Patients with
leprechaunism have
hyperinsulinemia and extreme
insulin resistance. The mechanism of the
insulin resistance has not been delineated. To examine postreceptor events in this unusual syndrome we have assayed the
enzyme guanylate cyclase [E.C.4.6.12], which is modulated by
insulin, and the concentration of the intracellular messenger
cyclic GMP in liver from two children with
leprechaunism and extreme
insulin resistance. Both patients exhibited down regulation of the red blood cell
insulin receptors, but normal
insulin receptor binding to Ebstein-Barr transformed IM-9 lymphocytes and monocytes. There was no evidence of antireceptor or antiinsulin
antibodies. Activity of liver
guanylate cyclase expressed as pmol/mg
protein/10 min incubation in the soluble and particulate fractions were, respectively, Ark-1 133 +/- 18, 25 +/- 6; Ark-2 129 +/- 17, 23 +/- 8; control children (six average) 287 +/- 16, 55 +/- 9. The concentration of
cyclic GMP was also 50% lower (0.08 +/- 0.03 in Ark-1 and 0.07 +/- 0.04 in Ark-2), compared to 0.19 +/- 0.07 pmol/mg
protein/min in the control livers. There was no change in
adenylate cyclase activity in children with
leprechaunism versus the control children. These data suggest an abnormality of a postreceptor event in this rare
genetic disease. These data, however, do not rule out that in some cases of
leprechaunism a receptor binding abnormality may be the primary defect. We speculate that a defect in
insulin action distal to plasma membrane receptor binding may be etiological in this unusual syndrome.