Serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and the acid-labile subunit as serum markers of body composition during growth hormone (GH) therapy in adults with GH deficiency.

Serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), the acid-labile subunit (ALS), insulin, and IGFBP-1 were evaluated as indicators of body composition during GH replacement therapy in 20 GH-deficient patients (9 women and 11 men), aged 22-57 yr, with IGF-I levels below -2 SD. The mean GH dose was 0.128 +/- 0.003 IU/kg.week during the first month and thereafter 0.23 +/- 0.01 IU/kg.week, divided into daily doses (0.7-4.3 IU/day). Serum levels of IGF-I, ALS, and IGFBP-3 above the normal range were reached in seven, five, and three subjects, respectively, after 12 months of GH therapy. IGF-I and ALS levels, but not IGFBP-3 levels, correlated with the total daily GH dose (r = 0.676; P = 0.001 and r = 0.631; P = 0.003). The mean increase in lean body mass (LBM) measured by dual energy x-ray absorptiometry was 3.0 +/- 0.5 kg (P < 0.001). At 12 months, the LBM values were significantly correlated to the IGF-I levels (r = 0.718; P < 0.001), but not to ALS or IGFBP-3 levels. No correlation was found before therapy, and the increase in LBM at 12 months correlated with the IGF-I increase (r = 0.514; P = 0.029) only after exclusion of two nonresponders. Both before and during therapy, LBM was inversely related to IGFBP-1 (r = -0.715; P < 0.004 at 12 months). None of the GH-induced proteins could be used as indicators of body fat changes. In conclusion, both IGF-I and ALS can be used as indicators to avoid GH excess during replacement therapy, but only IGF-I relates to changes in LBM.

Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19-82 years, in relation to those in healthy subjects.

Serum insulin-like growth factor I (IGF-I) levels within normal range for age have been reported to be common in adults with GH deficiency (GHD). Therefore, serum IGF-I levels were determined in 152 consecutive patients (71 women and 81 men) with evidence of hypothalamic-pituitary disorders or previous cranial radiation, who fulfilled the presently used criteria for GHD i.e. peak GH response below 3 microg/L at stimulation test. Patients treated for acromegaly were excluded. Forty-three patients, aged 19-63 yr, had childhood onset GHD, and 109, aged 23-82 yr, had adult-onset GHD. Their IGF-I levels were expressed in SD scores in relation to normal reference values based on 448 healthy subjects, aged 20-96 yr (247 women and 201 men). In healthy subjects a linear inverse correlation, without gender difference, was found between logarithmic transformed IGF-I levels and age (r = -0.774; P < 0.001). In contrast, no age dependency was found in GHD patients. All patients with childhood-onset GHD had IGF-I values below -2 SD, significantly lower than those in adult-onset GHD patients (-6.2 +/- 0.3 vs. -3.2 +/- 0.2 SD score; P < 0.001). In patients with adult-onset GHD, 34% of the IGF-I levels were within normal range, increasing to 40% in the subgroup above 60 yr of age, in whom 86% were diagnosed with hypothalamic-pituitary tumors. Normal IGF-I was more common in men than in women, but no difference was observed between patients with panhypopituitarism and those with partial pituitary insufficiency. High frequencies of IGF-I levels within the normal range were found in GHD patients with pituitary tumors (20 of 57 nonsecreting pituitary adenomas, 5 of 15 prolactinomas, 6 of 12 Cushing's disease, and 4 of 25 craniopharyngiomas), but in only 2 of 43 patients with GHD due to other causes. In conclusion, an IGF-I level below -2 SD seems to be of diagnostic value in GHD with onset in childhood or early adulthood, whereas values within normal range are common in patients over 60 yr of age, especially those with pituitary tumors. The outcome of GH replacement therapy may reveal whether the addition of IGF-I as a diagnostic criterion is of predictive value in older patients.

Effects of repeated subcutaneous administration of recombinant human insulin-like growth factor I in adults with growth hormone deficiency.

Insulin-like growth factor I (IGF-I) circulates bound to specific binding proteins (BPs) that modulate its effects at target cells. Hypoglycemia alters the serum levels of insulin-dependent IGFBPs and thus modifies the IGF-I action. We administered recombinant IGF-I (40 micrograms/kg body wt, from Kabi Pharmacia) in a morning dose (08.00 h) for seven consecutive days to six patients (21-47 years) with panhypopituitarism. This dose did not lead to hypoglycemia. Repeated blood sampling was performed on days 1 and 7, otherwise morning samples were drawn. The mean serum total IGF-I was maximal 3-4 h after the injection. A higher peak and basal value (p < 0.05) was observed on day 7 when compared to that observed on day 1. The concentrations were 237 vs 190 micrograms/l and 43 vs 22 micrograms/l. The mean free IGF-I increased concomitantly to 17 and 20 micrograms/l after 2-3 h on days 1 and 7. After 4 h, IGF-II was decreased (p < 0.05) from 340 to 291 micrograms/l on day 1 and from 341 to 252 micrograms/l on day 7. The IGF-I area under the curve on days 1 and 7 was correlated to the IGFBP-3 levels. Only the patient with the highest IGFBP-3 level obtained IGF-I levels above 100 micrograms/l for 24 h. In spite of unchanged glucose levels, there was a modest suppression of insulin levels (p < 0.05) between 0 and 4 h from 102 to 78 pmol/l on day 1 and from 90 to 60 pmol/l on day 7 when the subjects were fasting.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses of insulin-like growth factor (IGF)-I and IGF-binding proteins to nutritional status in peroxisome proliferator-activated receptor-alpha knockout mice.

Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in glucose and lipid homeostasis. Mice lacking PPARalpha(-/-) have a sexually dimorphic phenotype. We have characterized the IGF system in wild type and PPARalpha-/- mice. In normal mice fasting IGF-I and the IGFBP-3 ternary complex were 2-fold higher in males than in females. PPARalpha influenced the IGF/IGFBP response to feeding, particularly in males. Compared to wild type, male PPARalpha-/- mice had 40% lower total fasting IGF-I concentrations, decreased ALS and less IGFBP-3 ternary complex formation, but within 4 h of refeeding there was an increase in IGF-I and IGFBP-3 ternary complex to values similar to controls. Circulating IGFBP protease activity was induced in male PPARalpha-/- mice during refeeding. IGFBP-1 and insulin concentrations were higher in males than females, and were increased by PPARalpha knockout, suggesting significant hepatic insulin resistance. We speculate that gender differences in the IGF system contribute to the PPARalpha-/- phenotype.

Effects of recombinant human insulin-like growth factor I administration in adults with growth hormone deficiency.

Recombinant human insulin-like growth factor I (IGF-I), 40 micrograms/kg/body weight, was administered subcutaneously at 08.00 hours to six adult patients with growth hormone deficiency (GHD). The mean maximal IGF-I concentrations were found 2-6 hours after injection. Concentrations then gradually declined, though mean values were still above basal 24 hours after the injection. Only one patient maintained IGF-I levels above the lower normal range throughout 24 hours. There was a significant decrease in mean IGF-II concentrations when measured 4 and 24 hours after injection of IGF-I. The diurnal variations of insulin and IGF binding protein-1 were preserved. There were no side-effects, and blood glucose remained normal. These results show that in patients with low IGF-I levels resulting from GHD, it is necessary to administer IGF-I at intervals of less than 24 hours to obtain IGF-I levels that are within the normal range.

Specific cleavage of insulin-like growth factor-binding protein-1 by a novel protease activity.

Insulin-like growth factor-binding protein-1 (IGFBP-1) is secreted in a highly phosphorylated form that binds IGF-I with high affinity and is resistant to proteolysis. We have purified IGFBP-1-specific protease activity from the urine of an individual with multiple myeloma. This protease efficiently cleaves both phosphorylated and non-phosphorylated IGFBP-1 at Ile130-Ser131, generating fragments that together have higher association and dissociation rates for IGFs compared with intact IGFBP-1. The proteolytic fraction contained azurocidin, a protease homologue hitherto considered inactive. After cleavage of IGFBP-1, there was a lower affinity, but higher capacity for IGF-I binding, suggesting both N- and C-terminal fragments may interact with ligand independently. There was decreased inhibition of IGF-II-stimulated cell growth and glucose uptake. Alone, proteolysed IGFBP-1 stimulated glucose uptake in muscle. We conclude that specific cleavage of IGFBP-1 at target tissues is important in cellular growth and metabolism and opens novel strategies for targeting IGFBP-1 in treatment of disease.