Dual regulation of insulin-like growth factor binding protein-1 levels by insulin and cortisol during fasting

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) gene transcrip tion is known to be inhibited by insulin in vivo and in vitro. Levels of IG FBP-1 typically rise during fasting but also rise after acute hypoglycemia, including that induced by insulin, through an unknown mechanism that may i nvolve counterregulatory hormones such as cortisol. To study the regulation of IGFBP-1 secretion during fasting, we measured IGFBP-1, insulin, cortiso l, GH, and glucose during the course of standardized fasting studies in a t otal of 21 children. The fasting studies lasted 13-32 h and were terminated for a whole-blood glucose concentration of less than 50 mg/dL (2.8 mmol). Of the children studied, 9 children had no disorder, 8 had ketotic hypoglyc emia, 2 had isolated GH deficiency, and 2 had fatty acid oxidation disorder s. During fasting, IGFBP-1 rose above the mean baseline levels of 28 +/- 5 ng/mL, to a mean level +/- SEM of 336 +/- 59 ng/mL at the time of hypoglyce mia (P = 0.001). IGFBP-1 was strongly associated with serum insulin and cor tisol levels over the entire course of fasting (P < 0.0001)). The interacti on of the 2 hormones across time was also strongly significant (P < 0.0001) . There was no statistically significant association between IGFBP-1 and GH or glucose. At the time of hypoglycemia, insulin levels were suppressed to 1.7 mu U/mL or less, and there was no correlation between IGFBP-1 levels a t the end of fasting and find insulin level. In contrast, cortisol levels c orrelated with IGFBP-1 in the final hypoglycemic sample (r = 0.56, P < 0.01 ). Partial correlation analysis revealed that the relationship between IGFB P-1 and cortisol was unchanged when the data was controlled for insulin lev els. These data show that insulin and cortisol both regulate IGFBP-1 secret ion during fasting; the effects of insulin and cortisol are strong during t he course of fasting. Significant hypoglycemia stimulates a further rise in IGFBP-1, which seems to be regulated, in part, by cortisol. The cortisol-i nduced rise in IGFBP-1 during fasting and during hypoglycemia potentially s erves to prevent the hypoglycemic effects of free IGFs.