Regulation of insulin-like growth factor binding protein-1 (IGFBP-1) and implications in catabolic conditions

This thesis has studied the regulation of IGFBP-1 (insulin-like growth factor binding protein 1), which is one factor regulating the bioavailability of IGF-I with special interest how IGFBP-1 is regulated in vitro and in humans, especially in diabetes and catabolic conditions. The IGFBP-1 cDNA was cloned and used for studies in human hepatoma cells, HepG2, which showed that both insulin and IGF-I could decrease IGFBP-1 in the cell conditioned medium. IGF-I inhibited also IGFBP-1 production at the transcriptional level, which previously had been shown for insulin. The basal IGFBP-1 hepatic production and the effect of insulin was studied in normal healthy subjects showing a basal production of 7 ug/min which was completely inhibited after 180 min by insulin, 60 min Iater than in to type 1 diabetics. No basal hepatic IGF-I production was seen rather a net splanchnic uptake of IGF-I was observed in healthy subjects. Insulin did not affect the IGF-I exchange.

In uremic type 2 diabetics, a patient group at high risk for malnutrition, there was a high mean basal level of IGFBP-1 compared to type 2 diabetics with normal renal function. Insulin induced during the first 90 min a decrease in peripheral vein IGFBP-1 levels of the same magnitude in type 2 diabetics with or without uremia and in type 1 diabetics. After 90 min there was a blunted response to insulin in the uremic group depending on unknown factors. IGFBP-1 showed to be elevated in constitutionally short children with normal growth hormone secretion in relation to other IGFBPs studied by the Western ligand blot method when compared to control groups. IGF-I was decreased prepubertally but not during puberty in comparison to control groups. IGFBP-3 proteolysis was decreased in the short children. The combination of increased IGFBP-1 and decreased proteolysis of IGFBP-3 may explain the short stature by the decrease in bioavailable IGF-I.

Dialysis increased IGFBP-1 and decreased the IGF-I/IGFBP-1 ratio in uremic patients on hemodialysis treatment. Thus, the increase in IGFBP-1 may be of importance for the known catabolism induced by hemodialysis. However, when insulin infusion proceeded the hemodialysis in uremic type 2 diabetics the increase in IGFBP-1 and decrease of the IGF-I/ IGFBP-1 ratio after hemodialysis was blunted. A decrease in IGFBP-1 leading to more bioavailable IGF-I may favor anabolism in this patient group. IGF-I, the age corrected IGF-I standard deviation score and the IGF-I/IGFBP-1 ratio correlated to dietary protein intake when measured by indirect means in hemodialysis patients. Direct estimates of protein intake, was not correlated to IGF-I or indirect measures of protein intake. Thus IGF-I or IGF-I/IGFBP-1 ratio are good markers for nutrition better than direct estimates by food recalls in hemodialysis patients.

These studies have shown that insulin and IGF-I decrease hepatic IGFBP-1 in vitro and insulin inhibits the hepatic production of IGFBP-1 in normal subjects. Insulin infusion decreases serum IGFBP-1 with a similar response in type 1 and type 2 diabetics with normal renal function. In uremics, however, the insulin induced decrease in IGFBP-1 is impaired. High IGFBP-1 in uremics adults and growth retarded children may limit IGF-I bioactivity and explain catabolism in uremia and the short stature. Serum IGF-I and the IGF-I/IGFBP- I ratio can be used as a nutritional markers in uremics.