Transient neonatal diabetes: Delayed maturation of the pancreatic beta cell

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diabetic mothers with a slow intravenous drip of 10 per cent glucose from birth. Early oral feeding and frequent blood glucose monitoring are, of course, mandatory in these infants. We are grateful to the many people who collaborated in this study and especially to Dr. Valdine Pusey who was much involved in the early stages.

REFERENCES 1. McCann, M. L., and Likly, B. F.: The role of epinephrine prophylactic therapy in infants of diabetic mothers, Atlantic City, N. J., 1967, Society for Pediatric Research. 2. Porte, D., Jr., Graber, A. L., Kuzuya, T., and Williams, R. H. : The effect of epinephrine on immunoreactive insulin leveIs in man, J. Clin. Invest. 45: 228, 1966. 3. Chen, C. H., Adam, P. A. J., Laskowski, D. E., McCann, M. L., and Schwartz, R.: The plasma free fatty acid composition and blood glucose of normal and diabetic pregnant women and of their newborns, Pediatrics 36: 843, 1965.

Transient neonatal diabetes: Delayed maturation of the pancreatic beta cell Anthony S. Pagliara, M.D., * Irene E. Karl, Ph.D., and David B. Kipnis, M.D., St. Louis, M o .

From the Divisions of Endocrinology and Metabolism, The Edward Mallinckrodt Department of Pediatrics, and the Department of Medicine, Washington University School of Medicine. Supported by Research Grant No. AM01921-14 and Research Center Grant No. RRO0036, St. Louis Children's Hospital, from the National Institutes of Health. Reprint address: Anthony S. Pagliara, M.D., St. Louis Children's Hospital, 500 S. Kingshighway, St. Louis, Mo, 63110. ~Howard Hughes Research Investigator.

Brief clinical and laboratory observations

9 7

4. Light, I. J., Sutherland, J. M., Loggie, J. M., and Gaffney, T. E.: Impaired epinephrine release in hypoglycemic infants of diabetic mothers, N. Engl. J. Med. 277: 394, 1967. 5. Stern, L., Ramos, A., and Leduc, J.: Urinary catecholamine excretion in infants of diabetic mothers, Pediatrics 42: 598, 1968. 6. McCann, M. L.: Prevention of RDS and decreased mortality in infants of insulin dependent diabetic mothers (IDM) treated with epinephrine, Atlantic City, N. J., 1971, Society for Pediatric Research. 7. Cornblath, M., and Schwartz, R.: Disorders of carbohydrate metabolism in infancy, Philadelphia, 1966, W. B. Saunders Company, p. 57. 8. Huggett, A. St. G., and Nixon, D. A.: The use of glucose oxidase, peroxidase and odianisldine in determination of blood and urinary glucose, Lancet 2: 368, 1957. 9. Hohorst, H. J.: L-(+)-lactate determination with lactic dehydrogenase and DPN, in Bergmeyer, H. V., editor: Methods of enzymatic analysis, New York, 1963, Academic Press, Inc., p. 266. 10. Stevens, J. F.: Biochemical changes in the blood of the newborn, J. Med. Lab. Technol. 22: 47, 1965.

T R A N S IE N T diabetes mellitus of the newborn infant is an u n c o m m o n disorder of unknown etiology which occurs during the first six weeks of life. Hyperglycemia, glycosuria, and severe dehydration are invariably present, but ketosis, if present, is very mild. These infants require insulin replacement therapy but undergo spontaneous remission within a period of days to weeks and do not develop permanent diabetes in later life? Recently, we studied a patient with this syndrome during the acute diabetic phase and after remission. T h e findings suggested that the underlying defect may be related to delayed maturation of the adenyl cyclasecyclic adenosine monophosphate system due to either a deficient pancreatic beta cell adenyl cyclase or an increased activity of the nucleotide phosphodiesterase.

CASE REPORT The patient, a female infant, was born after an uneventful 40 week gestation. Birth weight was 1,600 Gm., and the Apgar score was 7 five rain-

98

Briei clinical and laboratory observations

The Journal o[ Pediatrics January 1973

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utes after delivery. The mother, a primipara, was 21-years-old, in good health, and did not have toxemia or diabetes. The family history was unremarkable. Two hours after birth, the infant's blood glucose and blood urea nitrogen were 148 and 40 rag. per 100 ml., respectively. Over the next five days, the child lost weight despite a normal intake of food and no vomiting or diarrhea; for this reason she was transferred to St. Louis Children's Hospital. On admission, she appeared alert, small, and dehydrated with loose skin and a marked decrease in subcutaneous tissue. Weight was 1,400 Gm., and length, 41 cm. On admission hemoglobin concentration was 25.2 Gm. per 100 ml., and hematocrit was 72 per cent. The urine contained 5 per cent glucose but no ketones. Plasma glucose was 350 mg. per I00 ml., insulin 16 ~tU per milliliter, and blood urea nitrogen, 21 mg. per 100 ml. Subsequent studies following correction of the hyperglycemia demonstrated several normal blood urea nitrogen concentrations (8 to 12 mg. per 100 ml.), normal thyroid function and urinary amino acids, and absent urinary mucopolysaccharides. Two to four units of crystalline insulin was given daily in divided doses for 25 days, at which time it was discontinued. On this regimen she gained weight and lost all evidence of the diabetic state (Fig. 1). She has had no evidence of diabetes mellitus during the past 12 months, and has had a normal rate of growth and development.

MATERIALS

AND METHODS

All studies were performed in the Clinical Research Center at St. Louis Children's Hospital. T o l e r a n c e tests were p e r f o r m e d six hours following a feeding a n d a dose of insulin. Plasma was obtained for determination of glucose 2 a n d immunoassayable insulin a following administration of caffeine benzoate (4 mg. per kilogram intramuscularly), tolbutamide (20 rag. per kilogram intravenously), a n d glucose (0.75 Gin. p e r kilogram intravenously). Caffeine benzoate was administered at 9 days of age, tolbutarnide at 18 a n d 52 days of age, and glucose at 59 days oi age; the latter two tests were performed while the child was euglycemic a n d after discontinuance of insulin therapy. RESULTS

Fig. 2 illustrates the responses of glucose and insulin to the administration of caffeine and t o l b u t a m i d e during the diabetic phase. Plasma insulin increased within 30 minutes following administration of caffeine to 40 /zU per milliliter, and by 45 minutes the value was 50 /~U p e r milliliter; however, there was only a slight decrease in glucose concentration (435 to 400 mg. p e r 100 m l . ) . T o l b u t a m i d e administered at 18

Volume 82 Number 1

Brie/ clinical and laboratory observations

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o 40 ' ' 60 MINUTES Fig. 2. Responses to intramuscular caffeine benzoate (4 rag. per kilogram) at 9 days of age and intravenous sodium tolbutamide (20 rag. per kilogram) at 18 days of age.

days of age resulted in no increase in plasma insulin and negligible changes in the concentration of plasma glucose. The second tolbutamide tolerance test (Fig. 3, A) was performed when the patient was 52 days of age and had not received insulin for 14 days. Two ndnutes following administration of tolbutamide, plasma insulin increased from 28 to 60 /xU per milliliter and plasma glucose decreased from 133 to 85 mg. per 100 ml. At 59 days of age, prior to an intravenous glucose tolerance test, the fasting plasma glucose value was 85 rag. per 100 ml. and that of insulin was 14 flu per milliliter. Following glucose administration, plasma insulin increased from 14 to 25 ,aU per milliliter within 20 minutes and to 38 flU per milliliter within 30 minutes. The disappearance rate of glucose was 2.5 per cent per minute, which is within the normal range 4 (Fig. 3, B). C O M M E N T

The etiology of this syndrome and its association with other forms of diabetes melli,

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Fig. 3. A, Response to intravenous sodium tolbutamide (20 mg. per kilogram) at 52 days of age. B, Response to intravenous glucose (0.75 Gm. per kilogram) at 59 days of age.

tus remains obscure. In a few patients studied at autopsy no characteristic abnormalities have been found in the pancreas, s-9 Gentz and Cornblath 1 reported two cases, one of which, at a time when the plasma insulin concentrations were 6 and 17 flU per milliliter, had blood glucose concentrations of 1,280 and 2,300 mg. per 100 ml., respectively. Following remission, oral and intravenous glucose tolerance tests were normal. Studies in full-term and premature infants have demonstrated impaired responses to glucose10, 11 and tolbutamide 17 stimulated insulin release, suggesting that the pancreas of the newborn infant responds less well to these two stimuli than that of the older child and adult. In vitro studies with cultured explants of rat fetal pancreas ~2 ,is and with 12 week old human pancreas ~4 have demonstrated that glucose and tolbutamide are poor stimulators of insulin release; however, in the presence of caffeine, insulin secretion

1 0 0 Brief clinical and laboratory observations

is markedly potentiated with each agent. Further, in premature newborn infants 15 and the primate fetus and newborn, 1~ both theophylline and gtucagon have been demonstrated to be potent insulinogenic secretagogues. These investigations suggest that both agents act by increasing intracellular levels of adenosine 3P,5' monophosphate (cyclic adenosine monophosphate) in the pancreatic beta cell, theophylline by inhibiting the nucleotide phosphodietserase, and glucagon by stimulating adenyl cyclase. I n the present study, glucose- and tolbutamide-mediated insulin release were absent during the diabetic phase, whereas caffeine administration resulted in a substantial increase in plasma concentrations of insulin. This latter observation indicates that insulin was present in the pancreas of the patient and was capable of being released. Following administration of caffeine, only a small decrease in plasma glucose concentration occurred (Fig. 2), a finding similar to that reported by others; it may reflect a simultaneous increase in hepatic cyclic adenosine monophosphate concentrations resulting in increased glucose output by the liver? ~ Fourteen clays following the infant's last dose of insulin, fasting plasma glucose and insulin concentrations were normal. Repeat tolbutamide testing resulted in a normal glucose and insulin response (Fig. 3, A). The intravenous glucose tolerance test was norreal; however, there was a marked delay in release of insulin; the peak level occurred 30 minutes following injection of glucose (Fig. 3, B). These findings suggest that the defect in this patient was initial failure of the beta cell to respond to glucose and tolbutamide at a time when insulin was present in the pancreas. Normal neonates also demonstrate varying degrees of decreased sensitivity of insulin release to glucose TM 1~ and tolbutamide. 17 Thus the defect seen in infants with transient neonatal diabetes may be quantitative in nature. Since caffeine, a phosphodiesterase inhibitor, is capable of re-

The Journal o[ Pediatrics January 1973

leasing insulin during the transient diabetic phase, it is postulated that the defect may be related to delayed maturation of the adenyl cyclase-cyclic adenosine monophosphate system as the result of a deficiency of pancreatic beta cell adenyl cyclase or of an increased activity of the nucleotide phosphodiesterase. REFERENCES

1. Gentz, J. C. H., and Cornblath, M.: Transient diabetes of the newborn, Adv. Pediatr. 16: 345, 1969. 2. Huggett, A. St. G., and Nixon, D. A.: Use of glucose oxidase, peroxidase and o-diansidase in determination of blood and urinary glucose, Lancet 2" 368, 1957. 3. Morgan, C. A., and Lazarow, A.: Immunoassay of insulin: Two antibody system, Diabetes 12: 115, 1963. 4. Cornblath, M., and Schwartz, R.: Disorders of carbohydrate metabolism in infancy, Phiiadelphia, 1967, W. B. Saunders Company, p. 205. 5. Devine, J.: A case of diabetes mellitus in a young infant, Arch. Dis. Child. 13: 189, 1938. 6. Lewis, E., and Eisenberg, H.: Diabetes meIlitus neonatorum, Am. J. Dis. Child. 49: 408, 1955. 7. Hickish, G.: Neonatal diabetes, Br. Med. J. 1: 95, 1956. 8. Tidd, J. T., and Stanage, W. F.: Congenital diabetes mellitus, South Dakota J. Med. 18" 15, 1965. 9. Osborne, G. R.: Congenital diabetes, Arch. Dis. Child. 40: 332, 1965. 10. Pildes, R. S., Hart, R. J., Warner, R., and Cornblath, M.: Plasma insulin response during oral glucose tolerance tests in newborns of normal and gestational diabetic mothers, Pediatrics 44: 76, 1969. 11. Isles, T. E., Dickson, M., and Farquhar, J. W.: Glucose tolerance and plasma insulin in newborn infants of normal and diabetic mothers, Pediatr. Res. 2: 198, 1968. 12. Lambert, A. E., Junod, A., Stauffacher, W., Jeanrenaud, B, and Renold, A. E.: Organ culture of fetal rat pancreas. 1. Insulin release induced by caffeine and by sugars and some derivatives, Biochem. Biophys. Acta 184: 529, 1969. 13. Lambert, A. E., Jeanrenaud, B., Junod, A., and Renold, A. E.: Organ culture of fetal rat pancreas. II. Insulin release induced by amino and organic acids, by hormonal pepI:ides, by cationic alterations of the medium mad by other agents, Biochim. Biophys. Acta 184: 540, 1969. 14. Esponosa, M. M. A., Driscoll, S. G., and Steinke, J.: Insulin release from isolated human fetal pancreas, Science 168: 1111, 1970.

Volume 82 Number 1

15. Grasso, S., Messina, A., Saporito, N., and Reitano, G.: Effect of theophylllne, glucagon and theophylline plus glucagon on insulin secretion in the premature infant, Diabetes 19: 837, 1970. 16. Chez, R. A., Mintz, D. H., and Hutchinson, D. L.: Effect of theophylline on glucagon and glucose mediated insulin responses in sub-

Type III

m ucopo lysaccha ridosis: Report of a case with severe mitral valve involvement j. Kenneth Herd, M.D., * S. Subramanian, M.B., and H. Robinson, M.D., Buffalo, N. Y.

T Y P 13 I I I mucopolysaccharidosis (HarrisSanfilippo syndrome) is characterized by severe mental retardation, hepatosplenomegaly, mild coarsening of the facies, stiff joints, nasal breathing, u r i n a r y excretion of increased amounts of h e p a r a n sulfate, a n d absence of corneal clouding a n d cardiovascular involvement. 1-a This p a p e r describes a patient with mucopolysaceharidosis I I I who h a d severe cardiovascular involvement. From the Departments of Pediatrics, Surgery, and Pathology, The Children's Hospital of Buffalo. Supported by a grant from the United Health Foundation of Western New York, Inc., and by Grant RR-05493 from the General Research Support Branch, Division of Research Resources, National Institutes of Health. Dr. Herd is the recipient of a Dr. Henry C. Buswell and Bertha H. Buswell Research Fellowship. ~'Address: Department of Pediatrics, Crelghton University School of Medicine, lOth and Castelar, Omaha, Neb. 68108.

Brief clinical and laboratory observations

10 1

human primate fetus and neonate, Metabolism 20: 805, 1971. 17. Velasco, M. S. A., and Paulsen, E. P.: The response of infants of diabetic women to tolbutamide and leucine at birth, and glucose and tolbutamide at 2 years of age, Pediatrics 43: 546, 1969.

CASE REPORT Patient S. N. P., a normal-appearing, 10 pound, white female infant was born following a 38 week uneventful pregnancy. During the first year of life she was slightly overweight and reached her developmental milestones slowly. At 15 months of age, she was noted to have hepatosplenomegaly, blood pressures of 150-160/85-100, a short neck, mild hypertelorism, and macroglossia. A harsh pansystolic heart murmur was heard at the apex, along the left sternal border, in the left axilla, and over the left chest posteriorly. Skeletal radiographs were normal except for prominent Hahn's clefts in the bodies of L 1 and L 2 and slight deformity of the body of L 2. The cardiothoracic ratio was 9.4/16.4. The electrocardiogram showed left ventricular hypertrophy. The hemogram, urinalysis, and serum chemical values were normal. Glucagon and galactose tolerance tests were normal. A toluidine blue spot test for urinary acid mucopolysaccharides was negative. Liver biopsy revealed early portal fibrosis and periodic acid-Schiff-positive, nonglycogen vacuoles. Following treatment with digoxin and antibiotics the respirations and pulse slowed, blood pressure and heart size decreased, but the hepatosplenomegaly remained unchanged. At 2 88 years of age, she developed pneumonia. A grade 3, pansystolie, blowing murmur was heard along the left sternal border. The urine contained increased acid mucopolysaccharides. A moderate conductive hearing loss was noted. During the next four months, severe congestive heart failure developed with radiographic signs of congested pulmonary vascularity, pleural fluid, and atelectasis. A grade 6 pansystolic apical murmur was associated with a banging first heart sound, a split second sound, and a grade 2 to 3 diastolic murmur along the left sternal border. Congestive failure subsided after therapy with digoxin and diuretics. Cinefluorography showed a large vigorous left ventricle, marked mitral in-