SUPPRESSION OF ENDOGENOUS INSULIN-SECRETION REGULATES THE RAPID RISE OF INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEIN (IGFBP)-1 LEVELS FOLLOWING ACUTE HYPOGLYCEMIA

OBJECTIVES Recent animal studies have suggested that insulin-like grow th factor binding protein (IGFBP)-l may regulate the insulin-like acti ons of the circulating IGFs. In man, IGFBP-1 levels change rapidly wit h nutritional status and are inversely related to changes in insulin. In-vitro studies have shown that both insulin and glucose independentl y regulate IGFBP-1 secretion in an inverse manner. A rapid rise of ser um IGFBP-1 levels following insulin-induced hypoglycaemia suggested th at glucose or glucose availability, rather than insulin, may be the ma jor regulator of IGFBP-1. DESIGN Three separate experiments both in pa tients and in normal volunteers were designed to examine the possibili ty that in these extreme circumstances glucose rather than insulin was the predominant regulator of IGFBP-1. METHODS Insulin tolerance tests (ITT) were performed during the routine assessment of pituitary funct ion in seven patients, four female and three male (mean age +/- SEM 36 .8 +/- 6.3 years, range 20.7-69.3 years) with pituitary disease. Hypog lycaemic glucose clamp studies (insulin 2 mU/kg/min for 180 minutes) w ere performed in five normal volunteers, two female and three male (me an age 33.6 +/- 2.2 years, range 23.5-42.0 years). A three-part infusi on study was performed in five volunteers, three female and two male ( mean age 22.9 +/- 0.9 years, range 20.8-25.0 years) who received for 4 5 minutes on three occasions separated by at least 7 days either octre otide (long-acting somatostatin analogue) (1 mug/min), adrenaline (3 m ug/min) or control. MEASUREMENTS Serum levels of IGFBP-1, insulin, glu cose, C-peptide and cortisol were measured at varying intervals during the three studies by radioimmunoassay (RIA). RESULTS Symptomatic hypo glycaemia (1.0 +/- 0.1 mmol/l) occurred at 30 minutes in all patients during the ITT. Serum IGFBP-1 levels rose from 28 +/- 7 to 86 +/- 15 m ug/l at 180 minutes. During the hypoglycaemic glucose clamp study plas ma glucose fell from 4.8 +/- 0.3 to 2.2 +/- 0.3 mmol/l. In contrast to the response observed during ITT, IGFBP-1 levels fell from 22 +/- 6 t o 10 +/- 1 mug/l by 180 minutes. During the octreotide infusion study there was no change in plasma glucose and plasma insulin levels fell f rom 5.8 +/- 1.9 to < 2.0 mU/l. Serum IGFBP-1 levels rose from 21 +/- 2 to 68 +/- 5 pg/l by 180 minutes. There was no change in IGFBP-1 durin g either the adrenaline infusion or the control study. The rise in IGF BP-1 following the octreotide infusion (68 +/- 5 mug/l) was similar to that in the patients undergoing the ITT (86 +/- 15 mug/1) (P = 0.3). CONCLUSION The rapid rise of serum IGFBP-1 levels induced by acute hyp oglycaemia could be reproduced in euglycaemic conditions with octreoti de when insulin secretion was suppressed, whereas IGFBP-1 levels did n ot rise with hypoglycaemia induced by a prolonged insulin infusion. Th ese findings suggest that the surprising rise of IGFBP-1 levels observ ed during ITT is not secondary to changes in glucose. The rapid remova l from the portal circulation of endogenous insulin with its inhibitor y effect on IGFBP-1 secretion therefore appears to be the likely cause for the rapid rise of IGFBP-1 following an ITT. This conclusion suppo rts the hypothesis thal IGFBP-1 may inhibit the insulin-like actions o f 'free' IGF when insulin secretion is low and so directly link the av ailability and hence actions of IGFs to acute but temporary changes in nutritional status.