Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor

Congenital hyperinsulinism (HI) is the most common cause of persistent hypo glycemia in infants under 1 yr of age. HI is most often due to defective gl ucose-insulin coupling by the beta-cell sulfonylurea receptor (SUR1) or glu tamate 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 po stulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tol erance. 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 SUR 1 (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 dehydr ogenase-1. All had suboptimal glycemic control and served as their own cont rols. 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 develop ed symptoms consistent with hypoglycemia. The fast was repeated 2 days late r with administration of rhIGF-I at 40 mu g/kg, sc, every 12 h. At the star t of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 +/- 11.1 us. 6.3 +/- 2.2 mu IU/mL; P < 0.04) and lowered the mean serum C pepti de level by 43% (2.1 +/- 0.7 vs. 1.2 +/- 0.6 ng/mL; P < 0.04). rhIGF-I supp ression of insulin and C peptide persisted throughout the fast. The duratio n of fasting did not change significantly with rhIGF-I treatment. We have d irectly demonstrated that rhIGF-I Inhibits insulin oversecretion in childre n with HI due to defective SUR1. Our data suggest that IGF inhibition of in sulin secretion does not require an intact SUR. rhIGF-I is unlikely to be e ffective monotherapy for HI, but may provide synergy to inhibit insulin sec retion when combined with agents acting via IGF-independent mechanisms.