppression of growth and hypertension. Subtotal pancreatectomy may be required, if the basic diet-steroid regimen is not effective. Though therapeutically helpful, 4 it is usually not curative. Thus, the introduction of a potentially effective drug which might lessen the requirement for subtotal pancreatectomy and avoid the side effects of steroid therapy promised a significant advance in the treatment of idiopathic hypoglycemia of infancy. Since July of 1965, 8 children with severe idiopathic hypoglycemia of infancy have been treated with Diazoxide at the Children's Hospital of Philadelphia. Appraisal of the clinical effectiveness of this drug, together with observations bearing on its possible mechanism of action, form the basis of this report. METHODS

AND

MATERIALS

Patients. Clinical data concerning the 8 patients are presented in Table I. The first

Volume 71 Number 4

Diazoxide treatment in hypoglycemia

495

T a b l e I. Clinical data on hypoglycemic patients Age at onset and symptoms

Sex

R.L.

F

5 Days; jaundice, lethargy, leading to twitching

5 Days

1. Steroids and low leucine diet a. Marked Cushingoid changes b. Poor control of symptoms leading to suspected brain damage

G.P.~

M

9 Months; staring episodes leading to twitching

9 Months

1. Steroids, low leucine diet, zinc glucagon and epinephrine a. Severe growth retardation b. Only fair control of hypoglycemia: 6 admissions in 1 year's time

B.P.~

M

6 Months; seizures

7 Months

1. Steroids, low leucine diet, zinc glucagon and long acting epinephrine a. Severe growth retardation b. Only fair control of hypglycemia: 5 admissions from 9/647/65 2. Subtotal pancreatectomy a. Normal pathology b. Recurrence of symptoms 2 months postoperative

C.H.

M

4 Months; convulsions

5 Months

1. Steroids a. Poor control: 5 admissions in 7 months. Anorexia associated with intercurrent illnesses caused hypoglycemic attacks

C.B.

F

4 Months; seizures

M.S.

M

2~2 Years; seizures

2%2 Years

1. Subtotal panereatectomy a. Pathology: islet cell hyperplasia b. Recurrence of hypoglycemic symptoms 2 months postoperatively

B.M.

M

2}[2 Years; coma

24"52 Years

1. Steroids a. Severe growth retardation b. Cushlngoid changes with striking hepatomegaly

S.D.

M

8 Months

1. No therapy tried before Diazoxide other than low leucine diet

7 Months; seizures accompanied by profuse sweating ~G. P. and B. P. are brothers.

Age at diagnosis

Therapy prior to Diazoxide therapy and results

Patient

10 Months (brought to Children's Hospital because of slow development; random OPD blood sugar -~ 3 mg. per 100 ml.)

6 members of this group received glucocorticoids in high dosage (1 to 2 mg. per kg. per day of prednisone or its equivalent) with only fair to poor results. R a n d o m fasting blood-sugar values were often low in these children, a n d the anorexia associated with i n t e r c u r r e n t illness frequently provoked frank hypoglycemic attacks. Thus, repeated

1. ACTH and steroids a. Poor control with many admissions b. Cushingold changes c. Still had occasional early morning seizures

hospitalizations for the p a r e n t e r a l administration of glucose were often necessary. Additional efforts at regulation of the hypoglycemia had included such measures as: low leucine f o r m u l a (S-14~), where indicated; zinc glucagon, long-acting epinephrine; in'*Obtained through Dr. John Silverio of Wyeth Laboratories Radnor, Pa.

496

Baker et al.

fusion of plasma from diabetic patients with elevated anti-insulin antibodiesS; and partial pancreatectomy. Patient M. S. was referred to the Children's Hospital after a partial (80 per cent) pancreatectomy performed at another institution. This operation had been successful in halting hypoglycemic symptoms for a period of only two months. This patient had not been given a therapeutic trial with glucocorticoids before or after surgery. Only the most recently treated patient in the series (S. D.) was placed initially on therapy with Diazoxide after the diagnosis of idiopathic hypoglycemia of infancy of the leucine sensitive variety was established. All patients were admitted to the Clinical Research Center of the Children's Hospital of Philadelphia. Oral glucose tolerance tests were performed before and shortly after the start of therapy, utilizing a dose of 1.75 Gin. per kilogram. Parameters measured during these tests included glucose, free fatty acid, insulin and growth hormone levels. In addition, where indicated, leucine tolerance tests were also performed, with 150 mg. per kilogram of 1-1eucine used orally. The 24 hour urinary excretion of catecholamines were measured during a control period before the start of Diazoxide therapy and again when the hypoglycemia appeared to be under good control after 7 to 10 days of Diazoxide therapy. The children have been evaluated at periodic intervals since the start of therapy. The evaluations have included: (1) fasting blood sugars; (2) complete blood counts, including platelet and reticulocyte determinations; (3) liver function tests, including transaminase levels; (4) blood-urea-nitrogen values and creatinine clearance; (5) uric acid levels; (6) 24 hour urinary excretion of catecholamines; and (7) radiotogical examination for bone age. Initially, patients received Diazoxide* in doses of 10 to 12 mg. per kilogram per day. Concurrent therapy has included the use of hydrochlorothiazide, 25 mg. per day. This was done because of the reports in adults concerning the sodium-retaining properties *Diazoxide supplied by Drs. J. Black and H. Schwartz of the Scherlng Corporation.

The Journal of Pediatrics October 1967

of Diazoxide and the theoretical potentiating effect which the thiazides may have when used in combination. With continuing experience concerning the side effects of Diazoxide, however, attempts have been made to begin at a lower dosage level (5 to 8 mg. per kilogram per day). The dose of the corticosteroid was rapidly tapered to the physiological level after the start of Diazoxide therapy. The use of the steroid was then gradually discontinued. Laboratory methods. Blood-glucose level was measured by the glucose oxidase method. 6 Free fatty acids were determined according to the colorimetric technique of Duncombe. z,s The radioimmunoassay of plasma insulin was performed by the technique of Yalow and Berson9 with Lilly pork insulin 818194, 25.7 units per mg.* used as a standard. The double antibody technique of Schalch and Parker 1~ was used for the estimation of growth hormone, with the use of Wilhelmi standard HS612B, 1.7 I.U. per milligram.t Urinary catecholamines were done by modification of the procedure of Anton and Sayre, TM 12 and Vanillylmandelic acid (3-hydroxy-4-methoxy-mandelic acid) was analyzed by the technique of Pisano and associates ~a and Connelian and colleagues? 4 RESULTS Clinical

General. The over-all clinical results are given in Table II. As can be seen, Diazoxide proved to be an extremely effective hyperglycemic agent. In one of the more dramatic instances, a child (G. P.) who had required five hospital admissions for control of hypoglycemia in the year prior to Diazoxide treatment now required only one further admission other than for investigative purposes. The use of Diazoxide has permitted discontinuation of steroid therapy in 5 of 6 patients who were on very high doses. One patient (R. L.) is still on a physiological dose of hydrocortisone which is presently being -~Supplied Laboratories, J-Supplied Biochemistry,

by Dr. Mary Root of the Lilly Research Indianapolis, Indiana. through Dr. A. E. WilhelIni, Professor of Emory University, Atlanta, Ga.

Volume 71 Number 4

Diazoxide treatment in hypoglycemia

49 7

T a b l e I I . Results of D i a z o x i d e t h e r a p y Patient R.L.

G.P.

B.P.

Age and date started

Results Side effects Miscellaneous 6 Weeks; August, Good 1. Hirsutism, striking Still has marked leu1965 a. Still requires small dose 2. Advancement of cine sensitivity of hydrocortisone bone age b. Growth and development 3. Neutropenia, trannormal sient 21 Months; August, 1965

4aA2 Years; September, 1965

C.H.

11 Months; October, 1965

C.B.

5 89 Years; October, 1965

Excellent a. No longer on steroids b. Growth spurt e. No severe hypoglycemic episodes d. Has had only one admission other than to CRC*

1. Hirsutism, striking Loss of marked leu2. IgG decrease cine sensitivity 3. Neutropenia, transient

Excellent 1. Hirsutism, striking Loss of marked leua. No longer on steroids 2. IgG decrease cine sensitivity b. Significant growth spurt 3. Neutropenia, tranc. No hypoglycemic episodes sient d. Has had only one admission other than to CRC ~ Excellent a. No longer on steroids b. No hospitalizations

1. Hirsutism, mild

Abnormal EEG; on phenobarbital

Excellent a. No longer on steroids b. No hospitalizations c. No severe hypoglycemic symptoms

1. Hirsutism, mild

Responded to diabetic plasma infusion. 5 Markedly retarded

M.S.

3~2 Years; May, Excellent 1966 a. No severe hypoglycemic episodes

1. Hirsutism, mild

Required increase in dosage after one mild staring attack

B.M.

2a~ Years; July, Excellent 1966 a. No longer on steroids b. Significant growth spurt c. No severe hypoglycemic episodes

1. Hirsutism, striking

S.D.

8 Months; August, 1966

Excellent 1. Hirsutism, striking Loss of marked leua. No hypoglycemic episodes cine sensitivity b. Growth and development completely normal

"~'Clinical Research Center.

tapered. T h e growth spurt which followed the cessation of steroid t h e r a p y has been impressive (see Fig. 1 for a representative example, G. P.). I m p r o v e d g r o w t h has been instrumental in the parents' a c c e p t a n c e of the side effects of Diazoxide. Side effects. T h e p r e d o m i n a n t side effect of Diazoxide t h e r a p y in the present group has been the d e v e l o p m e n t of hypertrichosis l a n u g i n o s a ? 5 T h e growth of vellus hair has

been stimulated, p r e d o m i n a n t l y on the face a n d the dorsal aspects of the trunk a n d limbs, along with involvement of the eyebrows a n d eyelashes. This has been observed as early as 6 weeks after the initiation of treatment. I n 4 patients, the hair growth has been striking a n d has been of cosmetic significance (see Fig. 2). I n the 4 other patients, increased hair growth was observed, b u t it was of a m i l d e r degree.

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Volume 71

Number 4

Diazoxide treatment in hypoglycemia

499

B

Fig. 2. A and B, Front and rear views of Patient R. L. Note the striking increase of hair growth. Details in text.

Transient neutropenia has been noted in three patient% but leukocyte levels returned to normal without change in drug dosage. Thrombocytopenia has not been noted in the current series. Liver function and renal function were not affected by the drug. Moderate hyperuricemia, with blood levels of 6.0 to 7.5 mg. per 100 ml., has been noted in all patients under therapy, but this has not been associated with symptoms nor with any change in creatinine clearance. None of the patients demonstrated hypotension or fluid retention. Depression of immunoglobulin-G levels was noted in 5 patients. This was not associated to date with any apparent increased susceptibility to infection. 1G Laboratory observations Blood glucose a. The ability to withstand fasting: Prolonged fasting experiments were not carried out. However, blood glucose levels obtained after an overnight fast of 8 to 12 hours were consistently above 45 nag. per 100 ml. after

therapeutic levels of Diazoxide had been achieved. b. Glucose tolerance tests: These are shown in the first column of Fig. 3. In general, there was a displacement upward of the glucose tolerance curve measured after the child had been treated with Diazoxide for approximately one week. In some patients, a rapid decrease in steroid dosage may have served to counterbalance some of the more favorable effects of Diazoxide on glucose tolerance. c. Leucine tolerance tests: 4 patients demonstrated leucine sensitivity initially; 3 of them (B. P., G. P., and S. D.) no longer exhibit leucine sensitivity while on Diazoxide therapy. It is interesting that this apparently is a cumulative effect of the drug: A leucine tolerance test performed 10 days after the start of Diazoxide therapy still demonstrated a marked hypoglycemie effect in Patient B. P., but another study 5 months later showed complete loss of leucine sensitivity (see Table I I I ) .

500

Baker et al.

The Journal o[ Pediatrics October 1967

Table I I I . Oral Ieucine tolerance tests on Patient B. P. Blood glucose , (rag.~ I I00 mI.)

_.

Free fatty acids (mEq./L.)

Insulin (~U/ml.)

9/15/65 (Steroids; no Diazoxide)

Fasting 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes

62 52 51 44 31 30

1.39 1.33 1.74 1.76 0.94 0.89

3 3 16 3 5 3

9/23/65 (After 1 week of Diazoxlde therapy; steroid dose within physiological range)

Fasting 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes

49 44 30 41 26 20

0.96 1.06 -0.98 0.77 0.47

0 2 -2 13 2

4/5/66 (5 89 months of Diazoxide therapy; no administration of steroids)

Fasting 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes

66 84 93 83 62 58

0.86 0.37 0.34 0.27 0.24 0.21

0 0 0 0 0 5

Free [atty acids. The second section of Fig. 3 shows free fatty acid levels in the hypoglycemic group during the standard glucose tolerance test performed before and after the start of Diazoxide therapy. No significant differences can be noted in these values. Insulin levels. Plasma insulin concentrations determined during the glucose tolerance tests are depicted in the third column of Fig. 3. In all subjects, Diazoxide appeared to decrease the insulin response to the standard glucose stimulus. The insulin levels obtained during sequential leucine tolerance studies in patient B. P. are shown in Table III. The loss of leucine sensitivity is shown here to be associated with a decrease in the concentration of insulin elicited by the leucine stimulus. Growth hormone. Growth hormone values during the glucose tolerance tests are graphieally depicted in the fourth column of Fig. 3. No consistent changes in growth hormone

levels can be seen which could be correlated with Diazoxide therapy. Despite the fact that several of these children were on high doses of steroids for long periods of time, no significant depression of growth hormone response can be noted. CatechoIamines. No consistent effect was detected on the pattern of excretion of epinephrine, norepinephrine, metanephrine, normetanephrine, and V M A in urines collected before and after the institution of Diazoxide therapy. The data are presented in Table IV. DISCUSSION A. Clinical. Diazoxide appears to be one of the most useful agents available for the treatment of idiopathic hypoglycemia of infancy. Of the 8 patients presented here,,7 were inadequately controlled with the use of current methods of dietary and highdosage steroid therapy. On this regimen, overnight fasting or intercurrent illnesses often provoked symptomatic hypogIycemia. With Diazoxide therapy, the necessity for hospital admissions, except for investigational purposes, has virtually ceased. It has been possible to discontinue steroid therapy in 5 of the 6 patients who had required pharmacologic dosages. The resultant growth spurt has been dramatic. There have been relatively few side effects to the Diazoxide therapy. No patient in this series has had thrombocytopenia. Transient neutropenia has been noted in three of the children, but has not been of sufficient magnitude to require the stopping of administration of the d r u g Y Advancement of bone age was noted in 1 patient (R. L.). Significant advancement of epiphyseal maturation was noted at the age of 6 weeks, before the start of Diazoxide treatment (chronological age, 6 weeks; bone age, 6 months). In this subject, bone age progressed rapidly coincident with the administration of Diazoxide, but now appears to be advancing at a rate commensurate with the chronological age (chronological age, 10 months; bone age, 2~2 years; chronological age now 15 months and bone age, 3 years). The phenomenon of advanced

Volume 71 Number 4

Diazoxide treatment in hypoglycemia

50 1

Table IV. Catecholamine excretion ~

Patient.I R.L. G.P. B.P. C.H. C.B. M.S. B.M.

E? 3.7 5.6 3.2 2.0 10.5 10.1 3.5

PreDiazoxide I NE I M 32.4 10.7 20.7 25.5 33.2 26.4 11.1

12 5 3.1 10.6 27.8 67.4 61.3 28.7

] NM

t VMA

91.1 27.6 45.6 31.3 92.5 132.4 32.0

540 729 950 790 1,334 1,489 804

PostDiazoxide E ) NE I M I N M ) V M A 4.9 7.9 9.7 4.2 8.2 5.3 8.1

29.9 34.5 94.1 14.4 37.7 21.6 10.9

15.1 14.6 38.3 13.3 40.4 72.8 21.7

135 76.3 313 38.1 107.3 73.1 63.7

616 1,267 2,450 464 1,062 866 546

~Total 9 24 hour urine specimen (mcg.). tE ~ epinephrine; NE ~ mandelie aeld.

noreplnephrlne;

M ---~ metanephrine; N M --~ normetanephrlne; VMA ~--- 3-hydroxy-4-methoxy

epiphyseal maturation has been reported in other patientlS; whether this represents a true end organ effect of Diazoxide or is perhaps a concomitant of hyperinsulinism is not apparent from current data. The development of hypertrichosis lanuginosa has been the most consistent side effect observed. With careful observation, an increase in hair growth over the forehead, nape of neck, and area of the sideburns can be noticed as early as six weeks after the start of daily Diazoxide treatment. As mentioned previously, significant stimulation of hair growth has been noted in all 8 patients on this drug, but has been of serious cosmetic proportions in only 4. This is in sharp contrast to the previously reported incidence in adults, where less than 1 per cent of patients treated with Diazoxide were noted to develop hirsutism? 9 Skin biopsies done in the present patients have revealed an impressive increase in the number of hair follicles in the active anagen phase, with large amounts of glycogen and a rich vascular network. This contrasts with the quiescent picture seen in control prepubertal children? 5 There is no clinical evidence of adrenal or gonadal overactivity, since pubic and axillary areas were unaffected by the general stimulation of hair growth. Urinary studies revealed normal 17ketosteroid and 17-hydroxysteroid excretion. Since the patient shown in Fig. 2 demonstrated the leonine facies associated with abnormalities in porphyrin metabolism, 24 hour urinary samptes obtained before and after treatment were assayed for porphyrin

intermediates. "~ These values were within the normal limits expected for the ages and weights of the children studied and showed no changes associated with the Diazoxide treatment. B. Investigation. The mechanism of the hyperglycemic effect of Diazoxide is still unexplained. The major hypotheses which have been brought forth concerning its mechanism of action are: (1) increased adrenergic activity2~ and (2) depression of insulin releaseY 1 These hypotheses have been correlated by the observation that epinephrine inhibits insulin release. 22 (3) I t has also been suggested that Diazoxide inhibits hepatic uptake of glucose, s3 The data presented in this paper do not support the hypothesis of increased adrenergic activity, since no consistent changes were evident in the urinary patterns of catecholamine excretion before and after therapy. Urinary catecholamine levels in hypoglycemic patients are, however, often difficult to interpret, since hypoglycemia itself is a potent stimulus for release of epinephrine. Thus, a slight increase in catecholamine excretion related to Diazoxide therapy might well be masked by the improved control of the hypoglycemic state. Diazoxide in experimental animals causes an acute elevation of plasma-free fatty acids. 2~ Since free fatty acid elevation may have an anti-insulin effect, 2s, 26 it has been ~Tlae assays were performed by Dr. George Ludw{g, Department of Medicine, I-IospRal of the University of Pennsylvania.

502

Baker et al.

The Journal o~ Pediatrics October 1967

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ide would seem to correlate more closely with reduced insulin release to the standard stimuhis.

Suppression of insulin release by Diazoxide has been demonstrated by several investigators.Z1, 22, 27 Glucose tolerance tests performed before and after the institution of Diazoxide therapy in the patients presented in this paper clearly demonstrated a reduc-

Volume 71 Number 4

Diazoxide treatment in hypoglycemia

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tion of insulin response. Variations from patient to patient emphasize the fact that changes in blood-glucose values do not always parallel the changes seen in plasmainsulin levels. This aspect of Diazoxide action has already been emphasized by Fajans and co-workers. 21 No previous data have been presented concerning the effect of Diazoxide on growth hormone responses in patients with idiopathic hypoglycemia. From the present data, it would appear that growth hormone does not play a prominent role in the hyperglycemic action of Diazoxide. SUMMARY AND C O N C L U S I O N S 1. Diazoxide, a nondiuretic benzothiadiazine, has been used in the treatment of 8

patients with severe idiopathic hypoglycemia of infancy. These patients range in age from 6 weeks to 5 89 years and have been followed under therapy for periods ranging from 4 months to 18 months. 2. Diazoxide appears to be a drug with a high degree of clinical effectiveness. Patients who had been inadequately controlled on high dosage steroid therapy responded well to the administration of Diazoxide. Moreover, continued use of the drug appears to enhance its effectiveness, at least insofar as the phenomenon of leucine sensitivity is concerned. The 3 patients who responded to leucine loading with a marked drop in their blood glucose values have not exhibited leucine sensitivity while on Diazoxide therapy.

504

Baker et al

3. T h e side effects noted in this series have not caused discontinuation of Diazoxide thera p y in a n y patient. Hypertrichosis lanuginosa has been observed in all 8 children, and has been of significant cosmetic importance in 4 patients. A d v a n c e m e n t of epiphyseal m a t u r a t i o n has been noted in 1 child. Depression of i m m u n o g l o b u l i n - G has been noted in 5 patients. This has tended to be self-limited, a n d to d a t e has been without obvious increase in susceptibility to infection. No changes have been noted in h e p a t i c or renal function. M o d e s t h y p e m r i c e m i a has not been a c c o m p a n i e d by a n y a p p a r e n t symptomatology. 4. Suppression of insulin response to a s t a n d a r d glucose or leucine stimulus appears to be an i m p o r t a n t p a r t of the mechanism of action of Diazoxide. G r o w t h h o r m o n e does not a p p e a r to p l a y a role. No significant changes in p l a s m a free f a t t y acid levels have been noted with prolonged Diazoxide a d m i n istration. 5. F u r t h e r evaluation of Diazoxide in the t r e a t m e n t of severe idiopathic h y p o g l y c e m i a of infancy a p p e a r s w a r r a n t e d . We gratefully acknowledge the contributions to this study of the nurses of the Clinical Research Center, the technical assistance of Miss Vernice Ruffin, and the secretarial services of Mrs. Margaret Pharr.

The Journal of Pediatrics October 1967

7. 8. 9. 10.

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REFERENCES

I. Rubin, A. A., Franklin, E. R., Taylor, R. M., and Rosenkilde, H.: Pharmacology of diazoxide, an antihypertensive, nondiuretic benzothiadiazine, J. Pharmacol. & Therap. 136: 344, 1962. 2. Dollery, C. T., Pentecost, B. L., and Samaan, N. A.: Drug induced diabetes, Lancet 9: 735, 1962. 3. Drash, A. L., and Wolff, F. W.: Drug therapy in Ieucine sensitive hypoglycemia, Metabolism 13: 487, 1964. 4. Hamilton, J. P., Baker, L., Kaye, R., and Koop, C. E.: Subtotal pancreatectomy in the management of severe persistent idiopathic hypoglycemia in children, Pediatrics 39: 49, 1967. 5. Young, R. B., Bongiovanni, A. M., Kaye, R., and Smolens, J.: Hyperglycemic factor in diabetic plasma: response in idiopathic hypoglycemia, Am. J. Med. Sciences 249: 499, 1965. 6. Washko, M. E., and Rice, E. W.: Determina-

18.

19. 20.

21.

22.

tion of glucose by an improved "Glucostat" procedure, Clin. Chem. 7: 542, 1961. Duncombe, W. G.: The colorimetrie microdetermination of Iong-chaln fatty acids, Biochem. J. 88: 7, 1963. Novak, M.: Colorimetric ultra micro method for the determination of free fatty acids, J. Lipid Res. 6: 431, 1965. Yalow, R. S., and Berson, S. A.: Immunoassay of plasma insulin, Methods of Bioehem. Anal. 12: 69, i964. Schalch, D. S., and Parker, M. D.: A sensitive, double antibody immunoassay for human growth hormone in plasma, Nature 203: 1141, 1964. Anton, A. H., and Sayre, D. F.: A study of the factors affecting the aluminum oxidetrihydroxy indol procedure for th~ analysis of catecholamines, J. Pharmacol. & Exper. Therap. 138: 360, 1962. Anton, A. H., and Sayre, D. F.: Distribution of metanephrine and normetanephrine in various animals and their analysis in diverse biologic material, J. Pharmacol. & Exper. Therap. 153: 15, 1966. Pisano, J. J., Crout, J. R., and Abraham, D.: Determination of 3-methoxy-4-hydroxy-mandelic acid in urine, Clin. chem. acta 7: 285, 1962. Connelian, T. P., and Godfrey, J. M.: The routine determination of urinary 4-hydroxy-3methoxy-mandelic acid, Clin. chem. acta 9: 410, 1964. Koblenzer, P. J., and Baker, L.: l-Iypertriehosis lanuginosa associated with Diazoxide therapy in pre-pubertal children: a clinieo-pathologic study, Ann. New York Aead. Sc. In press. Baker, L., and Miller, M.: Depression of immunoglobulin-G (IgG) levels associated with diazoxide therapy. Metabolism. In press. Combs, J. T., Grunt, J. A., and Brandt, I. K.: New syndrome of neonatal hypoglycemia: association with visceromegaly, macroglossia, microcephaly, and abnormal umbilicus, New England J. Med. 275: 236, 1966. Green, O. C.: Diazoxide as an inhibitor of pancreatic insulin release, The Society for Pediatric Research, 36th Annual Meeting, Atlantic City, N. J., ApriI 29, 1966, page 94. Investigators' brochure: Hirsutism during diazoxide administration, The Schering Corporation, March, 1966. Tabachnick, I. I. A., Gulbenkian, A., and Seidman, F.: The effect of a benzothiadiazine, diazoxide, on carbohydrate metabolism, Diabetes 13: 408, 1964. Fajans, S. S., Floyd, J. C., Jr., Knopf, I. F., Rull, J., Guntsche, E. M., and Corm, J. W.: Benzothiadiazine suppression of insulin release from normal and abnormal islet tissue in man, J. Clin. Invest. 45: 481, 1966. Porte, D., Jr., Graber, A. L., Knzuya, T., and Williams, R. H.: The effect of epinephrine on immunoreactive insulin levels in man, J. Clin. Invest. 45: 228, 1966.

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23. Spergel, G., and Bleicher, S. J.: Effects of diazoxide administration on plasma glucose, insulin and lipids in von Gierke's disease, Diabetes 15: 406, 1966. 24. Gulbenkian, A., Seidman, F., and Tabachnick, L I. A.: Diazoxide hyperglycemia and free fatty acid mobilization, Fed. Proc. 23: 542, 1964, 25. Randle, P. J., Garland, P. B., Hales, C. N., and Newsholme, E. A.: The glucose fatty acid cycle and diabetes mellitus, in Cameron, M. P., and O'Connor, M., editors: Aetiology of Diabetes Mellitus and its Complications, Ciba

Foundation Colloquia on Endocrinology, Boston, 1964, Little, Brown, & Company, vol. 15. 26. Sehalch, D. S., and Kipnis, D. M.: Abnormalities in carbohydrate tolerance associated with elevated plasma nonesterified fatty acids, J. Clin. Invest. 44: 2010, 1965. 27. Seltzer, H. F., and Allen, E. W.: Inhibition of insulin secretion in "diazoxide diabetes," Diabetes (abst.) 14: 439, 1965. 28. Graber, A. L., Porte, D., and Williams, R. H.: Clinical use of diazoxide and mechanism for its hyperglycemic effects, Diabetes 15: 143, 1966.