HYPERINSULINISM IN INFANTS AND CHILDREN

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Hyperinsulinism is undoubtedly the most important cause of hypoglycemia in early infancy. Transient hyperinsulinism is not only well recognized in infants of diabetic mothers but also has been implicated in the prolonged hypoglycemia seen in SGA or asphyxiated newborns. Persistent hypoglycemia occurs in a group of disorders of congenital hyperinsulinism that comprise the most common cause of hypoglycemia in early infancy beyond the immediate neonatal period. Recent advances have begun to unravel specific genetic defects in this important group of disorders. Patients affected with any of the various forms of hyperinsulinism are at high risk for seizures and permanent brain damage. Therefore, efficient diagnosis and treatment are essential. The purpose of this article is to provide a practical outline of the various forms of hyperinsulinism and a logical approach to diagnosis and treatment.

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β-CELL REGULATION OF INSULIN SECRETION

Figure 1 briefly outlines the pathways involved in regulation of insulin secretion by the pancreatic β cell19 and indicates the site of action of diazoxide and somatostatin, drugs that may be useful in treatment of patients with hyperinsulinism. Glucose and other fuels, such as amino acids, stimulate insulin secretion through their metabolism to raise the intracellular ratio of ATP to ADP. Glucokinase, the enzyme that initiates β-cell glucose metabolism, has a high Km for glucose and, thus, the

Infants of Diabetic Mothers

Hyperinsulinism in infants of diabetic mothers is a well-recognized and well-understood disorder. Poorly controlled maternal diabetes exposes the fetus to excessively high levels of glucose, which results in fetal hyperinsulinism and excessive fetal growth. These infants are typically large for gestational age (LGA) and are at high risk for hypoglycemia immediately after birth. High rates of glucose administration are required until β-cell insulin regulation adapts to normoglycemia, which

CLINICAL MANIFESTATIONS OF HYPERINSULINISM

The primary feature of hyperinsulinism is recurrent episodes of symptomatic hypoglycemia. In severe cases, such as neonatal onset congenital hyperinsulinism, hypoglycemia occurs soon after or even despite feedings. In patients with milder cases, symptomatic hypoglycemia may not develop until the patient has fasted for 12 to 24 hours, although blood sugar levels tend to be erratic and fasting tolerance unpredictable. Signs and symptoms in neonates and young infants usually include seizures.

DIAGNOSIS OF HYPERINSULINISM

Hyperinsulinism can be suspected based on clinical clues, such as LGA (or SGA) birthweight, perinatal asphyxia, or high glucose requirement. The diagnosis can only be established by analysis of circulating hormone and substrate concentrations at times of hypoglycemia,26 however. Blood specimens taken during hypoglycemia have been termed the critical blood sample not only because they are obtained when the patient is, or is on the brink of becoming, critically ill but also because the laboratory

TREATMENT OF HYPERINSULINISM

Figure 3 diagrams a logical sequence of medical and surgical steps to control hypoglycemia in patients with hyperinsulinism.24, 28 Treatment must be aggressively applied to prevent the possibility of severe and irreversible brain damage. The goals for therapy are to achieve a regimen that is practical for use at home and that successfully keeps the blood glucose levels at more than 60 mg/dL while the child is on a feeding schedule that is age appropriate.3 Ideally, successful treatment implies

PROGNOSIS

In the past, it was speculated that there is a spontaneous remission of congenital hyperinsulinism or that the disorder may progress to diabetes mellitus.24 This has sometimes had the unfortunate consequence of fostering a gradualistic approach to therapy and a high risk for brain damage caused by inadequate control of hypoglycemia. Based on the increasing evidence that genetic defects of β-cell regulation are responsible for most cases, it now seems likely that remission of congenital

FUTURE DIRECTIONS

The increasing evidence that most cases of congenital hyperinsulinism have a genetic basis has important implications. Families with affected children should be provided genetic counseling and information about a possible 25% risk for recurrence. Information about specific genetic defects is clearly necessary for improving the treatment of this group of disorders. Only one genetic disorder, recessively inherited SUR defects, has been clearly defined, but others are likely to be recognized in

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    Address reprint requests to Charles A. Stanley, MD, Division of Endocrinology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104

    Supported in part by grants from the National Institutes of Health, RR-00240 and RO1-DK43841.

    *

    From the Division of Endocrinology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

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