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Suppression of Insulin Oversecretion by Subcutaneous Recombinant Human Insulin-Like Growth Factor I in Children with Congenital Hyperinsulinism Due to Defective ß-Cell Sulfonylurea Receptor¹

Division of Endocrinology/Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania (L.E.L.K., R.J.F., C.A.S., L.B.), Philadelphia, Pennsylvania 19104-4399; the Division of Pediatric Endocrinology, Department of Pediatrics, Duke University Medical Center (P.F.C.-S.), Durham, North Carolina 27710; and the Division of Pediatric Endocrinology, Department of Pediatrics, University of California (P.C.), Los Angeles, California 90095-1752

Address all correspondence and requests for reprints to: Lorraine E. L. Katz, M.D., Division of Endocrinology/Diabetes, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Room 8416 Main, Philadelphia, Pennsylvania 19104-4399. E-mail: katzl{at}email.chop.edu

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age. HI is most often due to defective glucose-insulin coupling by the ß-cell sulfonylurea receptor (SUR1) or glutamate dehydrogenase. HI-induced hypoglycemia carries significant morbidity, and current therapies are suboptimal. Insulin-like growth factor I (IGF-I) decreases insulin secretion in vitro and in healthy adults in vivo. We postulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tolerance. We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1. All had suboptimal glycemic control and served as their own controls. Subjects underwent 24-h glucose monitoring under their home regimens, followed by a supervised fasting study. The controlled fast was terminated when the subject became hypoglycemic (blood glucose, <50 mg/dL) or developed symptoms consistent with hypoglycemia. The fast was repeated 2 days later with administration of rhIGF-I at 40 µg/kg, sc, every 12 h. At the start of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 ± 11.1 vs. 6.3 ± 2.2 µIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 ± 0.7 vs. 1.2 ± 0.6 ng/mL; P < 0.04). rhIGF-I suppression of insulin and C peptide persisted throughout the fast. The duration of fasting did not change significantly with rhIGF-I treatment. We have directly demonstrated that rhIGF-I inhibits insulin oversecretion in children with HI due to defective SUR1. Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.