Hypoglycemia and resistance to ketoacidosis in a subject without functional insulin receptors

Humans with congenital absence of the islets of Langerhans and mice rendere d null for the insulin receptor rapidly develop severe hyperglycemia and ke toacidosis and, if untreated, die in the early neonatal period. In contrast , children with homozygous or compound heterozygous mutations of the insuli n receptor gene, although hyperglycemic postprandially, survive for many mo nths without developing ketoacidosis. Paradoxically, they often develop hyp oglycemia. The rarity of the condition and the difficulties of undertaking metabolic studies in ill infants have limited the physiological information that might explain the clinical features. We studied a boy with Donohue's syndrome who represents a further example of the null phenotype, with two d ifferent and novel nonsense mutations in the alpha -subunit of the receptor . He survived for 8 months without developing ketoacidosis, and fasting hyp oglycemia was a frequent problem. Despite the complete absence of insulin r eceptors, evidence for persistent insulin-like effects on fat and liver was seen; fasting plasma beta -hydroxybutyrate and nonesterified fatty acid le vels were low, fell further during the early postprandial period, and faile d to rise in response to hypoglycemia. The inverse relationships between pl asma insulin and insulin-like growth factor-binding protein-1 levels were m aintained, suggesting persistent hepatic effects of insulin. GH levels meas ured over a 6.5-h period were low throughout. Thus, the differences between congenital insulin deficiency vs. insulin receptor deficiency in humans ma y be explained by persistent insulinomimetic activity of the grossly elevat ed plasma insulin presumably being mediated through the type 1 insulin-like growth factor receptor. As GH plays a critical role in the regulation of k etogenesis during insulinopenia in humans, but not in rodents, this may con tribute to the distinct phenotype of human vs. mouse insulin receptor knock outs.