Plasma IGF-binding Protein-3 Research Articles

Relation of insulin-like growth factor (IGF) I and IGF-binding protein 3 concentrations with intakes of fruit, vegetables, and antioxidants

Fruit, vegetable, and antioxidant intakes may reduce the risk of several insulin-like growth factor (IGF)-related chronic diseases, such as certain types of cancers and cardiovascular diseases. This study investigated whether intakes of fruit, vegetables, and antioxidants (beta-carotene, lycopene, and vitamin C) are associated with plasma IGF-I and IGF-binding protein 3 (IGFBP-3) concentrations. Plasma IGF-I and IGFBP-3 concentrations were measured in 1542 healthy women by enzyme-linked immunosorbent assay. A self-administered semiquantitative food-frequency questionnaire was used to estimate mean daily dietary intakes of fruit, vegetables, and antioxidants over the year preceding blood sampling. Multivariate analyses were performed by using generalized linear models to evaluate the association of quintiles of daily intakes with concentrations of growth factors. A higher intake of citrus fruit was associated with higher concentrations of IGF-I (215 ng/mL for quintile 5 compared with 205 ng/mL for quintile 1; P for trend = 0.04) and with lower concentrations of IGFBP-3 (4803 ng/mL for quintile 5 compared with 4960 ng/mL for quintile 1; P for trend = 0.04). Higher dietary vitamin C intake was associated with higher concentrations of IGF-I (214 ng/mL for quintile 5 compared with 204 ng/mL for quintile 1; P for trend = 0.02) and lower concentrations of IGFBP-3 (4813 ng/mL for quintile 5 compared with 4953 ng/mL for quintile 1; P for trend = 0.03). Total intake of fruit and vegetables and intakes of other botanical fruit and vegetable subgroups, beta-carotene, and lycopene were not related to either IGF-I or IGFBP-3 concentrations. Women with higher intakes of citrus fruit or dietary vitamin C tend to have higher plasma concentrations of IGF-I and lower plasma concentrations of IGFBP-3.

Prostate Cancer Risk in Relation to Selected Genetic Polymorphisms in Insulin-like Growth Factor-I, Insulin-like Growth Factor Binding Protein-3, and Insulin-like Growth Factor-I Receptor

We conducted a nested case-control study within a cohort of elderly Americans to examine the role of the insulin-like growth factor (IGF) signaling pathway in prostate cancer etiology. The distribution of genotypes of IGF-I (CA)n, IGF binding protein-3 (IGFBP-3) A-202C, and of the 2-bp deletion and (AGG)n polymorphisms in IGF-I receptor (IGF-IR) was compared between men with prostate cancer (n = 213) and equal number of controls matched on year of blood draw, survival until the date of diagnosis, race, and age. Among controls, the number of CA repeats in IGF-I was not correlated to any appreciable degree with plasma IGF-I concentration, whereas the IGFBP-3 CC genotype was associated with a relatively low level of plasma IGFBP-3. There was no association between prostate cancer risk and the number of CA repeats in IGF-I, IGFBP-3 genotype, or the presence of the 2-bp deletion in IGF-IR. There was a small increased risk among men who did not carry two copies of the (AGG)7 allele of IGF-IR. These results add to the evidence that the number of IGF-I CA repeats is not associated with prostate cancer risk. Our observation that men who do not carry two copies of the IGF-IR (AGG)7 allele are at increased risk of prostate cancer merits further investigation.

Ethnic Disparity in the Relationship between Obesity and Plasma Insulin-Like Growth Factors: The Multiethnic Cohort

Previous studies on the relationship between obesity and circulating insulin-like growth factor (IGF) hormones show inconsistent findings and have not considered the possibility of racial/ethnic-specific differences that may exist. We therefore examined the relationship between obesity status [as measured by body mass index (BMI)] and plasma levels of the IGF proteins, IGF-I, IGF-binding protein 3 (IGFBP-3), and the molar ratio of IGF-I/IGFBP-3 in Whites, African Americans, Latinos, Japanese Americans, and Native Hawaiians from the ongoing Hawaii and Los Angeles Multiethnic Cohort Study. We measured plasma IGF-I and IGFBP-3 by ELISA in a random sample of 811 Multiethnic Cohort participants (53% male, age range = 47-82 at blood draw). In a multivariate regression of IGF-I levels, we found a statistically significant interaction between race/ethnicity and obesity status (P = 0.005). Plasma IGF-I levels declined with increasing BMI most dramatically in Latinos and Japanese. This decline was attenuated in Whites and absent in African-American and Native Hawaiian subjects. In Japanese, the quadratic term (BMI(2)) was statistically significant in a multivariate model (P = 0.002). In Latinos, the adjusted least-squares mean IGF-I levels in ng/mL for BMI < 25, 25 to 29.99, and >or=30 were 184.6, 147.7, and 132.7, respectively. No interaction between race/ethnicity and BMI explained the plasma IGFBP-3 levels in these data. These results may help to resolve the uncertainty in the relationship between circulating IGF levels and obesity and highlight the potential importance of racial/ethnic-specific effects among these factors in explaining ethnic disparities in obesity-related cancers.

Influence of Insulin-like Growth Factors on the Strength of the Relation of Vitamin D and Calcium Intakes to Mammographic Breast Density

Diets with higher vitamin D and calcium contents were found associated with lower mammographic breast density and breast cancer risk in premenopausal women. Because laboratory studies suggest that the actions of vitamin D, calcium, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 (IGFBP-3) on human breast cancer cells are interrelated, we examined whether IGF-I and IGFBP-3 levels could affect the strength of the association of vitamin D and calcium intakes with breast density. Among 771 premenopausal women, breast density was measured by a computer-assisted method, vitamin D and calcium intakes by a food frequency questionnaire, and levels of plasma IGF-I and IGFBP-3 by ELISA methods. Multivariate linear regression models were used to examine the associations and the interactions. The negative associations of vitamin D or calcium intakes with breast density were stronger among women with IGF-I levels above the median (beta = -2.8, P = 0.002 and beta = -2.5, P = 0.002, respectively) compared with those with IGF-I levels below or equal to the median (beta = -0.8, P = 0.38 and beta = -1.1, P = 0.21; P(interaction) = 0.09 and 0.16, respectively). Similar results were observed within levels of IGFBP-3 (P(interaction) = 0.06 and 0.03, respectively). This is the first study to report that the negative relation of vitamin D and calcium intakes with breast density may be seen primarily among women with high IGF-I or high IGFBP-3 levels. Our findings suggest that the IGF axis should be taken into account when the effects of vitamin D and calcium on breast density (and perhaps breast cancer risk) are examined at least among premenopausal women.

The Relationships between Plasma Insulin-like Growth Factor (IGF)-1 and IGF-Binding Proteins (IGFBPs) to Growth Pattern, and Characteristics of Plasma IGFBPs in Steers

This study was conducted to determine the characteristics of IGFBPs in plasma of steers, and to profile the relationship between growth and plasma IGF-1 and IGFBPs with aging in Holstein steers. Four blots of IGFBP at molecular weights of 38-43, 34, 29-32 and 24 kDa bands were detected by western ligand blot assay using 125 I-IGF-1. On the basis of immunoblotting with anti-bovine IGFBP-2 and -3 antiserums, we observed the band for IGFBP-2 at approximately 34 kDa, and the IGFBP-3 band was detected at 38-43 kDa and 34 kDa in adult steers and calves. The IGFBP-3 antiserum used on the blots exhibited significant cross-reactivity with 34 kDa IGFBP-2. Furthermore, the 38-43 kDa IGFBP-3 bands were reduced to a 36 kDa band after deglycosylation, whereas the 34 kDa IGFBP-2 was intact. The plasma IGF-1, IGFBP-3 and other IGFBPs showed stability throughout a whole day. The change in live weight was found to be positively correlated to the plasma IGF-1 concentration (r = 0.6801, n = 64, p<0.05) and plasma IGFBP-3 (r = 0.6321, n = 64, p<0.05), while inversely correlated to plasma IGFBP-2 (r = -0.2919, n = 64, p<0.05). Furthermore, plasma IGF-1 was positively correlated to plasma IGFBP-3 (r = 0.6191, p<0.001), but was not correlated to plasma IGFBP-2. The portion of IGFBP-2 for total IGFBPs in calves was higher than in adult steers (p<0.05) and was decreased with growth, whereas that of IGFBP-3 was increased with increased live weight (p<0.05). The ratio IGFBP-3 for IGFBP-2 (BP-3/BP-2) was increased with growing of liveweight. Therefore, the changes in plasma IGF-1 level with increased liveweight may be related to the changes in plasma IGFBP-3 level and IGFBP-2 may give an important role in anabolic action of IGF-1 with the growth of body during calfhood in Holstein steers. (Asian-Aust. J. Anim. Sci. 2005. Vol 18, No. 11 : 1575-1581)

Insulin Resistance, Apoptosis, and Colorectal Adenoma Risk

Compelling evidence from epidemiologic studies indicates that elevated circulating insulin-like growth factor (IGF)-I, insulin resistance, and associated complications, such as elevated fasting plasma insulin, glucose and free fatty acids, glucose intolerance, increased body mass index, and visceral adiposity, are linked with increased risk of colorectal cancer. However, the role of insulin and markers of glucose control in the development of adenomas, precursors to colorectal cancer, has not been fully explored. We evaluated the relationship between plasma insulin, glucose, IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), apoptosis, and colorectal adenomas in a case-control study. Participants were drawn from consenting patients undergoing colonoscopy at the University of North Carolina hospitals (Chapel Hill, NC). Participants were classified as cases or controls based on whether they had one or more colorectal adenomatous polyps. Fasting plasma insulin, IGF-I, IGF-II, and IGFBP-3 levels were assessed by ELISA. Glucose was measured by glucose hexokinase assay. Apoptosis was assessed by morphology on H&E-stained sections. Dietary and lifestyle information were obtained by telephone interview. Logistic regression was used to examine the association between adenoma status and insulin-IGF markers. Adenoma cases (n = 239) and adenoma-free controls (n = 517) provided rectal biopsies and/or blood samples and interview data. Consistent with prior findings, cases were more likely to be males, older, have higher waist-to-hip ratio, lower calcium intake, lower apoptosis, and less likely to report nonsteroidal anti-inflammatory drug use. Those in the highest quartile of insulin (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.2) and glucose (adjusted odds ratio, 1.8; 95% confidence interval, 0.9-3.6) were more likely to have an adenoma compared with the lowest quartile. Similarly, subjects in the highest two quartiles of insulin were more likely to be in the lowest two quartiles of apoptosis. Overall, there were no significant differences between mean circulating levels of glucose, IGF-I, IGF-II, and IGFBP-3 among cases and controls and no association between these variables and apoptosis. The results provide novel evidence that elevated insulin and glucose are associated with increased adenoma risk and decreased apoptosis in normal rectal mucosa. These findings suggest that insulin may act early in the adenoma-carcinoma sequence to promote the development of colorectal adenoma by decreasing apoptosis in the normal mucosa.

Effect of protein supplementation during a 6-mo strength and conditioning program on insulin-like growth factor I and markers of bone turnover in young adults1–3

Exercise is beneficial for bone when adequate nutrition is provided. The role of protein consumption in bone health, however, is controversial. The objective was to ascertain the effect of high protein intake on insulin-like growth factor I (IGF-I) and markers of bone turnover during 6 mo of exercise training. Fifty-one subjects aged 18-25 y (28 men, 23 women) received a protein supplement (42 g protein, 24 g carbohydrate, 2 g fat) or a carbohydrate supplement (70 g carbohydrate) twice daily. Exercise consisted of alternating resistance training and running 5 times/wk. Plasma concentrations of IGF-I, insulin-like growth factor-binding protein 3, serum bone alkaline phosphatase, and urinary N-telopeptide collagen crosslink (NTx) concentrations were measured at 0, 3, and 6 mo after 24 h without exercise and a 12-h fast. Three-day diet records indicated no difference in energy intake between the groups. Average protein intakes after supplementation began in the protein and carbohydrate groups were 2.2 +/- 0.1 and 1.1 +/- 0.1 g/kg, respectively (P < 0.001). The increase in plasma IGF-I was greater in the protein group than in the carbohydrate group (time x supplement interaction, P = 0.01). There were no significant changes over time or significant differences by supplement in plasma insulin-like growth factor-binding protein 3 (44 and 40 kDa). Serum bone alkaline phosphatase increased significantly over time (P = 0.04) and tended to be higher in the protein group than in the carbohydrate group (P = 0.06). NTx concentrations changed over time (time and time squared; P < 0.01 for both) and were greater in the protein group than in the carbohydrate group (P = 0.04). Men had higher NTx concentrations than did women (74.6 +/- 3.4 and 60.0 +/- 3.8 nmol/mmol creatinine; P = 0.005). Protein supplementation during a strength and conditioning program resulted in changes in IGF-I concentrations.

Association of an Exon 1 Polymorphism in theIGFBP3Gene with Circulating IGFBP-3 Levels and Colorectal Cancer Risk: The Multiethnic Cohort Study

Laboratory and seroepidemiologic studies have suggested that insulin-like growth factor binding protein-3 (IGFBP-3), the main binding protein for IGF-I, may be protective against colorectal cancer. We investigated the association of two polymorphisms (A-202C and G2133C) in the IGFBP3 gene with plasma IGF hormone levels among 887 randomly selected participants in the Multiethnic Cohort study. We found that these two genetic variants were in strong linkage disequilibrium and were both inversely associated with plasma IGFBP-3. However, the effect on plasma IGFBP-3 levels was stronger for the G2133C variant than the A-202C variant. Thus, we assessed the colorectal cancer risk associated with the G2133C in a case-control study of 817 cases and 1,995 controls nested within the Multiethnic Cohort study. Under the assumption of dominant genetic model, carriers of the 1233C allele were at 32% increased risk of colorectal cancer [95 % confidence interval (95% CI) for the odds ratio (OR), 1.07-1.62] and that this effect seemed stronger for the rectum (OR for the C allele, 1.95; 95% CI, 1.35-2.83) than the colon (OR, 1.16; 95% CI, 0.92-1.45). These data suggest that the exon 1 G2133C missense variant in IGFBP3 may be a susceptibility factor for colorectal cancer.

Plasma insulin-like growth factor-1 and binding protein-3 and subsequent risk of prostate cancer in the PSA era

The insulin-like growth factor (IGF) axis is thought to contribute to the growth and progression of prostate cancer. Some prospective studies support a direct association between IGF-1 and prostate cancer, in particular advanced disease, whereas both inverse and direct associations with prostate cancer have been reported for insulin-like growth factor binding protein-3 (IGFBP-3), the major IGF-1 binding protein in circulation. We prospectively investigated the associations of plasma IGF-1 and IGFBP-3 concentrations with prostate cancer detected in the PSA era. We identified 462 prostate cancer cases diagnosed after providing a blood specimen in 1993, but before January 1998 among men in the Health Professionals Follow-up Study. Controls were 462 age-matched men without prostate cancer who had had a PSA test after providing a blood specimen. We measured plasma concentrations of IGF-1 and IGFBP-3 by ELISA. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer. Men with higher concentrations of IGF-1 (comparing extreme quartiles OR=1.37, 95% CI 0.92-2.03, p-trend=0.05) and IGFBP-3 (OR=1.62, 95% CI 1.07-2.46, p-trend=0.08) had a higher risk of prostate cancer. After mutual statistical adjustment, these associations were attenuated for both IGF-1 (OR=1.17, 95% CI 0.69-1.99, p-trend=0.29) and IGFBP-3 (OR=1.40, 95% CI 0.80-2.44, p-trend=0.56). We found no significant association of IGF-1 with regionally invasive or metastatic (>/=T3b, N1, or M1) prostate cancer, although the number of these cases was small (n=42). Our findings for IGF-1 and prostate cancer diagnosed in the PSA era are similar to most previous studies, albeit weaker in magnitude. Our suggestive positive findings for IGFBP-3 are similar to some studies, but in direct contrast to others.

Insulin-like Growth Factor Binding Protein 3 in Inflammatory Bowel Disease

Epithelial cell growth regulation has been reported to be altered in inflammatory bowel disease (IBD) patients. The cell growth regulatory factor, insulin-like growth factor binding protein 3 (IGFBP-3), may be partly responsible for this phenomenon. So far, IGFBP-3 levels have been assessed as values of total protein, which is a sum of bioactive intact 43- to 45-kDa protein and its inactive proteolytic cleavage fragments. We aimed to assess the levels of intact IGFBP-3 and its cleaving protease MMP-9 in IBD. Patients with IBD and controls were included. Total plasma IGFBP-3 concentration was measured in ELISA. Western blot analysis, which distinguishes between intact and cleaved IGFBP-3, was performed in order to determine the ratio of intact to total protein; this ratio was used to calculate the concentration of intact IGFBP-3. The profile of plasma proteases was evaluated in zymography and MMP-9 levels were determined in ELISA. The concentration of intact IGFBP-3 was significantly decreased in patients with moderate to severe IBD activity compared to those in remission or controls. Of note, a dramatic depletion of intact IGFBP-3 was found in 7.4% of patients with IBD. Zymography revealed that the dominant gelatinase was the pro-form of MMP-9. However, no differences in MMP-9 levels were noted between those with active disease and controls. The level of intact IGFBP-3 is decreased in IBD patients with moderate to severe disease activity. This decrease may be linked to altered IGFBP-3 production or to increased cleavage by proteases other than MMP-9.

Salinity acclimation affects the somatotropic axis in rainbow trout

In this study, we set out to examine the role of the somatotropic axis in the ion-regulation process in rainbow trout. Specifically, our objective was to examine whether plasma insulin-like growth factor-binding proteins (IGFBPs) are modulated by gradual salinity exposure. To this end, freshwater (FW)-adapted rainbow trout were subjected to gradual salinity increases, up to 66% seawater, over a period of 5 days. During this acclimation process, minimal elevations in plasma Ca2+ and Cl- were seen in the salinity-acclimated groups compared with FW controls. There were no changes in plasma Na+ levels, and only a minor transient change in plasma cortisol levels was seen with salinity exposure. The salinity challenged animals responded with elevations in plasma growth hormone (GH) and IGF-I levels and gill Na+-K+-ATPase activity. We identified IGFBPs of 21, 32, 42, and 50 kDa in size in the plasma of these animals, and they were consistently higher with salinity. Despite the overall increase in IGFBPs with salinity, transient changes in individual BPs over the 5-day period were noted in the FW and salinity-exposed fish. Specifically, the transient changes in plasma levels of the 21-, 42-, and 50-kDa IGFBPs were different between the FW and salinity groups, while the 32-kDa IGFBP showed a similar trend (increases with sampling time) in both groups. Considered together, the elevated plasma IGFBPs suggest a key role for these binding proteins in the regulation of IGF-I during salinity acclimation in salmonids.

Open surgery induces a dramatic decrease in circulating intact IGFBP-3 in patients with colorectal cancer not seen with laparoscopic surgery

As shown earlier by the authors via Western blot analysis, open (OS) but not laparoscopic surgery (LS) induces a qualitative decrease in plasma insulin-like growth factor-binding protein 3 (IGFBP-3) levels on postoperative day 1 (POD 1). Intact IGFBP-3 has tumor suppressive effects, but its degradation products do not. Enzyme linked immunoassay (ELISA) inevitably measures both. In this study, using a novel combined Western blot and ELISA analysis method, precise plasma levels of intact IGFBP-3 on POD2 after open and closed colorectal cancer resection (stage I-III) were determined. This study included 15 OS patients with a mean incision length of 26.7 +/- 15.5 cm and 16 LS patients with a mean incision length of 5.3 +/- 3.1 cm. Intact IGFBP-3 levels were determined via ELISA and Western blot analysis in plasma collected preoperatively and postoperatively. In the OS patients, the mean preoperative concentration of intact 43-45 kDa IGFBP-3 protein was 1920 +/- 1430 ng/ml. It decreased dramatically on POD2 to 355 +/- 545 ng/ml (p < 0.005). In the LS group, no significant difference was noted between the preoperative level (1305 +/- 807 ng/ml) and the POD2 level (922 + 714 ng/ml). Open cancer resection, unlike its minimally invasive alternative, induces a dramatic decrease in concentration of intact IGFBP-3, which may have important implications with regard to colon cancer recurrence.

Effects of dietary protein and growth hormone-releasing peptide (GHRP-2) on plasma IGF-1 and IGFBPs in Holstein steers

This study was conduct to determine the influence of dietary protein on the response of plasma insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding proteins (IGFBPs) to exogenous growth hormone releasing peptide-2 (GHRP-2 or KP 102) in Holstein steers. Eight 16-month-old Holstein steers were grouped by liveweight to two feeding treatments; high protein (HP; CP 1.38 kg/day and TDN 4.5 kg/day DM intake, n = 4) or low protein (LP; CP 0.66 kg/day and TDN 4.42 kg/day DM intake, n = 4). The experiment was a single reverse design whereby each group was injected twice daily with GHRP-2 (12.5 μg/kg body weight (BW)/day) or saline solution into the jugular vein for a 6-day period. Plasma IGF-1 in the HP group were higher than in the LP group ( P < 0.05), but plasma 34 kDa IGFBP-2 was lower in the HP than the LP group ( P < 0.05). The amplitude of the maximum growth hormone (GH) peaks responding to GHRP-2 injection were higher at day 1 than at day 6 of saline or GHRP-2 treatment in both LP and HP steers ( P < 0.05). The area under the GH response curve for 180 min after the GHRP-2 injection was not significantly different between the LP and the HP groups at days 1 and 6. A response in plasma IGF-1 concentration to GHRP-2 treatment in the HP group was observed at day 1 (198.9 ± 18.1 ng/ml), day 2 (195.2 ± 21.1 ng/ml) and day 6 (201.3 ± 14.8 ng/ml) ( P < 0.05). No increase in plasma IGF-1 was observed from GHRP-2 administration in the LP group. Although the response of plasma IGF-1 concentration to GHRP-2 administration was increased in the HP group ( P < 0.05), there was no apparent effect of GHRP-2 treatment on plasma 38–43 kDa IGFBP-3 and 34 kDa IGFBP-2 at days 2 and 6 of treatment. In conclusion, it is proposed that the 34 kDa IGFBP-2 is sensitive to dietary protein level and may play an important role in the regulation of circulating IGF-1 in ruminant. In addition, increased plasma IGF-1 concentration observed in the HP group in response to the GHRP-2 treatment did not appear to affect plasma IGFBPs.

Insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and mammographic breast density

9501 Background: A few small studies have suggested that higher IGF-I and lower IGFBP-3 may be associated with increased premenopausal mammographic breast density, one of the strongest known breast cancer risk factors. This large cross-sectional study was designed specifically to evaluate the associations of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio with breast density. Methods: For this study, 784 premenopausal and 791 postmenopausal healthy women were recruited during screening mammography examinations. Using a computer-assisted method, a single observer assessed mammographic breast density with high reproducibility (intraclass correlation coefficient = 0.98). Blood samples collected at the time of the mammography allowed measurement of plasma IGF-I and IGFBP-3 levels by ELISA methods (coefficients of variation below 10% and 13%, respectively). Spearman's partial correlation coefficients (r) were used to evaluate the associations while adjusting for confounding factors including age, body mass index and IGF-I or IGFBP-3 when applicable. Results: Among premenopausal women, breast density is positively associated with IGF-I and IGF-I/IGFBP-3 ratio (r = 0.084, p = 0.019 and r = 0.070, p = 0.051, respectively) and negatively associated with IGFBP-3 (r = −0.123, p = 0.0005). No significant correlations were observed among postmenopausal women. Correlations among postmenopausal women (p-values) for IGF-I, IGFBP-3 and their ratio were 0.038 (0.282), −0.019 (0.593) and 0.035 (0.332), respectively. Conclusions: To date, this is the largest study of the relation of IGF to breast density. IGF-I and the IGF-I/IGFBP-3 ratio were correlated with mammographic breast density among premenopausal women supporting the view that the IGF axis plays a role in the development of some breast cancers among premenopausal women by its influence on breast density. No significant financial relationships to disclose.

Insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and mammographic breast density

9501 Background: A few small studies have suggested that higher IGF-I and lower IGFBP-3 may be associated with increased premenopausal mammographic breast density, one of the strongest known breast cancer risk factors. This large cross-sectional study was designed specifically to evaluate the associations of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio with breast density. Methods: For this study, 784 premenopausal and 791 postmenopausal healthy women were recruited during screening mammography examinations. Using a computer-assisted method, a single observer assessed mammographic breast density with high reproducibility (intraclass correlation coefficient = 0.98). Blood samples collected at the time of the mammography allowed measurement of plasma IGF-I and IGFBP-3 levels by ELISA methods (coefficients of variation below 10% and 13%, respectively). Spearman's partial correlation coefficients (r) were used to evaluate the associations while adjusting for confounding factors including age, body mass index and IGF-I or IGFBP-3 when applicable. Results: Among premenopausal women, breast density is positively associated with IGF-I and IGF-I/IGFBP-3 ratio (r = 0.084, p = 0.019 and r = 0.070, p = 0.051, respectively) and negatively associated with IGFBP-3 (r = −0.123, p = 0.0005). No significant correlations were observed among postmenopausal women. Correlations among postmenopausal women (p-values) for IGF-I, IGFBP-3 and their ratio were 0.038 (0.282), −0.019 (0.593) and 0.035 (0.332), respectively. Conclusions: To date, this is the largest study of the relation of IGF to breast density. IGF-I and the IGF-I/IGFBP-3 ratio were correlated with mammographic breast density among premenopausal women supporting the view that the IGF axis plays a role in the development of some breast cancers among premenopausal women by its influence on breast density. No significant financial relationships to disclose.

Disparate regulation of insulin-like growth factor-binding proteins in a primitive, ictalurid, teleost ( Ictalurus punctatus)

Vertebrate growth is principally controlled by growth hormone (GH) and, its intermediary, insulin-like growth factor-I (IGF-I). The actions of IGF-I are modulated by high-affinity binding proteins called insulin-like growth factor binding-proteins (IGFBPs). Channel catfish exhibit atypical responses (increased percentage body fat and reduced percentage protein) to GH treatment, despite GH-dependent IGF-I production. Among possible explanations for this atypical response to GH treatment is an unusual regulation of blood IGFBPs. In this species, there has been one report of a single 33-kDa plasma binding protein. To examine the occurrence and regulation of plasma IGFBPs in this species, two strains of channel catfish (Norris and USDA-103) were treated with weekly injections of recombinant bovine GH at different temperatures (21 °C versus 26 °C). In a separate experiment involving catfish of a different strain, endogenous GH levels were altered via injection of the GH secretogogue, bGHRH 1–29-amide, and held in fresh water or transferred to brackish water (12 ppt). Following these treatments, the type and regulation of plasma IGFBPs in these catfish strains were examined by Western ligand blotting. We have identified five IGFBPs (19, 35, 44, 47, and >80 kDa) in catfish plasma that are differentially altered by experimental treatment and genetic lineage. Levels of the 19-kDa IGFBP were elevated in catfish of Norris and USDA-103 strains that were exposed to a higher environmental temperature (26 °C versus 21 °C), but was not seen in those animals used for the GH secretogogue/salinity study. In most vertebrates, treatment with GH increases levels of plasma IGFBP-3 (∼40–50 kDa). In the USDA-103 and Norris catfish strains, bGH injection reduced plasma levels of the 44- and 47-kDa IGFBPs. Similarly, elevations in plasma GH levels in GH secretogoge-treated and brackish water-adapted catfish resulted in reductions of the 44- and 47-kDa IGFBPs as well as a reduction in presence of a 35-kDa IGFBP that was not detected in the Norris or USDA-103 strains. Reduced levels of the 35, 44, and 47 kDa IGFBPs, seen in the plasma of the GH secretogogue-treated and brackish water-adapted animals, suggests that the atypical response of channel catfish to GH treatment is not attributed to the use of heterologous (bovine) GH. This negative response of the 35–47 kDa IGFBPs to GH has not been reported in any teleost or vertebrate (healthy) and may be partly responsible for the atypical physiological responses of channel catfish to GH treatment.

Dual mode of cortisol action on GH/IGF-I/IGF binding proteins in the tilapia, Oreochromis mossambicus.

Glucocorticoids are known to impede somatic growth in a wide range of vertebrates. In order to clarify the mechanisms through which they may act in an advanced teleost fish, we examined the effects of cortisol administration on the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF-binding protein (IGFBP) system in the tilapia (Oreochromis mossambicus). In a short-term experiment, fish were injected intraperitoneally with cortisol (2 or 10 microg/g), and killed at 2, 4, 8 and 24 h after the injection. In a longer-term experiment, fish were killed 24 and 48 h after cortisol injection (2, 10 and 50 microg/g). Cortisol at doses of 2 and 10 microg/g significantly increased IGFBPs of four different sizes (24, 28, 30, and 32 kDa) in the plasma within 2 h without altering plasma levels of IGF-I or GH. On the other hand, cortisol at doses of 10 and 50 microg/g significantly reduced plasma IGF-I levels after 24 and 48 h. IGF-I mRNA levels in the liver were also significantly reduced by cortisol at doses of 10 and 50 microg/g after 48 h, suggesting that a decrease in plasma IGF-I levels is mediated through the attenuation of IGF-I gene expression in the liver. In contrast, no significant change was observed in plasma or pituitary contents of GH at any time point examined, which would appear to indicate that cortisol reduces IGF sensitivity to GH (GH-resistance). These results clearly indicate that cortisol induces a rapid increase in plasma IGFBPs and a more delayed decrease in IGF-I production. The dual mode of cortisol action may contribute to the inhibitory influence of cortisol on somatic growth in teleosts.

The effects of intensive training on insulin-like growth factor I (IGF-I) and IGF binding proteins 1 and 3 in competitive cyclists: relationships with glucose disposal

The aim of the present study was to determine whether 4 months of intensified training would result in modified plasma insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 1 (IGFBP-1) or IGFBP-3 in eight competitive cyclists and eight sedentary individuals and to define the relationships of these factors with glucose disposal. Insulin sensitivity and glucose effectiveness — that is, the fractional disappearance of glucose independent of any change in insulinaemia — were measured with the minimal model (mathematical analysis of frequently sampled intravenous glucose tolerance test). Both glucose effectiveness and insulin sensitivity were higher in the cyclists than in the sedentary individuals, but did not increase further with training. IGF-I was higher in the cyclists than in the sedentary group only after training (P<0.05). Plasma IGFBP-1 and IGFBP-3 increased after training (38 and 20%, respectively; P<0.05) in the cyclists and were higher than in the sedentary individuals (P<0.05). IGF-I was negatively correlated with insulin sensitivity before and after training (r=−0.66 and −0.67, respectively; P<0.05) and IGFBP-1 was negatively correlated with glucose effectiveness before and after training (r=−0.68 and −0.77, respectively; P<0.05). Our results show that strenuous endurance training improves the somatotrope axis (growth hormone—IGF) and that IGFBP-1 may be involved in glucose homeostasis, possibly by limiting the exercise-induced increase in glucose disposal, in competitive cyclists.

Anthropometric and behavioral correlates of insulin-like growth factor I and insulin-like growth factor binding protein 3 in middle-aged Japanese men.

High levels of plasma insulin-like growth factor I (IGF-I) and low levels of insulin-like growth factor binding protein 3 (IGFBP-3) have been related to increased risk of several cancers. Little is known about the behavioral determinants of these biologic markers. The authors examined the relation of anthropometric and behavioral factors to plasma concentrations of IGF-I and IGFBP-3 in a cross-sectional study of 616 Japanese men aged 45-55 years in 1995-1996. In univariate analyses, body mass index was strongly, positively associated with both IGF-I and IGFBP-3. The waist/hip ratio was also linearly related to IGF-I and IGFBP-3 up to the third quartile level. Height was weakly, positively associated with IGF-I and IGFBP-3. Smoking was inversely associated with IGF-I and IGFBP-3. Alcohol use was associated inversely with IGF-I and positively with IGFBP-3. Neither IGF-I nor IGFBP-3 was related to physical activity. Results of the multivariate analysis were essentially the same as those of the univariate analyses. The findings regarding body mass index are in contrast to those of previous studies showing null or inverse associations, and they suggest that the relation of body mass index to IGF-I or IGFBP-3 may vary among populations. The study also indicates that smoking and alcohol use might affect plasma IGF-I and IGFBP-3.

Insulin-like growth factor-I and analogues increase growth in artificially-reared neonatal pigs.

Exogenous insulin-like growth factor (IGF)-I has been shown to increase growth rate in neonatal pigs while an analogue of IGF-I, long arginine (LR3) IGF-I, has been shown to be more potent than IGF-I in the rat. Therefore, two studies were conducted to determine whether IGF-I and LR3IGF-I increase growth in the artificially-reared neonatal pig. Expt 1 involved forty-two (2 kg initial weight) pigs infused with either control, IGF-I (2, 4 or 8 microg/h) or LR3IGF-I (2, 4 or 8 microg/h) infusions for 8 d. Pigs were weighed and then offered 1.7 MJ (gross energy) milk replacer/kg0.75 per d. Expt 2 involved eighteen pigs (2 kg initial weight) treated with control saline, IGF-I (8 microg/h) or LR3IGF-I (8 microg/h) infusions. After 9 d an additional pump was inserted to increase the infusion rates of each of the growth factors (16 microg/h) for a further 9 d. Cows' milk was provided ad libitum. In Expt 1 there was no overall effect of growth factors on daily weight gain or slaughter weight. However, milk intake was greater in pigs infused with growth factors (909 v. 867 g/d, P=0.027), with an apparently greater milk intake by the pigs infused with IGF-I compared with LR3IGF-I (920 v. 898 g/d, P=0.12). Infusion of LR3IGF-I decreased plasma IGF-I concentrations, but had no effect on plasma IGF-II concentrations. In Expt 2, neither IGF-I nor LR3IGF-I infusion had any effect upon daily weight gain over the first 9 d of the study. However, over the second 9 d of the study, daily weight gain was increased in LR3IGF-I-infused pigs (457 v. 386 g/d, P<0.01), but not in pigs infused with IGF-I (413 v. 386 g/d, P=0.15). Milk intake was not different during the first 9 d of the study but was significantly greater in pigs infused with growth factors over the second half of the study (3407 v. 2905 g/d, P<0.01). Plasma IGF-binding protein-3 concentrations were highly correlated (R=0.85) with average daily gain over the 3 d preceding blood sampling. In conclusion, exogenous IGF-I and particularly LR3IGF-I can increase growth rate and milk intake in artificially-reared pigs fed ad libitum but not in limit-fed piglets.