High Insulin-like Growth Factor Binding Research Articles

Abstract 12938: Intrathoracic Visceral Adiposity is Inversely Associated With Insulin Like Growth Factor Binding Protein 1: The Longenity Study

Introduction: Higher insulin-like growth factor binding protein 1 (IGFBP-1) level in serum has been variably associated with better insulin sensitivity and lower rates of obesity, diabetes mellitus, and atherosclerosis; suggesting that it may have a protective role in cardiometabolic aging. We hypothesized that epicardial, intrathoracic, or total thoracic adiposity (EAT, IAT, or TTA, respectively) measured on thoracic CT, were inversely associated with IGFBP-1, providing an assessment of cardiometabolic status by computed tomography (CT). Methods: Participants (n=104) were prospectively enrolled from the LonGenity study at Albert Einstein Institute of Aging. Participants were of Ashkenazi descent and ≥65 years, 53% were offspring of parents with exceptional longevity (OPEL) and 47% were offspring with usual survival (OPUS). Exclusion criteria were prior coronary artery bypass or stent, heart rate > 100 beats/minute or not in sinus rhythm. Participants underwent a non-contrast gated CT. Adiposity was quantified using QFAT software (Cedars Sinai, CA). IGFBP-1 measures closest to the CT were used, ranging from 58 months before to 16 months after, with the majority within 1 year of the scan. Associations between IGFBP-1 and the adiposity were evaluated with linear regression with square-root of adiposity measures as the outcome. Each subject was weighted by the inverse of the years between CT and closest IGFBP-1 measurement. Results: IGFBP-1 levels were inversely associated with EAT (p =0.007), IAT (p = 0.003) and TTA (p = 0.003) after adjustment for age, sex, body mass index, OPEL/OPUS, diabetic medication, statin use, and high- and low-density lipoprotein levels. BMI explained 27.2% of the variation of TTA (p < 0.001) and IGFBP-1 explained an additional 6% of the variation. There was no association of OPEL/OPUS status with adiposity measures. Conclusion: In conclusion, higher IGFBP-1 was associated with lower cross-sectional TTA, suggesting that IGFBP-1 may be indicative of a favorable cardiometabolic environment in aging. Future studies should evaluate the utility of IGFBP-1, epicardial and thoracic visceral adiposity as indicators of cardiometabolic disease.

Endocrine factors, memory and perceptual capacities and aging in Asian men

Background: This cross-sectional study examined the associations of hormones and age with short-term memory and perceptual capacity in 472 healthy Asian men.Methods: The symbol digit and digit span tests from the Swedish Performance Evaluation System were used to assess perceptual capacity and memory. Linear regression analyses with the stepwise method were carried out with the SPSS 21.0 package.Results: Age was associated with lower dehydorepiandrosterone sulphate (DHEA/S), insulin growth factor-1 (IGF-1), thyroxine (T4), testosterone (T), bioavailable T (BioT) and error rate (Err) but higher glucose (GLU), sex hormone binding globulin (SHBG), estradiol (E2) and retention time (RT). High GLU was associated with higher error rate, longer RT of the perceptual capacity domain and shorter digit span (DSpan) of the short-term memory domain. Higher insulin-like growth factor binding protein-3 (BP3) was associated with longer DSpan. High cortisol (Cor) was associated with higher Err, while high DHEA/S was associated with shorter RT. All other hormones from the adrenal, somatotrophic and gonadal were not significantly associated with cognition.Conclusion: The findings suggest (1) a role for tighter control of blood glucose levels in cognitive decline with aging in men, (2) different hormones may be related to different parameters of cognition and “cognition” is not a unitary phenomenon and (3) further investigation of the potential for exogenous DHEA/S to slow cognitive decline in aging, especially as it relates to reaction time.

How height is related to our health and longevity

Most people believe that being taller and heavier is a sign of higher social status and privilege; however, an objective evaluation of the advantages and disadvantages of increased body size (excluding obesity) indicated that shorter, smaller bodies have numerous advantages in terms of health and longevity. With healthful nutrition and lifestyles, and good medical care, shorter people are less likely to suffer from age-related chronic diseases and more likely to reach advanced ages. A variety of biological factors explain the inherent benefits of smaller bodies. These include reduced cell replication, much lower DNA damage and reduced cancer incidence. Other beneficial factors include higher sex hormone binding globulin, higher insulin-like growth factor binding protein-1, lower insulin and lower insulin-like growth factor-1. We discuss recommendations for how taller people can minimize their risks. Future public health practices should focus on healthful nutrition, without promoting continued secular growth in height and weight.

Advances in insulin like growth factor binding protein 1 in the prognosis of acute myocardial infarction.

Insulin-like growth factor (IGF) is closely associated with cardiovascular diseases. Low IGF-I level and high insulin-like growth factor binding protein-1 (IGFBP-1) level in serum can be used as a marker in predicting the long term morbidity and mortality of acute myocardial infarction (AMI). The article reviews the recent advances in IGFBP-1 in the prognosis of AMI.

Diagnostic and prognostic role of the insulin growth factor pathway members insulin-like growth factor-II and insulin-like growth factor binding protein-3 in serous effusions

We recently reported on higher expression of the insulin-like growth factor pathway genes IGF-II and IGFBP3 in serous ovarian/peritoneal carcinoma compared to malignant peritoneal mesothelioma. The present study analyzed the diagnostic and clinical role of these proteins in serous effusions. Effusions (n = 327), including 294 carcinomas (205 ovarian, 48 breast, 17 cervical/endometrial, 12 lung, 12 gastrointestinal/genitourinary) and 33 malignant mesotheliomas, were immunostained for insulin-like growth factor-II and insulin-like growth factor binding protein-3. Surgical ovarian carcinoma (n = 124) and peritoneal mesothelioma (n = 18) specimens were additionally studied. Insulin-like growth factor binding protein-3 levels were measured in 148 effusion supernatants (114 ovarian carcinomas, 18 breast carcinomas, 16 mesotheliomas) using enzyme-linked immunosorbent assay. Insulin-like growth factor binding protein-3 promoter methylation was analyzed in 11 ovarian carcinoma effusions. Insulin-like growth factor binding protein-3 (P = .002) and insulin-like growth factor-II (P < .001) expression by immunohistochemistry was significantly higher in carcinomas compared to mesotheliomas, with diagnostic sensitivity of 77% and 70% and specificity of 55% and 70%, respectively. In surgical specimens, insulin-like growth factor binding protein-3 expression was higher in ovarian carcinomas compared to peritoneal mesotheliomas (P = .007), whereas insulin-like growth factor-II expression was comparable (P = .505). Insulin-like growth factor binding protein-3 levels by enzyme-linked immunosorbent assay were comparable in the 3 analyzed cancer types. Insulin-like growth factor binding protein-3 promoter methylation was found in 6 of 11 effusions. High insulin-like growth factor binding protein-3 expression in prechemotherapy and high insulin-like growth factor-II expression in postchemotherapy ovarian carcinoma effusions correlated with poor overall survival (P = .031 and P = .024, respectively). Insulin-like growth factor-II expression in postchemotherapy effusions was an independent prognostic factor in Cox multivariate analysis (P = .04). In conclusion, insulin-like growth factor-II and insulin-like growth factor binding protein-3 are more frequently expressed in metastatic carcinomas compared to mesothelioma in effusions but are less specific than currently used markers. Insulin-like growth factor-II and insulin-like growth factor binding protein-3 may be novel prognostic markers in metastatic ovarian carcinoma.

High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly

Low levels of insulinlike growth factor 1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulinlike growth factor binding protein 1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in patients with CHF and has been associated prospectively with increased mortality among older adults and survivors of myocardial infarction. We investigated the association between fasting plasma levels of IGF-I, IGFBP-1, IGFBP-3, and insulin and risk of incident CHF in the prospective Cardiovascular Health Study. From among 5,888 adults 65 years old and older in the Cardiovascular Health Study, we studied 566 incident CHF cases and 1,072 comparison subjects after exclusion of underweight individuals (body mass index <18.5 kg/m(2)) and insulin users. Hazard ratios (HRs) with 95% CIs for CHF were estimated after adjustment for age, race, sex, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and body mass index. High baseline IGFBP-1 level was a significant predictor of CHF, independent of established CHF risk factors and inflammation markers. The HR per SD of IGFBP-1 was 1.22 (95% CI 1.07-1.39, P < .01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95% CI 0.96-1.74, P = .09) for the second IGFBP-1 tertile and 1.47 (95% CI 1.06-2.04; P = .02) for the highest IGFBP-1 tertile (tertile cut points 19.5 and 35.8 ng/mL). Total IGF-I, IGFBP-3, or insulin levels had no association with CHF after adjustment for CHF risk factors. High circulating IGFBP-1 level may be a CHF risk factor among older adults.

Regulation of insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in preterm fetuses

Objective: Our purpose was to evaluate which factors regulate insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in preterm fetuses. Study design: We studied 76 singleton births between 25 and 36 weeks of gestation. Forty-nine pregnancies were complicated by hypertensive disease; 24 pregnancies were complicated by preterm labor or preterm rupture of membranes; and antenatal glucocorticoids were given in 49 pregnancies. Pathology reports showed infarct(s) or hematoma(s) in 31 of 69 placentas. We recorded blood gas values in umbilical artery and vein and measured glucose, C-peptide, and insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in umbilical vein. Results: Birth weight correlated with umbilical vein insulin-like growth factor-I (r = 0.68, P < .0001) and inversely with insulin-like growth factor binding protein-1 (r = −0.26, P = .02). Babies with birth weight of ≤25th percentile had lower insulin-like growth factor-I but higher insulin-like growth factor binding protein-1 levels than babies at >25th percentile. Two-factor analysis of variance showed that umbilical vein insulin-like growth factor-I was determined by gestational age (P = .0004) and birth weight percentile (P < .0001), whereas insulin-like growth factor binding protein-1 was not affected by gestational age. Umbilical vein C-peptide was highly correlated with insulin-like growth factor binding protein-1 (r = −0.55, P < .0001), but not insulin-like growth factor-I, levels. Blood gas values in umbilical artery and vein, particularly umbilical artery PO2, were correlated with umbilical vein insulin-like growth factor-I and insulin-like growth factor binding protein-1 (r = 0.51 and −0.48, respectively; P < .0001); changes in insulin-like growth factor-I and insulin-like growth factor binding protein-1 occurred at umbilical artery PO2 <14.8 mm Hg. Multiple regression analysis showed that umbilical vein insulin-like growth factor-I was predicted by umbilical artery PO2, gestational age, and the presence of placental infarcts/hematomas (R2 of model = 0.58, P < .0001), and umbilical vein insulin-like growth factor binding protein-1 by umbilical vein C-peptide, umbilical artery PO2, and placental infarcts/hematomas (R2 = 0.49, P < .0001). Conclusion: In the preterm fetus, circulating insulin-like growth factor-I is related to gestational age and the in utero growth potential, whereas insulin-like growth factor binding protein-1 is related only to the in utero growth potential. The PO2 is a robust determinant of both insulin-like growth factor-I and insulin-like growth factor binding protein-1 levels; hypoxia may restrain fetal growth through its effects on the insulin-like growth factor/insulin-like growth factor binding protein axis. Insulin is a powerful determinant of insulin-like growth factor binding protein-1, but not insulin-like growth factor-I, concentrations in the preterm fetus. (Am J Obstet Gynecol 2003;188:485-91.)

Genital Skin Fibroblasts (GF) of Patients with Androgen Insensitivity Syndrome Express Higher Insulin-Like Growth Factor Binding Protein (IGFBP)-2, -3 and -5 than GF of Normally Virilized Males

Background: We investigated the effects of androgens, estradiol (E₂) and insulin-like growth factor (IGF)-I on IGF-II, insulin-like growth factor binding protein (IGFBP)-2, -3 and -5 and mRNA in genital fibroblasts (GF) from patients with complete androgen insensitivity (CAIS) and normally virilized males (C). Methods: Proteins were measured by specific RIA and Western ligand blot, and specific mRNA levels by RT-PCR normalized by GAPDH levels. Results: Secretion of IGF-II was lowered in CAIS (p < 0.001) GF and by testosterone + IGF-I in C GF. Secretion of IGFBP-2 was higher (p < 0.001) in CAIS GF and IGFBP-2 mRNA levels were increased by E₂ in C GF (p < 0.05). E₂ stimulated IGFBP-2, -3 and -5 expression in CAIS GF. CAIS GF also secreted more IGFBP-3 (p < 0.001) and accumulated 3–5 times more IGFBP-5 mRNA than C GF (p < 0.001). Conclusion: In contrast to C GF, the availability of IGF-II in CAIS GF is apparently decreased by two facts: by the decreased expression and by increased expression of IGFBP-2, -3 and -5. Furthermore, E₂ and IGF-I modulate the expression of IGF-II and IGFBP in GF. This may play a role in the failure to develop male external genitals in CAIS patients.

Evaluation of plasma insulin-like growth factor binding protein-2 as a marker for adrenocortical tumors.

Recent studies have pointed to the role of the IGF system in the pathogenesis of adrenocortical tumors, and it was shown recently that malignant adrenocortical tumors exhibit a high insulin-like growth factor binding protein (IGFBP)-2 content. Circulating markers specific for adrenocortical carcinoma are needed and the aim of this study was to evaluate plasma IGFBP-2 as a marker for these malignant tumors. Plasma IGFBP-2 was determined in 51 patients referred to our institutions for adrenocortical tumors. Fifteen patients were in complete remission (group 1), eight patients had preoperative localized tumors (group 2) and 28 patients had metastatic tumors (group 3). Thirty-six healthy volunteers constituted a control group. There was no significant difference in plasma IGFBP-2 concentration between healthy controls and patients with complete remission or localized tumors. In contrast, patients with metastatic disease had significantly higher IGFBP-2 plasma levels than the control group (P<0.001). IGFBP-2 levels in patients with metastatic disease were inversely correlated with survival (R2=0.308; P=0.0026). In patients with localized tumors, there was no correlation between plasma IGFBP-2 concentration and tumor size or histological features. Analysis of individual IGFBP-2 concentrations showed that five patients (17.8%) with metastatic tumors had normal IGFBP-2 levels and two patients (13.3%) in complete remission had high plasma IGFBP-2 levels. The influence of nutrition, hormone secretion and treatment on IGFBP-2 levels was examined. Nutritional status was evaluated by determining IGF-I levels and was found to be normal in 16 patients (61.5%) with high IGFBP-2 levels, suggesting that malnutrition was not responsible for the high IGFBP-2 concentrations in these patients. IGFBP-2 levels did not differ significantly according to tumor secretion or mitotane treatment. In a follow-up study, plasma IGFBP-2 concentration remained stable in patients with complete remission or stabilized disease and was a late marker of tumor progression in patients with progressive metastatic disease. These results indicate that plasma IGFBP-2 is elevated in patients with malignant adrenocortical tumors and that the major factor affecting IGFBP-2 levels in these patients is tumor stage. However, plasma IGFBP-2 was less sensitive than expected for a tumor marker, which may limit its value in the diagnosis and follow-up of adrenocortical carcinoma.

Initial characterization of the GH-IGF axis and nutritional status of the Ati Negritos of the Philippines.

The Ati Negritos are a Pygmy-like aboriginal population from the Philippines with physical characteristics of short stature, dark skin and woolly, kinked hair. Their final height, components of their GH-IGF axis and various nutritional markers are described. SUBJECTS, DESIGN AND MEASUREMENTS: Auxological data and sera for the components of the GH-IGF axis and nutritional parameters were collected from 9 adult Ati Negritos in their native environment and 10 Filipinos in Sydney. The height SDS (- 3.66 +/- 1.1 vs. - 1.01 +/- 1.2), weight SDS (- 2.30 +/- 1.6 vs. 0.10 +/- 0.7), and BMI SDS (- 1.4 +/- 1.8 vs. - 0.2 +/- 0.5) between the two groups were significantly different (P < 0.01). The mean height of the 6 male Ati Negritos was 149 +/- 7 and 144 +/- 3 cm for the females and are comparable with the African Pygmies and the Mountain Ok people of Papua New Guinea. The Ati Negritos showed lower growth hormone binding protein (GHBP), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), acid labile subunit (ALS), zinc, albumin, ferritin, iron, iron saturation and much higher insulin-like growth factor binding protein 2 (IGFBP-2) and plasma transferrin concentrations. No differences were noted in random growth hormone (GH), plasma insulin-like growth factor II (IGF-II), nor in their plasma concentrations of prealbumin, thyroid stimulating hormone (TSH) and free thyroxine (T4). Perturbations of both the GH-IGF-I axis and nutritional markers exist in the Ati Negritos. These findings may be determinants of their stature; however, the aetiology of these changes remains to be fully elucidated.

High insulin-like growth factor binding protein 1 levels in cirrhosis: Link with insulin resistance

Hyperinsulinemic euglycemic clamps were performed on six patients with compensated alcoholic cirrhosis and on six normal comparison subjects. As in previous studies, glucose uptake in the cirrhotic patients was only 21% of the comparison value. The cirrhotic patients had high growth hormone (GH) and low insulin-like growth factor-I (IGF-I) levels, with low insulin-like growth factor-binding protein (IGFBP)-3 levels, but surprisingly high IGFBP-I levels (26.8 ± 8.4 microgH vs. 3.2 ± 0.2 microm/L, P < .001). The log IGFBP-1 level was inversely correlated with the log insulin sensitivity (r = -.95). The clamps were repeated with a somatostatin infusion to suppress GH secretion. IGFBP-1 increased in both groups, especially in the cirrhotic subjects. Insulin sensitivity increased in the normal subjects but was unchanged in the cirrhotic patients. Following GH treatment (0.13 U/kg/d for 5 days), the clamps were repeated. GH, IGF-1, and IGFBP-3 levels were now similar in the two groups; IGFBP-1 levels decreased in the cirrhotic patients but remained fivefold higher than the comparison value (10.6 ± 3.7 vs. 2.1 ± 0.4, P < .05). Glucose uptake in the cirrhotic patients remained only 29% of the comparison value, but the change in their insulin sensitivity was inversely correlated with the change in their IGFB-1 levels (r = -.84). These results suggests an important role for IGFBP-1 in modulating insulin sensitivity in cirrhosis. (Hepatology 1996 Jul;24(1):127-33)