Insulin-like growth factor binding protein-2 (IGFBP-2) is one of a family of IGFBPs that are present in extracellular fluids, and binds both IGF-II and IGF-I with high affinity. These studies were conducted to determine the nutritional and hormonal variables that regulate plasma IGFBP-2 concentrations in humans. The mean plasma IGFBP-2 concentration for 38 normal adult subjects was 150 +/- 61 micrograms/L and was 4.7-fold greater than their mean fasting IGFBP-1 value. Mean IGFBP-2 values in cord sera of 26 normal term infants was 3.8-fold greater than the normal adult mean value. Likewise, the mean value for 44 hypopituitary adults was increased 2-fold compared to normal. There was no suppression of IGFBP-2 values in acromegaly. Normal adult subjects showed minimal fluctuations (less than 2-fold changes) in plasma IGFBP-2 concentrations during a 48-h sampling period. These changes were significantly less than the changes that occurred in plasma IGFBP-1 during the same interval. Plasma IGFBP-2 did not change significantly post prandially or after a glucose infusion. Extreme insulin deficiency, after 9 days of fasting, was associated with a 1.7-fold increase in plasma IGFBP-2. Administration of GH, which is known to cause a major decrease in plasma IGFBP-1 and in IGFBP-2 in hypophysectomized animals, did not result in a change in calorically restricted normal adult subjects, suggesting that a normal caloric intake is required for GH to suppress IGFBP-2. In summary, these results show that plasma IGFBP-2 is regulated differently than IGFBP-1. Acute stimulation of insulin secretion does not suppress IGFBP-2, and there is much less daily fluctuation compared to IGFBP-1. These findings suggest that plasma IGFBP-2 levels are more stable than IGFBP-1, and therefore IGFBP-2 may serve as a larger reservior that is available for IGF transport.