Reduced Insulin-like Growth factor-I Levels Research Articles

Treatment of acromegaly has substantial effects on body composition: a long-term follow-up study.

Acromegaly is associated with changes in body composition. Long-term changes following acromegaly treatment and the impact of different treatments have been less investigated. We performed a retrospective study in 201 patients with acromegaly. Body composition was assessed by dual-energy X-ray absorptiometry. To investigate the specific effects of treatment vs aging, changes in body composition were compared in one group of patients evaluated both at the time of active and controlled disease (active-to-controlled (A>C); n = 31) and in another group of patients evaluated two times while the disease was controlled (controlled-to-controlled (C>C); n = 32). In the whole cohort, insulin-like growth factor I (IGF-I) was correlated with fat (r = -0.369; P < 0.001) and lean mass (r = 0.383; P < 0.001). Patients from A>C and C>C groups were comparable for age, sex, BMI and follow-up duration (P = n.s.). Reduction in IGF-I levels was associated with an increase in fat mass and a decrease in lean mass in the A>C group, which was four and eight times more pronounced compared to the C>C group (fat mass: +39 ± 34% vs +10 ± 15%, P < 0.001; lean mass: -8 ± 8% vs -0.2 ± 6%, P < 0.001, respectively). Changes in fat mass were negatively associated with IGF-I (r = -0.450; P = 0.011) and independent of the individual therapy. The daily dose of pegvisomant correlated with fat mass (r = 0.421; P = 0.002) and insulin sensitivity index (r = -0.466; P < 0.001). Treatment of acromegaly strongly impacts body composition until biochemical disease remission, characterized by an increase in fat mass and a decrease in lean mass. These changes are closely associated with the normalization of IGF-I. Thereafter, body composition changes are similar to what is observed with aging.

Combination of pasireotide and octreotide: effects on GH and IGF-I secretion and glucose metabolism in healthy volunteers.

To assess the pharmacokinetics, pharmacodynamics and tolerability of different doses of octreotide and pasireotide (subcutaneous [sc] and long-acting release [LAR]) when co-administered in healthy volunteers. This was an exploratory, Phase I, single-centre study. Healthy adults were enrolled in a staggered approach into seven cohorts to receive octreotide and pasireotide (sc and LAR formulations), alone or in combination. Plasma drug concentrations, growth hormone (GH), insulin-like growth factor I (IGF-I), and plasma glucose were assessed at baseline, immediately after sc treatment, and 21 and 28 days after LAR treatment. Of 88 enrolled subjects, 52 and 82 participated in sc and LAR dosing phases, respectively. There were no relevant pharmacokinetic interactions between octreotide and pasireotide. In combination, pasireotide sc (150 µg) and octreotide sc (100/300 µg) resulted in numerically greater reductions in insulin levels and a higher incidence of AEs than either single agent; the rapid (within 1 h) increase in plasma glucose after pasireotide was delayed with combination treatment. Octreotide sc and pasireotide sc, alone or in combination, reduced IGF-I levels and led to undetectable GH levels in most subjects. During the LAR phase, addition of a low dose of pasireotide (5 mg) to a standard dose of octreotide (20 mg) resulted in an ~2-fold reduction in median IGF-I versus octreotide 20 mg 21 days post-dose; this effect was numerically greater than seen for pasireotide 20 mg alone. Peak plasma glucose was substantially lower after LAR than sc dosing. Interestingly, glucose levels were also numerically lower in the pasireotide 5 mg plus octreotide 20 mg group than for 20 mg of octreotide or pasireotide alone. AEs were less frequent after LAR than sc dosing. Combined low doses of pasireotide LAR (5 mg) and octreotide LAR (10-30 mg) provided greater suppression of IGF-I than either single agent and did not increase blood glucose or incidence of AEs versus either agent alone.

Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice.

Growth hormone (GH) and/or insulin-like growth factor I (IGF-I) are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic properties of GH, medical strategies have been considered to raise GH to improve body composition and metabolic function in elderly and obese patients. Since hyperlipidemia, inflammation, insulin resistance and obesity increase breast cancer risk, elevating GH may serve to exacerbate cancer progression. To better understand the role GH/IGF-I plays in tumor formation, this study used unique mouse models to determine if reducing GH/IGF-I in adults protects against 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary tumor development, and if moderate elevations in endogenous GH/IGF-I alter DMBA-induced tumorigenesis in mice fed a standard-chow diet or in mice with altered metabolic function due to high-fat feeding. We observed that adult-onset isolated GH-deficient mice, which also have reduced IGF-I levels, were less susceptible to DMBA-treatment. Specifically, fewer adult-onset isolated GH-deficient mice developed mammary tumors compared with GH-replete controls. In contrast, chow-fed mice with elevated endogenous GH/IGF-I (HiGH mice) were not more susceptible to DMBA-treatment. However, high-fat-fed, HiGH mice showed reduced tumor latency and increased tumor incidence compared with diet-matched controls. These results further support a role of GH/IGF-I in regulating mammary tumorigenesis but suggest the ultimate consequences of GH/IGF-I on breast tumor development are dependent on the diet and/or metabolic status.

Hypophysectomy for prostate cancer: a revival of old knowledge?

The growth of prostate cancer is controlled by several hormones and growth factors. In cases of metastasized prostate cancer, antigonadotropic therapy is currently considered state-of-the-art treatment. Surgical therapies such as adrenalectomy and hypophysectomy are no longer in use. Nevertheless, hypophysectomy has proven efficacy for palliative pain treatment as well as increasing duration of survival. The authors present the case of a 63-year-old man with metastatic prostate cancer who presented with high serum prostate-specific antigen levels (1216 microg/L) and cavernous sinus syndrome. His disease was progressing despite leuprorelin and docetaxel therapy, and he had severe bone pain despite high-dose pain therapy. He was also anemic. Contrast-enhanced MR imaging showed a pituitary lesion as well as metastatic infiltration of the skull base including the cavernous sinus. The patient's serum level of prolactin was mildly elevated, testosterone was below the detection limit, and insulin-like growth factor-I (IGF-I) was in the upper range for a patient of his age (233 microg/L). Because of the elevated prolactin and high-normal IGF-I levels he was offered a hypophysectomy in addition to pituitary tumor removal. Histological examination of the resected lesion confirmed a nonsecreting pituitary adenoma with infiltration of prostate cancer cells. Postoperatively the patient's prostate-specific antigen levels dropped to 876 microg/L, his bone pain resolved, and the cavernous sinus syndrome improved. Nevertheless, he died of septicemia 4 months after surgery. Older publications as well as this case have shown the benefit of hypophysectomy for pain treatment. A reduction of IGF-I levels even in the final stage metastasized prostate cancer may play a major role. Respectively, clinical studies with somatostatin analogs are currently in progress, which may lead to a "new" way of treatment in these otherwise hopeless patients. On the basis of the pain relief seen after hypophysectomy in this case and similar benefits reported in older publications, the authors raise the question whether this treatment should be offered more frequently, and whether additional medical options of hormone treatment may be beneficial in similar cases.

Session 7: Early nutrition and later health early developmental pathways of obesity and diabetes risk.

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.

Lack of growth enhancement by exogenous growth hormone treatment in yellow perch ( Perca flavescens) in four separate experiments

The effect of exogenous growth hormone (GH) treatment on the growth of juvenile yellow perch ( Perca flavescens) was investigated in four experiments. In the first two experiments, juvenile yellow perch were reared at either 13 °C or 21 °C, and injected weekly with bovine GH (bGH) at 0.1, 1.0 or 10.0 μg/g body weight for 84 days. No significant growth enhancement in GH-treated fish was measured in fish in either of the experiments. In the third experiment, juvenile yellow perch were treated with estradiol-17β (E 2, 15 μg/g of diet), bGH (1.0 μg/g body weight) injected weekly or both hormones for 70 days at 21 °C. E 2 alone stimulated growth, but no further growth stimulation occurred in the E 2 + bGH-treated fish. In addition, no growth enhancement was found in fish treated with bGH alone. We measured no difference in serum insulin-like growth factor-I (IGF-I) levels between the treatment groups at 12 and 24 h after the final injection of GH; however, a drop in IGF-I levels after 24 h was observed. In a fourth study, the effect of recombinant yellow perch GH (rypGH, 0.2 or 1.0 μg/g body weight) injected weekly was evaluated in yellow perch juveniles. The fish were reared for 42 days at 18 °C. Neither GH dosages improved growth compared to control-injected and non-injected fish. Taken together, the lack of effect of mammalian GH or rypGH in our experiments suggests (1) low binding affinity between these hormones and the GH receptor in yellow perch, (2) that the endogenous GH levels were already at biologically maximal levels or (3) that other endocrine factors are needed in order for GH to promote yellow perch growth. The reduction in IGF-I levels 24 h after handling suggests a negative effect of handling stress on the GH-IGF-I axis in yellow perch.

GH/IGF-I axis in anorexia nervosa

Patients with anorexia nervosa (AN) may develop multiple endocrine abnormalities, including amenorrhea, hyperactivity of the hypothalamus-pituitary-adrenal axis, hypothyroidism and particular changes in the activity of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. Exaggerated GH secretion and reduced IGF-I levels are usually found in AN, as well as in conditions of malnutrition and malabsorption, insulin-dependent diabetes mellitus, liver cirrhosis and catabolic states. In AN, GH hypersecretion at least partially reflects malnutrition-induced peripheral GH resistance, which leads to reduced IGF-I synthesis and release; this implies an impairment of the negative IGF-I feedback action on GH secretion. On the other hand, primary alterations in the neural control of GH secretion cannot be ruled out. The neuroendocrine alterations include enhanced somatotroph responsiveness to growth hormone releasing hormone (GHRH) and impaired GH response to most central nervous system-mediated stimuli. Particular resistance to cholinergic manipulation has also been demonstrated, thus suggesting a somewhat specific alteration in the somatostatin (SS)-mediated cholinergic influence on GH secretion. Moreover, paradoxical GH responses to glucose load, thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH) have also been reported. The effect of reduced leptin levels on GH hypersecretion in AN is still unclear, but ghrelin (the gastric hormone that is a natural ligand of the GH secretagogue receptor and strongly stimulates somatotroph secretion) is thought to play a major role. Regardless of the supposed central and peripheral alterations, it has to be emphasised that the activity of the GH/IGF-I axis in AN is generally restored by nutritional and stable weight gain. It therefore reflects an impaired nutritional state and cannot be considered a primary hallmark of the disease.

Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure

ObjectivesWe sought to assess the role of insulin-like growth factor-I (IGF-I) in muscle wasting in chronic heart failure (CHF), serum concentrations and local muscular IGF-I expression were determined in patients with severe CHF. BackgroundChronic heart failure is associated with progressive muscle atrophy, leading to cardiac cachexia. Skeletal muscle disuse and inflammatory activation with elevated cytokine levels have been implicated; however, the pathomechanism involved remains largely unknown. MethodsSerum levels of IGF-I were measured by competitive solid phase immunoassay in 47 patients with severe CHF (left ventricular ejection fraction ≤30%) and 15 age-matched healthy subjects (HS). Insulin-like growth factor-I and IGF-I receptor expression were assessed in vastus lateralis biopsies by real-time PCR and Western blot analysis. ResultsAlthough serum IGF-I was not significantly different (175 ± 10 ng/ml in CHF vs. 170 ± 12 ng/ml in HS, p = NS), local muscle IGF-I mRNA expression was reduced by 52% in CHF (6.7 ± 0.4 vs. 14.0 ± 0.9 arbitrary units in HS, p < 0.001). This was accompanied by an increase in IGF-I receptor mRNA expression (86.8 ± 5.4 in CHF vs. 23.1 ± 1.8 arbitrary units in HS, p < 0.001). Local IGF-I expression was significantly correlated with muscle cross-sectional area (R = 0.75, p = 0.01). Chronic heart failure patients with a body mass index of <25 kg/m2showed signs of peripheral growth hormone (GH) resistance, as indicated by elevated serum GH, and reduced IGF-I levels. ConclusionsIn CHF patients, muscle IGF-I expression is considerably reduced in the presence of normal serum IGF-I levels, possibly contributing to early loss of muscle mass. These findings are consistent with a potential role of IGF-I for skeletal muscle atrophy in CHF.

Anticholinergic treatment improves glycaemic control in adolescent girls with insulin-dependent diabetes mellitus

Metabolic control often deteriorates during puberty in girls with insulin-dependent diabetes. It is well accepted that there is an abnormality in the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis in these girls, resulting in reduced IGF-I levels and elevated GH. As GH antagonizes insulin, attempts have previously been made to reduce excess GH secretion through anticholinergic treatment. However, most of these studies have been performed on adult patients. The aim of the present study was to evaluate the effects of 12 wk of oral anticholinergic treatment with Pirenzepine, 100 mg twice daily, in 16 adolescent girls with diabetes. Serum samples of IGF-I, glycated haemoglobin and fasting IGF-binding protein 1 were analysed at initiation and after 3, 8 and 12 wk of Pirenzepine therapy. Nocturnal urinary GH excretion was also examined. Glycated haemoglobin declined significantly after 3 wk of Pirenzepine therapy (9.8 ± 0.18 vs 9.2 ± 0.17; p < 0.001) and was still improved at the end of the study. Unexpectedly, nocturnal urinary GH excretion did not change. Serum IGF-I continuously increased during the study, while IGF-binding protein 1 levels were not significantly altered. Conclusion: Anticholinergic treatment with Pirenzepine improves glycaemic control in adolescent girls with diabetes. Although nocturnal urinary GH excretion was unchanged there may still be changes in pituitary GH secretion to explain the improvement. Effects of Pirenzepine on gastrointestinal motility can represent other possible mechanisms behind the improved metabolic control.

Effects of spaceflight and thyroid deficiency on hindlimb development. I. Muscle mass and IGF-I expression.

Thyroid deficiency (TD) in neonatal rats causes reduced growth of skeletal muscle that is disproportionately greater than that for other tissues (G. R. Adams, S. A. McCue, M. Zeng, and K. M. Baldwin. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 276: R954-R961, 1999). TD depresses plasma insulin-like growth factor I (IGF-I) levels, suggesting a mechanism for this effect. We hypothesized that TD and exposure to spaceflight (SF) would interact to reduce skeletal muscle growth via a reduction in IGF-I levels. Neonatal rats were flown in space for 16 days. There was a similar, nonadditive reduction in the growth of the body ( approximately 50%) and muscle weight (fast muscles, approximately 60%) with either TD or SF. In the soleus muscle, either SF or TD alone resulted in growth reductions that were augmented by SF-TD interactions. There were strong correlations between 1) muscle mass and muscle IGF-I levels and 2) circulating IGF-I and body weight. These results indicate that either hypothyroidism or exposure to SF will limit the somatic and muscle-specific growth of neonatal rats. The impact of these perturbations on skeletal muscle growth is relatively greater than the effect on somatic growth. The mechanisms by which either TD or SF impact growth appear to have a common pathway involving the control of plasma and muscle IGF-I concentrations.

Relationship between Plasma IGF-I Levels,in VitroCorrelates of Immunity, and Human Senescence

Insulin-like growth factor-I (IGF-I) is a polypeptide mitogen which is regulated by growth hormone (GH). IGF-I mediates many of the biological functions of GH, including the maintenance of lymphoid mass and functions. Since GH secretion declines with age, we asked whether changes in the availability of IGF-I might contribute to age-associated alterations in immune functions. As a first step, we examined relationships between plasma levels of IGF-I andin vitrocorrelates of immunity in young and elderly subjects. Heparinized plasma and lymphocytes were collected from the peripheral blood of 34 healthy young (aged 27 ± 0.9 years, mean ± SEM) and 41 elderly (79 ± 1.3 years) volunteers (31 males and 44 females in total). Plasma levels of IGF-I, measured by radioimmunoassay after the removal of IGF-I-binding proteins, were reduced among elders compared to young controls (138 ± 8.7 ng/mL vs 80.2 ± 4.7 ng/mL,P< 0.001). The number of circulating lymphocytes did not change with age. The proliferative response ([3H]thymidine uptake into DNA) of T-cells to concanavalin A and B-cells to pokeweed mitogen were reduced among elders (P< 0.05). An increased spontaneous antitumor natural killer (NK) activity (P< 0.001) was accompanied by a higher percentage of CD16+NK cells among lymphocytes in older subjects (P< 0.001). The NK cell number was positively related to IGF-I levels in young volunteers but not among elders. Correlation analysis demonstrated a highly significant relationship between plasma IGF-I levels and T-cell (but not B-cell) proliferative response during aging (r= 0.492,P< 0.001). Our results imply that reduced immunocompetence may be one of the consequences of reduced IGF-I levels in human aging. Among the three types of immune cells tested, the T-cells were most sensitive to fluctuations in IGF-I levels. Reduced IGF-I availability may be one of the determinants of the decline in T-cell-mediated immune function in the elderly. To our knowledge, this is the first report presenting correlative data on concurrent changes in IGF-I levels and immune parameters in human aging.

Decline in insulin-like growth factor I levels after clomiphene citrate does not correct hyperandrogenemia in polycystic ovary syndrome.

It is widely accepted that the action of clomiphene citrate (CC) is mediated through its antiestrogenic properties on the hypothalamic-pituitary axis. Although insulin-like growth factor I (IGF-I) enhances the thecal cell response to LH, and estrogen treatment is associated with a reduction in IGF-I levels, CC is known to decrease circulatory IGF-I levels in polycystic ovary syndrome (PCOS) patients. The impact of lowering IGF-I levels on androgen levels in PCOS is unknown. This study was designed to examine the impact of CC treatment on the interrelationships of IGF-I, androgens, and estrogens in normal subjects and patients with PCOS. IGF-I, gonadotropin, androgen, estrogen, and sex hormone-binding globulin levels were measured in 8 PCOS patients and 10 normal subjects before and after treatment with the antiestrogen CC. Studies were performed in the early follicular phase, days 4-6 of the menstrual cycle in normal subjects. In normal subjects, CC treatment led to a significant increase in estradiol (84 +/- 10 to 234 +/- 62 pmol/L, untreated and CC treated; P < 0.05) and estrone (125 +/- 14 to 257 +/- 29 pmol/L; P < 0.05) levels with a significant lowering of IGF-I levels (297 +/- 25 to 230 +/- 17 micrograms/L; P < 0.05). Similarly, in PCOS patients a significant increase in estradiol (110 +/- 11 to 245 +/- 58 pmol/L; P < 0.05) and estrone (301 +/- 32 to 401 +/- 90 pmol/L; P < 0.05) levels and a significant lowering of IGF-I levels (330 +/- 43 to 214 +/- 27 micrograms/L; P < 0.05) were observed after CC treatment. However, no significant correlation was observed between changes in IGF-I and changes in estradiol in either group. Compared to pretreatment levels, no significant changes in the following parameters were observed after 5 days of CC treatment in either study group: testosterone, testosterone/sex hormone-binding globulin ratio, and androstenedione. The relationship among CC treatment, gonadotropin, estrogen, and IGF-I levels is complex. Changes in blood IGF-I levels are not associated with changes in androgen levels, although paracrine and or autocrine effects cannot be excluded.

Pituitary size assessed with magnetic resonance imaging as a measure of growth hormone secretion in long term survivors of childhood cancer.

We investigated 37 long term survivors of childhood cancer to study the relationship among growth, GH secretion, and pituitary size. The median follow-up time after diagnosis was 13.2 yr. The pituitary gland was visualized with magnetic resonance imaging. Radiated patients (n = 25) had a reduced relative height and showed a greater reduction in relative height after diagnosis than nonradiated patients (n = 12). The patients had lower spontaneous nocturnal GH secretion than controls due to a reduced peak amplitude. Spontaneous GH secretion was lower in radiated patients than in nonradiated subjects. The patients had lower plasma insulin-like growth factor-I (IGF-I) and serum IGF-binding protein-3 (IGFBP-3) concentrations than the controls. Radiated subjects had decreased IGF-I and IGFBP-3 concentrations compared to nonradiated subjects. Half of the patients (20 of 37) evaluated with magnetic resonance imaging had a reduced pituitary size (pituitary height, < -2 SD score). Radiated subjects had smaller pituitary glands than nonradiated ones. Seventeen of 20 patients (85%) with reduced pituitary size had decreased nocturnal GH release. There was a positive correlation between nocturnal GH secretion, plasma IGF-I, and serum IGFBP-3 levels, on the one hand, and pituitary height, on the other. These results indicate that cranial radiation may result in tissue damage, leading to decreased pituitary size, reduced spontaneous GH secretion, and impaired linear growth. The finding of reduced IGF-I levels in both radiated and nonradiated patients combined with decreased IGFBP-3 concentrations in radiated patients, indicates that cytotoxic chemotherapy may induce hepatic damage resulting in decreased IGF-I synthesis.

Increased proteolysis of insulin-like growth factor-binding protein-3 (IGFBP-3) in noninsulin-dependent diabetes mellitus serum, with elevation of a 29-kilodalton (kDa) glycosylated IGFBP-3 fragment contained in the approximately 130- to 150-kDa ternary complex.

Insulin-like growth factor-I (IGF-I) in serum is predominantly bound in a ternary complex, consisting of IGF peptide, IGF-binding protein-3 (IGFBP-3), and an acid-labile subunit, or a binary complex, consisting of IGF peptide and any of the six IGFBPs. In the binary complex, IGF-I is more bioavailable and has a faster turnover rate. Proteolysis of IGFBP-3 may alter the distribution of IGF-I between these complexes by reducing IGFBP-3 affinity for IGF-I and/or acid-labile subunit and may offer an additional mechanism for regulation of IGF availability. In the present study, sera from patients with noninsulin-dependent diabetes mellitus (NIDDM) were found to have significantly higher IGFBP-3 proteolytic activity than sera from age-matched healthy subjects (188 +/- 12% vs. 104 +/- 6% of a control serum pool; P < 0.001). The mean (+/- SE) of serum IGFBP-3 levels determined by Western ligand blotting was lower in NIDDM patients than in healthy control subjects (61.5 +/- 5% and 79 +/- 5% of a control serum pool, respectively; P < 0.01). However, IGFBP-3 concentrations determined by RIA did not differ. This discrepancy could be explained by IGFBP-3 proteolysis, resulting in IGFBP-3 fragments that are detectable by RIA, but not by Western ligand blotting. Western immunoblotting of sera with or without prior treatment with endoglycosidase-F demonstrated that a glycosylated 29-kilodalton (kDa) IGFBP-3 form with a protein core of 20 kDa was present in sera from healthy controls, and this fragment was increased in NIDDM and term pregnancy sera, suggesting that it is produced by endogenous proteolysis. The presence of the 29-kDa IGFBP-3 proteolytic fragment at about 130-150 kDa after neutral size chromatography of pooled sera may suggest that 29-kDa IGFBP-3 participates in ternary complex formation. Further studies are required to determine whether the avidity of ternary complex formation with the 29-kDa IGFBP-3 fragment is reduced and whether the resulting increased IGF turnover can explain the reduced IGF-I levels (z scores) observed in NIDDM patients compared to healthy subjects (-0.81 +/- 0.32 SD vs. +0.26 +/- 0.17 SD; P < 0.001). Neutral size-chromatography of sera demonstrated that IGFBP-3 protease activity in the approximately 130- to 150-kDa mol wt range is regulated by NIDDM and pregnancy in parallel with that of unfractionated sera.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth failure and decreased levels of insulin-like growth factor I in obstructive jaundice are reversed by bile diversion

Insulin-like growth factor I (IGF-I) is one of the principal stimuli of linear growth. Growth failure in children with chronic cholestatic jaundice may be related to decreased hepatic synthesis of IGF-I. It was hypothesized that (1) biliary obstruction would lead to growth retardation and decreased circulating IGF-I levels; and (2) surgical drainage of the obstructed biliary system would reverse these effects. To test this hypothesis, the following study of male Sprague-Dawley rats (135 g; 10 animals per group) was performed. Group I underwent common bile duct ligation (CDL); group II underwent choledochoduodenostomy 2 weeks following CDL; group III were sham-operated and pair-fed with CDL rats; and group IV were sham-operated and fed ad libitum. Daily food intake and weekly body weight were recorded. Statistical analysis was by repeated-measures analysis of variance and individual comparisons were evaluated by Student's t test. Biliary obstruction results in decreased food intake, rate of weight gain, and IGF-I levels. A significant reduction in IGF-I levels was also noted in the pair-fed sham-operated rats (group III). Relief of obstructive jaundice by surgical drainage results in a reversal of these changes. It is concluded that the growth failure and decreased IGF-I levels associated with obstructive jaundice can be reversed by surgical drainage of the obstructed biliary system and, in part, are due to inadequate nutrition.