Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality

CONTEXT: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGF-I. OBJECTIVE: Our objective was to study IGF-I bioactivity in relation to human survival. DESIGN, SETTING, AND STUDY PARTICIPANTS: We conducted a prospective observational study at a clinical research center at a university hospital of 376 healthy elderly men (aged 73-94 yr). MAIN OUTCOME MEASURES: IGF-I bioactivity was determined by the IGF-I kinase receptor activation assay. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months). RESULTS: During the follow-up period of 8.6 yr, 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group [hazard ratio (HR) = 1.8; 95% confidence interval (95% CI) = 1.2-2.8; P = 0.01] as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4; 95% CI = 1.3-4.3; P = 0.003) or a high inflammatory risk profile (HR = 2.3; 95% CI = 1.2-4.5; P = 0.01). Significant relationships were not observed for total or free IGF-I. CONCLUSION: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk.     

Preeclampsia is associated with low circulating levels of insulin-like growth factor I and 1,25-dihydroxyvitamin D in maternal and umbilical cord compartments

Insulin-like growth factor I (IGF-I) stimulates renal and placental 1,25-dihydroxyvitamin D [1,25-(OH)2D] and is considered an important regulator of fetal growth. As 1,25-(OH)2D and birth weight are low in preeclampsia, this study was undertaken to determine whether circulating levels of IGF-I were associated with serum 1,25-(OH)2D concentrations in preeclamptic (PE group) and normotensive (NT group) pregnancies. Maternal and umbilical cord serum levels of IGF-I and 1,25-(OH)2D were significantly (P < 0.01) lower in the PE group than in the NT group. The concentrations of these two hormones correlated significantly in the umbilical cord (P < 0.05) and in the maternal (P < 0.001) compartments of the PE and NT groups, respectively. The amount of IGFBP-3 was 64% lower whereas that of IGFBP-1 was 2.9-fold higher in umbilical cord serum of the PE group compared with the NT group. In addition, maternal and umbilical cord serum IGF-I correlated significantly (P < 0.05) with weight and length at birth only in the PE group. In conclusion, the results of this study indicate that circulating IGF-I and 1,25-(OH)2D levels in both maternal and umbilical cord compartments are low in preeclampsia. Furthermore, this study suggests a differential regulatory effect of IGF-I on 1,25-(OH)2D synthesis and fetal growth depending on the presence or absence of preeclampsia.     

Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling

The IGFs promote the growth and development of the feto-placental unit during gestation, and impairment of their placental actions may result in altered intrauterine growth of the fetus. In this study, proteins involved in IGF signaling were investigated in human placentas from pregnancies complicated by intrauterine growth restriction (IUGR) compared with those from normal pregnancies. IUGR placentas exhibited 33% reduction in the protein content of IGF-I receptors, but no changes in insulin receptor protein levels. In addition, insulin receptor substrate-2 (IRS-2) protein levels were reduced in IUGR placentas, with no changes in IRS-1 or Shc protein content, and this was associated with a parallel decrease in IRS-2-associated phosphatidyl inositol 3-kinase. Akt protein expression was also reduced in IUGR, whereas phosphorylation of Akt and its substrate glycogen synthase kinase-3 was unchanged. Finally, in IUGR placentas there was impaired activation of multiple members of the MAPK family, because phosphorylation of p38 and c-Jun N-terminal kinase was reduced 70%. In conclusion, human placentas from pregnancies complicated by IUGR are characterized by decreased IGF-I receptor content, selective impairment of the IRS-2/ phosphatidyl inositol 3-kinase pathway, and reduced p38 and c-Jun N-terminal kinase activation. The observed abnormalities in IGF-I signaling may contribute to altered fetal growth and development in human IUGR.     

Obesity is associated with increased levels of circulating hepatocyte growth factor

OBJECTIVES: This study evaluated whether obesity in humans was associated with an increase in circulating hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels. BACKGROUND: Obesity acts as a cardiovascular risk factor by mechanisms that are not fully understood. Adipose tissue is able to secrete multiple cytokines and growth factors ex vivo. We hypothesized that the increased presence of adipose tissue in obese subjects results in systemic elevations of the mitogenic factors HGF and VEGF. METHODS: Blood samples were obtained from lean (n = 21) and obese (n = 44) volunteers. Serum HGF and VEGF levels were assessed by enzyme-linked immunoadsorbent assay. Insulin and fasting glucose levels were measured to evaluate insulin sensitivity. Conditioned medium of adipose cells was assayed for HGF secretion. RESULTS: Serum HGF levels in obese subjects were more than three-fold higher than those of lean subjects (2,462 +/- 184 pg/ml vs. 765 +/- 48 pg/ml, p < 0.0001). The VEGF levels were not significantly elevated in obese subjects (135 +/- 31 pg/ml vs. 128 +/- 37 pg/ml). The HGF concentrations, but not VEGF concentrations, were significantly correlated with body mass index (BMI) (p < 0.0001, r = 0.74). The observed increases in HGF concentrations of obese subjects were not secondary to insulin resistance or hypertension. Freshly isolated human adipose cells secreted HGF. CONCLUSIONS: Our results indicate that obesity is associated with a marked increase in circulating HGF levels, which correlate linearly with BMI. Because vascular growth factors have been associated with the pathogenesis of atherosclerosis, the possible role of such humoral factors as a link between obesity and cardiovascular disease is very intriguing.     

Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome

CONTEXT: Cerebrovascular disease is highly prevalent in the general population, frequently leading to permanent invalidity and reduced quality of life. IGF-I is recognized as an important neuroprotective factor against cerebral hypoxic insult. OBJECTIVE: The objective of the study was to evaluate pituitary function, in particular GH-IGF-I axis, in adult patients receiving rehabilitation after an ischemic stroke. SUBJECTS AND METHODS: We studied 42 patients (12 females; age range, 50-88 yr) during rehabilitation after stroke, evaluating the relationship between the GH-IGF-I axis and the severity (National Institutes of Health stroke scale) and outcome [Rancho Los Amigos Scale of Cognitive Functioning (LCFS); Functional Independence Measure (FIM); modified Ranking Scale] from stroke. RESULTS: GH deficiency was demonstrated in five patients (11.9%). Peak GH after GHRH + arginine test and IGF-I levels did not correlate with severity of stroke. IGF-I was positively correlated with LCFS (r = 0.305, P < 0.05) and the difference between FIM on admission and at discharge from rehabilitation (DeltaFIM; r = 0.361, P < 0.02). Outcome indexes (LCFS, FIM at discharge, DeltaFIM) and occurrence of favorable outcome (modified Ranking Scale 0-1) were significantly (P < 0.05) higher in patients with IGF-I levels 161.8 mug/dl or greater (50th percentile of the patient distribution). LH-FSH deficiency (three cases), ACTH deficiency (one case), and hyperprolactinemia (two cases) were detected. One patient had primary hypogonadism, and six males had low testosterone with normal LH and FSH levels. By multivariate analysis, IGF-I level was the main significant predictor of DeltaFIM and LCFS. CONCLUSIONS: Ischemic stroke may be associated with pituitary dysfunction, particularly GH and gonadotropin deficiencies. The higher IGF-I levels observed in patients with better outcome suggest a possible neuroprotective role of IGF-I. Circulating IGF-I may predict functional performance during rehabilitation and ischemic stroke outcome.     

Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice

Serum levels of GH and insulin-like growth factor I (IGF-I) were genetically increased to investigate the physiological activities of these proteins. Lines of mice expressing chimeric genes composed of bovine GH, human GRF, or human IGF-I coding sequences fused to the mouse metallothionein I promoter were examined for consequences of chronic exposure to high levels of these peptides. Animals with elevated serum levels of GH (either bovine GH or mouse GH) have selective splanchnomegaly coupled with glomerular sclerosis and hepatocellularmegaly. Serum levels of insulin and cholesterol are increased. In contrast (with the exception of selective enlargement of organs), the chronic expression of IGF-I results in a different pattern of abnormalities. These findings suggest that the pathogenesis of GH-related disorders is not mediated solely by IGF-I.     

Intracerebral administration of insulin-like growth factor I decreases circulating growth hormone levels in the fetal pig

Radioimmunoassayable IGF-I levels were measured in the cerebrospinal fluid and plasma of pig fetuses at 94 days gestational age. Mean plasma IGF-I levels were 128.5 +/- 5.8 micrograms/l while the concentration in the cerebrospinal fluid was 25.8 +/- 4.4 micrograms/l. The effect of intracerebroventricular administration of IGF-I on circulating GH levels was also studied in pig fetuses in utero. Eighteen pig fetuses were fitted with indwelling carotid artery and jugular vein catheters. Nine fetuses were given 1500 ng of pure IGF-I in 100 microliters 0.9% saline by direct injection into a right lateral ventricle. Nine further fetuses (controls) were similarly given 100 microliters of saline without IGF-I. GH levels in the control fetuses were approximately 200 micrograms/l and showed marked fluctuations with episodic intervals of about 40 min. By contrast, in the IGF-I-treated fetuses, GH levels were dramatically lowered by 20 min after IGF administration and remained low throughout the 4-h study. The episodic variations in GH were abolished and levels remained fairly constant at ca. 40 micrograms/l. From these results we surmise that the low levels of IGF-I in the fetus may contribute to their high GH levels. At this stage it is not possible to identify whether the IGF-I inhibition is a direct effect on the pituitary or is mediated by increased somatostatin, decreased GHRH or both.     

Abnormalities of renal function in essential hypertension with increased circulating levels of insulin-like growth factor I.

An increase in glomerular filtration rate and in tubular Na+ reabsorption from the parenteral administration of insulin-like growth factor I (IGF-I) have been reported in human subjects. To evaluate whether glomerular hyperfiltration and Na+ hyper-reabsorption present in some essential hypertensives are associated to an excess of IGF-I, the plasma levels of this factor and several parameters of renal function were studied in 30 non-treated essential hypertensives and in 30 normotensive controls. IGF-I levels were higher in hypertensive as compared to controls. With the 95% (upper) limit of the normotensive population as a cut-off point, a subgroup of six hypertensives had an abnormally high IGF-I level. Mean blood pressure was slightly lower in these six patients (112 +/- 7 mmHg) than in the remaining patients (120 +/- 2 mmHg). As compared to normotensives and hypertensives with normal IGF-I levels, patients with increased IGF-I levels were characterized by lower (P < 0.01) fractional Na+ excretion and higher (P < 0.05) creatinine clearance. The analysis of the relation of plasma renin activity and the concurrent daily rate of Na+ excretion showed that patients with increased IGF-I were low-renin hypertensives and patients with normal IGF-I were normal-renin hypertensives. These results indicate that an association exists between exaggerated circulating levels of IGF-I and abnormalities of renal function present in some patients with essential hypertension. It is suggested that IGF-I can play a role in low-renin essential hypertension.     

Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulation in women. Previous studies suggest that the pathogenesis of PCOS may involve interrelated abnormalities of the insulin-like growth factor (IGF) and ovarian steroidogenesis systems. We investigated this hypothesis in fasting serum samples from 140 women with PCOS (age, 27.4 +/- 0.4 yr; body mass index, 26.3 +/- 0.5 kg/m2; mean +/- SEM). IGF-related parameters were also studied in a group of normoovulatory women (n = 26; age, 26 +/- 4 yr; body mass index, 23.6 +/- 4.3 kg/m2). For the PCOS group, the mean testosterone (T) level was 2.5 +/- 0.1 nmol/L, and it was significantly correlated with LH (r = 0.41; P < 10(-6)), estrone (r = 0.33; P = 0.016), estradiol (r = 0.18; P = 0.04), and androstenedione (AD; P < 10(-6)), but not with dehydroepiandrosterone sulfate (P = 0.71), a marker of adrenal steroidogenesis. T and AD were also related to total ovarian follicle number and ovarian size, as previously found with normoovulatory women (1). There were no differences between the PCOS subjects and the normoovulatory group for total IGF-I, IGF-II, or IGF-binding protein-3 (IGFBP-3). However, IGFBP-1 levels were significantly decreased in the PCOS group (1.0 +/- 0.2 vs. 7.3 +/- 1.1 ng/mL; P < 0.001) and were inversely correlated with serum insulin levels (r = -0.50; P < 10(-8)). Serum levels of free IGF-I (fIGF-I) were elevated (5.9 +/- 0.3 vs. 2.7 +/- 0.3 ng/mL; P < 0.001) in inverse relation with IGFBP-1 (r = -0.31; P = 0.046). Serum fIGF-I levels were related to total follicle number (r = - 0.35; P < 10(-4)) and to the ratio of sex hormone-binding globulin to T (r = -0.23; P = 0.009). However, these relationships were not independent of other variables. Despite the more than 2-fold elevation in fIGF-I levels, significant relationships between fIGF-I and markers of ovarian steroidogenesis (T, AD, estradiol, and estrone) could not be demonstrated. In conclusion, although we confirmed correlations between LH and hyperandrogenemia and have found abnormalities in the IGF system in a large cohort of PCOS subjects, a direct relationship between hyperandrogenism and the IGF system could not be shown. Previous studies suggest that elevated LH and hyperinsulinemia lead to excess ovarian androgen synthesis in PCOS and that the intraovarian IGF system is important for normal follicle development and may be important in the arrested state of follicle development in PCOS. However, the data presented in this cross-sectional study suggest that insulin-related changes in circulating IGFBP-1 and subsequent elevation of fIGF-I reflect insulin resistance and have little enhancing effects on ovarian steroidogenesis in this disorder.     

The bone mineral density in acquired growth hormone deficiency correlates with circulating levels of insulin-like growth factor I.

Insulin-like growth factor I (IGF-I) is an important anabolic factor for osteoblasts in vitro. Low plasma levels of IGF-I have been observed in young men with osteoporosis. In the present study, we have studied bone mineral density (BMD) and the circulating levels of IGF-I and growth hormone (GH) in adults with acquired GH deficiency. BMD was determined by dual-energy x-ray absorptiometry in 17 men and 12 women (age 27-54 years). Spinal BMD was positively correlated with the plasma levels of IGF-I (r = 0.43, P = 0.019), with the median of GH values obtained by repeated sampling at night (r = 0.43, P = 0.0019), and with the peak of GH values during GHRH provocation test (r = 0.49, P = 0.039). The total BMD was positively related to plasma IGF-I and median of GH values, but not to peak GH by GHRH provocation. In a multiple regression analysis model, IGF-I, peak GH by GHRH provocation test and duration of GH deficiency explained 49% of the variation in spinal BMD. As compared to healthy controls, total, but not spinal, bone mass was lower in men with GH deficiency, but no clinical symptoms of osteoporosis were observed. The positive relationships between BMD and circulating IGF-I and other indices of GH secretion suggest that IGF-I has an endocrine effect on bone mass.     

Expression of insulin-like growth factor I in transgenic mice with elevated levels of growth hormone is correlated with growth

To study the role of insulin-like growth factor I (IGF-I) in mediating the growth-promoting function of GH, IGF-I expression was assayed in transgenic mice carrying either GH or GRF fusion genes. These mice exhibit enhanced growth as a result of high level ectopic expression of GH and have 2-fold elevation of both hepatic IGF-I mRNA levels and circulating IGF-I levels. Hepatic IGF-I mRNA levels are low at birth regardless of GH levels; they increase approximately 10-fold during postnatal development and become GH inducible 2 weeks after birth. The ontogeny of circulating IGF-I is similar. Accelerated growth in transgenic mice with GH fusion genes commences 3 weeks after birth despite high circulating GH levels at least as early as birth. In addition, endogenous mouse GH-secreting somatotroph cells in the pituitary are present in normal numbers at 3 weeks, but are undetectable 4 weeks after birth. Because the time at which IGF-I expression becomes GH responsive slightly precedes both the initiation of accelerated growth and the time when endogenous GH disappears, we conclude that IGF-I is directly involved in mediating the GH signal and that delayed induction of IGF-I gene expression is responsible, at least in part, for the delayed onset of other GH-responsive events.     

Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia

Summary Non-islet cell tumour hypoglycaemia (NICTH) is characterised by severe and recurrent fasting hypoglycaemia, and is usually caused by secretion of insulin-like growth factor-II (IGF-II) by the tumour. This induces secondary changes in the circulating levels of insulin, growth hormone (GH), and the IGF-binding proteins (IGFBPs), resulting in an increased insulin-like hypoglycaemic activity of IGF-II. A participating role of IGF-I is not established. We measured serum levels of free IGF-I and free IGF-II, total IGF-I, total IGF-II, big IGF-II and IGFBP-1, IGFBP-2 and IGFBP-3 in patients with NICTH before (n = 14) and after surgical removal of the tumour (n = 3). A control group (n = 20) was included for comparison. In NICTH patients, free IGF-II was 20-fold increased (26.8 ± 8.1 [mean ± SEM] vs. 1.3 ± 0.1 μg/l), and free IGF-I was four fold increased (2.8 ± 0.4 vs. 0.7 ± 0.1 μg/l), as compared to control subjects (p < 0.0001). In accordance with earlier observations levels of total IGF-I, total IGF-II, and IGFBP-3 were decreased, whereas IGFBP-1 and IGFBP-2 were increased in NICTH (all p-values < 0.05). The highly elevated levels of free IGF-I and free IGF-II most likely imply a considerable hypoglycaemic insulin-like activity, and may, by negative feedback explain the marked suppression of the GH/IGF-I axis observed in NICTH. Finally, free IGF-II seems to be a powerful biochemical marker in the diagnosis of NICTH. [Diabetologia (1998) 41: 589–594] Received: 21 October 1997 and in final revised form: 15 December 1997     

Evidence that potassium deficiency induces growth retardation through reduced circulating levels of growth hormone and insulin-like growth factor I.

Growth retardation and impaired protein synthesis are major characteristics of potassium (K)-deficiency in animals and man. We have evaluated the effect of K-deficiency on growth, serum growth hormone (s-GH), insulin-like growth factor I (s-IGF-I), and insulin (s-insulin) in young rats. After 10 days on K-deficient fodder, 4 1/2-week-old rats showed a 54% reduction in serum potassium (s-K) and a weight gain that was reduced by 97%, compared with pair-fed controls. In addition, tail length, tibia length, and muscle weight of soleus in K-depleted animals were all significantly reduced compared with pair-fed controls. The growth retardation was accompanied by a 46% reduction in s-IGF-I, while s-insulin showed no decrease. K-repletion in animals depleted for 7 days showed complete normalization of s-K within 24 hours, in addition to a significant increase in both s-IGF-I and weight. In 4-week-old rats maintained on K-deficient fodder with variable K-content (1 to 260 mmol/kg) for 1 week, a strong correlation between the K-content of fodder and s-IGF-I could be established (r = .88, P less than .001), as well as between s-IGF-I and weight gain (r = .90, P less than .001). Furthermore, a stepwise reduction in basal s-GH was seen with the graded reduction of dietary K-content.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum levels of insulin-like growth factor I and insulin-like growth factor-binding protein 1 correlate with serum free testosterone and sex hormone binding globulin levels in healthy young and middle-aged men

OBJECTIVE Administration of testosterone has been reported to increase serum levels of IGF-I in men with isolated hypogonadotrophic hypogonadism. An inverse relation between serum IGF-I and sex hormone binding globulin (SHBG) is seen in GH deficient children. The biological action of IGF-I is thought to be influenced by binding proteins, one of which is insulin-like growth factor-binding protein-1 (IGFBP-1), which is not only a carrier protein but also actively regulates the cellular actions of IGF-I. These observations suggest associations between IGF-I, IGFBP-1, testosterone and SHBG in serum. The aim of the present study was to investigate these associations in normal healthy men. DESIGN AND PATIENTS The associations between the serum levels of IGF-I and IGFBP-1 on one hand, and testosterone and SHBG on the other were investigated in 38 normal healthy young and middle-aged men. RESULTS Serum levels of IGF-I decreased both with increasing age (r = ? 0.66, P < 0.001) and increasing SHBG levels (r = ? 0.46, P = 0.002), but increased with increasing free testosterone (f-testosterone) (r = 0.42, P = 0.005). These associations remained after mutual simultaneous adjustments in a multiple regression analysis. IGFBP-1 did not display any significant univariate correlation with age (r = ? 0.25, P = 0.06) or SHBG (r = 0.18, P = 0.14), but showed a significant positive correlation with both f-testosterone (r = 0.42, P = 0.004), and total testosterone (t-testosterone) (r = 0.39, P = 0.008). In a multiple regression analysis IGFBP-1 was positively correlated with both SHBG and f-testosterone, but not with t-testosterone. CONCLUSION The present study suggests that among healthy young and middle-aged men, there is an association between serum levels of free-testosterone and SHBG on the one hand, and serum IGF-I and IGFBP-1 on the other.