Fasting IGF-I Research Articles

Elevated Peptide YY Levels in Adolescent Girls with Anorexia Nervosa

Peptide YY (PYY) is an intestinally derived anorexigen that acts via the Y2 receptor, and Y2 receptor deletion in rodents increases bone formation. Anorexia nervosa (AN) is associated with a deliberate reduction in food intake and low bone density, but endocrine modulators of food intake in AN are not known. In addition, known regulators of bone turnover, such as GH, cortisol, and estrogen, explain only a fraction of the variability in bone turnover marker levels. We hypothesized that PYY may be elevated in AN compared with controls and may contribute to decreased food intake and bone formation. Fasting PYY was examined in 23 AN girls and 21 healthy adolescents 12-18 yr old. We also examined GH, cortisol, ghrelin, and leptin (overnight frequent sampling) and fasting IGF-I, estradiol, total T3, and bone markers. Macronutrient intake and resting energy expenditure (REE) were measured. AN girls had higher PYY levels compared with controls (17.8 +/- 10.2 vs. 4.8 +/- 4.3 pg/ml; P < 0.0001). Predictors of log PYY were nutritional markers, including body mass index (r = -0.62; P < 0.0001), fat mass (r = -0.55; P = 0.0003), and REE (r = -0.51; P = 0.0006), and hormones, including GH (r = 0.38; P = 0.004) and T3 (r = -0.59; P = 0.0001). Body mass index, fat mass, REE, GH, and T3 explained 68% of the variability of log PYY. Log PYY predicted percentage of calories from fat (r = -0.56; P = 0.0002) and independently predicted osteocalcin (r = -0.45; P = 0.003), bone-specific alkaline phosphatase (r = -0.46; P = 0.003), N-telopeptide/creatinine (r = -0.55; P = 0.0003), and deoxypyridinoline/creatinine (r = -0.52; P = 0.001) on regression modeling. Elevated PYY may contribute to reduced intake and decreased bone turnover in AN.

Dietary intake and the insulin-like growth factor system: effects of migration in two related populations in India and Britain with markedly different dietary intake

The insulin-like growth factor (IGF) system is implicated in the pathogenesis of diabetes and cardiovascular disease. We report the effects of total energy intake on the IGF system in two populations with markedly different dietary macronutrient intake and cardiovascular event rate. Dietary macronutrient intake was measured in a specific Gujarati migrant community in Sandwell, UK (n=205) compared with people still resident in the same villages of origin in India (n=246). Fasting IGF-I, IGF-binding protein (IGFBP)-1 and IGFBP-3, insulin and glucose (0 and 2-hour) were measured. Total energy and total fat intake were higher in UK migrants, as were IGFBP-3 and IGF-I (mean (95% confidence interval): 145.9 (138.1-153.6) vs. 100.9 (94.6-107.3) ng ml(-1); F=76.6, P<0.001). IGFBP-1 was lower in UK migrants (29.5 (25.9-33.0) vs. 56.5 (50.6-62.5) microg l(-1); F=48.4, P<0.001). At both sites, IGF-I correlated positively with total energy (Spearman's rho=0.45, P<0.001) and total fat (rho=0.44, P<0.001) as did IGFBP-3 with total energy (rho=0.21, P<0.05) and fat (rho=0.26, P<0.001). Conversely, in Indian Gujaratis, IGFBP-1 fell with increasing total energy (rho=-0.27, P<0.001) and fat intake (rho=-0.26, P<0.01) but not in UK Gujaratis. Multiple linear regression modelling showed that increasing quartiles of fat intake were associated with higher IGF-I (beta=0.42, P=0.007) independent of age, body mass index, plasma insulin, fatty acids and 2-hour glucose. In these genetically similar groups, migration to the UK and adoption of a different diet is associated with marked changes in the IGF system, suggesting that environmental factors profoundly modulate serum concentrations and actions of IGFs.

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.

Growth hormone binding protein and acid labile subunit levels in the assessment of acromegaly treatment

Post-treatment monitoring of acromegalic patients is a matter of controversy, as discrepancies between GH and IGF-I levels have been reported. The aim of our study was to evaluate the role of acid-labile subunit (ALS), a component of the 150 kD IGF-I/IGFBP-3/ALS complex, and the growth hormone binding protein (GHBP) in the follow-up of patients with acromegaly after therapeutic intervention. Forty-one patients with acromegaly, 10 at the time of diagnosis and 31 post therapeutic intervention, were studied. Patients were evaluated by the determination of baseline (fasting) IGF-I, ALS and GHBP and of glucose and GH during OGTT. Significantly lower ALS and higher GHBP levels were detected in successfully treated acromegalics compared to patients before treatment (34.1+/-1.6 vs. 52.8+/-2 mg/L and 0.9+/-0.08 vs 0.4+/-0.1 ìg/L, respectively P<0.05). Furthermore, no difference was noted in ALS and GHBP values between patients successfully treated with either somatostatin analogues or another type of treatment. a) Successfully treated acromegalic patients demonstrate lower ALS and higher GHBP levels than patients before treatment, and b) somatostatin analogue treatment does not have a direct effect on GHBP and ALS concentration in acromegaly. Studies in larger groups of patients are needed to disclose whether these alterations will be useful in the post-treatment assessment of acromegalic patients.

The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men

Ageing and obesity result in decreased activity of the GH/IGF-I axis and concomitant impaired GH responses to secretory stimuli. We therefore determined the validity of the GH cut-off value of 15.0 microg/l in the GH-releasing hormone (GHRH)/GH releasing peptide-6 (GHRP-6) test for the diagnosis of GH deficiency in elderly or severely obese men. We performed a combined GHRH/GHRP-6 test in ten elderly men (mean age 74 years; mean body mass index (BMI) 24.6 kg/m(2)), nine obese men (mean age 47 years; mean BMI 40.6 kg/m(2)) and seven healthy male controls (mean age 51 years, mean BMI 24.3 kg/m(2)). After assessment of fasting plasma GH, IGF-I and IGF-binding protein-3 (IGFBP-3), GHRH (100 microg) and GHRP-6 (93 microg) were given intravenously as a bolus injection. Repeated GH measurements were performed for two hours. Both peak GH levels and areas under the curve (AUC) were significantly lower in the obese than in the controls (peak 13.2 vs 53.4 microg/l, P = 0.001; AUC 707 vs 3250 microg/l x 120 min; P = 0.001). Mean GH response in the elderly was lower than in the controls (peak 35.0 microg/l; AUC 2274 microg/l x 120 min), but this was not statistically significant. In contrast, GH peak levels in seven obese men remained below the cut-off level of 15.0 microg/l associated with severe GH deficiency. All others had GH peak levels exceeding this threshold. IGFBP-3 levels were significantly lower in the elderly than in the controls (1.35 vs 2.05 mg/l, P = 0.001). Baseline GH or IGF-I did not differ significantly between groups. GH responses following GHRH/GHRP-6 administration were significantly reduced in severely obese men, but were not significantly reduced in elderly men, despite a negative trend. Our data indicate that the cut-off GH level of 15.0 microg/l after GHRH + GHRP-6 administration for the diagnosis of severe GH deficiency cannot be used in severely obese men.

Relationship between Disease-Related Morbidity and Biochemical Markers of Activity in Patients with Acromegaly

The criteria for biochemical control of acromegaly that will best reduce disease-related morbidity in acromegaly are debated. We therefore studied the relationship of biochemical markers with an important metabolic parameter, insulin sensitivity, and clinical parameters reflecting disease activity in acromegaly. Newly diagnosed and postoperative patients with acromegaly underwent assessment of fasting IGF-I and fasting and postoral glucose tolerance test GH and insulin levels and completed a numeric signs and symptoms questionnaire. Insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and the composite insulin sensitivity index. Patients were divided into three groups: group I, normal IGF-I and nadir GH less than 0.14 mug/liter (n = 21); group II, normal IGF-I and nadir GH 0.14 mug/liter or more (n = 20); group III (active), elevated IGF-I (n = 25). Age, sex, and body mass index were comparable in these groups. Insulin sensitivity was reduced in group III (QUICKI: 0.33 +/- 0.01 and composite index: 3.44 +/- 0.54), compared with group II (0.38 +/- 0.01, P = 0.002 and 8.18 +/- 1.21, P = 0.0008), group I (0.38 +/- 0.01, P = 0.0008 and 8.91 +/- 1.34, P = 0.00001), and healthy controls (0.37 +/- 0.008, P = 0.009). When other nadir GH cut-offs were analyzed, insulin sensitivity remained relatively reduced in the elevated IGF-I group. IGF-I was a significant predictor for decreasing insulin sensitivity as calculated by QUICKI (r = 0.6, P < 0.0001) independently of nadir GH. Signs and symptom scores were higher in group III (mean 38.5 +/- 3.6%), compared with group II (mean 23.5 +/- 3.2%, P = 0.004) and group I (mean 20.5 +/- 3.7%, P = 0.0008) but not between the latter two groups. Our data indicate that overall and specifically in the presence of discordant serum IGF-I and nadir GH levels, IGF-I was more predictive than GH levels of insulin sensitivity and clinical symptom score in patients with acromegaly.

Effect of Short-Term Prednisone Use on Blood Flow, Muscle Protein Metabolism, and Function

Glucocorticoids can cause muscle atrophy, but the effect on muscle protein metabolism in humans has not been adequately studied to know whether protein synthesis, breakdown, or both are altered. We tested the effect of 6 d of oral prednisone (Pred, 0.5 mg/kg.d) on muscle protein metabolism and function. Six healthy subjects (three men/three women, 22-41 yr) completed two trials (randomized, double-blind, cross-over) with Pred and placebo. Fasting glucose, insulin, IGF-I, and glucagon were higher on Pred vs. placebo, whereas IGF-II and IGF binding protein-1 and -2 were lower. Whole-body amino acid fluxes, blood urea nitrogen, and urinary nitrogen loss were not statistically different between trials. Leg blood flow was 25% lower on Pred leading to 15-30% lower amino acid flux among the artery, vein, and muscle. However, amino acid net balance and rates of protein synthesis and breakdown were unchanged, as were synthesis rates of total mixed, mitochondrial, sarcoplasmic, and myosin heavy chain muscle proteins. Muscle mitochondrial function, muscle strength, and resting energy expenditure were also unchanged. These results demonstrate that a short-term moderate dose of prednisone affects glucose metabolism but has no effect on whole-body or leg muscle protein metabolism or muscle function.

Free Rather than Total Circulating Insulin-Like Growth Factor-I Determines the Feedback on Growth Hormone Release in Normal Subjects

Pituitary GH secretion is feedback regulated by circulating IGF-I. However, it remains to be determined whether the feedback control is mediated through circulating free or total IGF-I. To study this, we compared the temporal changes in circulating levels of GH vs. free and total IGF-I during fasting. Seventeen healthy normal-weight subjects (body mass index 23.4 +/- 0.6 kg/m(2)) were studied during 80 h of fasting. Serum was assayed for GH every 3 h; total, free, and bioactive IGF-I, IGF binding protein (IGFBP)-1, -2, and -3 as well as IGFBP-1 bound IGF-I were assayed every morning. During fasting, mean 24-h GH levels increased from 1.41 +/- 0.20 to 3.01 +/- 0.46 and 2.09 +/- 0.30 microg/liter (d 1 vs. d 2 and 3; P < 0.03). After 24 h of fasting, free and bioactive IGF-I had decreased by 40 +/- 5 and 17 +/- 5%, respectively (P < 0.02), and both concentrations remained suppressed for the rest of the study. In contrast, total IGF-I remained unchanged until the end of d 3, at which levels were slightly reduced (P < 0.007). IGFBP-1 increased from 38 +/- 2 to 137 +/- 24, 212 +/- 32, and 214 +/- 22 microg/liter (d 1 vs. d 2, d 3, and end of d 3; P < 0.0001), and these changes closely paralleled those of IGFBP-1-bound IGF-I (P < 0.0001). IGFBP-2 increased only transiently at d 2 (P < 0.05), and IGFBP-3 remained unchanged. The increase in mean 24-h GH levels from d 1 to d 2 correlated inversely with the relative reduction in free IGF-I from d 1 to d 2 (r = -0.51; P = 0.04), i.e. the larger the reduction in free IGF-I, the larger the increase in GH. None of the other IGF-related parameters correlated with GH. In conclusion, the temporal relationship between the increase in GH and the reduction in free IGF-I supports the hypothesis that circulating free IGF-I mediates the feedback regulation of GH secretion.

The influence of dietary intake on the insulin-like growth factor (IGF) system across three ethnic groups: a population-based study.

The insulin-like growth factor (IGF) system has been implicated in the aetiopathogenesis of cancer, cardiovascular disease and diabetes. Since dietary factors and ethnicity are considered contributory to the development of these diseases, we examined the IGF system in relation to nutritional intake by ethnic group. Dietary intake in 257 subjects of White European, African-Caribbean and Pakistani ethnic origin living in Manchester, UK was assessed using ethnic-group-specific food-frequency questionnaires to assess habitual nutrient intake over the previous 12 months. Fasting IGF-I, IGF-II and IGF-binding protein-1 (IGFBP-1) concentrations were determined and their relationship to specific dietary constituents was analysed. Analysis by quintiles of nutrient intake showed a significant increase in circulating IGF-I concentration with increasing dietary fat intake (F for trend=3.9, ), saturated fat intake and for protein intake There was also a significant increase in IGF-II by quintiles of dietary protein intake There was a trend for increasing IGF-I with increasing energy intake. The relationships between circulating concentration of IGFBP-1, an acute regulator of IGF action, and fat/protein intake were opposite to those for IGF-I and IGF-II. Multiple linear regression modelling showed that people of Pakistani origin and older subjects had lower levels of IGF-I (Pakistani origin vs. others, ) (age, for both). There was an independent inverse relationship between IGF-I and dietary carbohydrate intake This study provides evidence for a dietary contribution to regulation of the IGF system, although the effects of ethnicity on circulating IGF levels remain dominant. We propose that the IGF system's influences on cancer risk in specific ethnic groups are potentially modifiable by dietary intervention.

Amplified and orderly growth hormone secretion characterizes lean adolescents with polycystic ovary syndrome.

The present study evaluated the hypothesis that pulsatile GH secretion is altered in adolescents with polycystic ovary syndrome (PCOS). Thirteen adolescent girls with PCOS (ages 13-19 years) and ten eumenorrheic controls (ages 14-19 years) matched for a range of body mass index (BMI) values underwent blood sampling every 20 min for 12 h overnight. Serum concentrations of GH and LH were measured by specific immunofluorometric assays (IFMA). Pulsatile secretion was quantitated by deconvolution analysis and pattern orderliness by the approximate entropy (ApEn) statistic. Fasting serum androstenedione, testosterone, 17-hydroxyprogesterone, estrone, estradiol, insulin and IGF-I concentrations were measured by RIA, GH-binding protein (GHBP) by IFMA and IGF-binding protein (IGFBP)-1 and IGFBP-3 by IRMA. Twelve-hour mean and integrated GH concentrations, the mass of GH secreted per burst, and the GH pulse frequency were not distinguishable in patients with PCOS and controls as a whole. Subanalysis of non-obese (BMI<25 kg/m(2)) PCOS and healthy volunteers disclosed elevated 12-h GH production rates (P=0.03) and integrated serum GH concentrations (P=0.04) in (lean) patients with PCOS. ApEn analysis of the orderliness of GH release showed remarkably more regular GH secretion patterns (lower ApEn of GH release) in girls with PCOS compared with controls (P=0.02). Serum GHBP, IGF-I and IGFBP-3 concentrations were similar in both groups, whether lean or obese. However, IGFBP-1 levels were lower in the combined group of PCOS subjects compared with BMI-matched controls (P<0.05). In volunteers with PCOS, mean (12-h) serum GH concentrations correlated positively with mean serum LH levels (P=0.006). Based on deconvolution analysis, the 12-h production rate and the mass of GH secreted per burst also correlated strongly with the cognate LH measure (both predicted) (P=0.004) in PCOS. Androstenedione levels were also related to the 12-h GH secretion rate (P=0.02). This study shows that non-obese adolescents with PCOS secrete GH at a higher rate and with more orderly patterns, resembling a male profile. Determining whether this pattern reflects an intrinsic hypothalamic abnormality or is secondary to androgen excess in PCOS will require further studies.

Accelerated Escape from GH Autonegative Feedback in Midpuberty in Males: Evidence for Time-Delimited GH-Induced Somatostatinergic Outflow in Adolescent Boys

A single injected pulse of GH inhibits the time-delayed secretion of GH in the adult by way of central mechanisms that drive somatostatin and repress GHRH outflow. The marked amplification of spontaneous GH pulse amplitude in puberty poses an autoregulatory paradox. We postulated that this disparity might reflect unique relief of GH-induced autonegative feedback during this window of development. The present study contrasts GH autonegative feedback in: 1) normal prepubertal boys (PP) (n = 6; Tanner genital stage I, chronologically aged 8 yr, 9 months to 10 yr, 1 month; median bone age 8.5 yr); 2) longitudinally identified midpubertal boys (MP) (n = 6; Tanner genital stages III/IV, aged 12 yr, 6 months to 15 yr, 6 months; median bone age 15 yr); and 3) healthy young men (YM) (n = 6, aged 18–24 yr; bone age >18 yr). Subjects each underwent four randomly ordered tandem peptide infusions on separate mornings while fasting: i.e. 1) saline/saline infused iv bolus at 0830 h and 1030 h; 2) saline/GHRH (0.3 μg/kg iv bolus) at the foregoing times; 3) recombinant human (rh) GH (3 μg/kg as a 6-min square-wave iv pulse)/saline; and 4) rhGH and GHRH. To monitor GH autofeedback effects, blood samples were obtained every 10 min for 5.5 h beginning at 0800 h (30 min before GH or saline infusion). Serum GH concentrations were quantitated by ultrasensitive chemiluminometry (threshold 0.005 μg/liter). On the day of successive saline/saline infusion, MP boys maintained higher serum concentrations of: 1) GH (μg/liter), 2.2 ± 0.25, compared with PP (0.61 ± 0.10) or YM (0.88 ± 0.36) (P = 0.011); 2) IGF-I (μg/liter), 493 ± 49 vs. PP (134 ± 16) and YM (242 ± 22) (P < 0.001); 3) T (ng/dl), 524 ± 58 vs. PP (<20) (P < 0.001); and 4) E2 (pg/ml),19 ± 3 vs. PP (< 10) (P = 0.030) (mean ± sem). Consecutive saline/GHRH infusion elicited comparable peak (absolute maximal) serum GH concentrations (micrograms per liter) in the three study groups, i.e. 18 ± 5.0 (PP), 9.6 ± 1.7 (MP), and 14 ± 5.3 (YM) (each P < 0.01 vs. saline; P = NS cohort effect). Injection of rhGH attenuated subsequent GHRH-stimulated peak serum GH concentrations (micrograms per liter) to 7.8 ± 1.9 (PP), 5.8 ± 1.2 (MP), and 4.8 ± 1.1 (YM) (each P < 0.01 vs. saline; P = NS pubertal effect). GH autofeedback reduced non-GHRH-stimulated (basal) serum GH concentrations by 0.74 ± 0.28 (PP), 5.7 ± 1.7 (MP) and 1.4 ± 0.27 (YM) fold, compared with saline (P = 0.016 for MP vs. PP or YM). In addition to greater fractional autoinhibition, MP boys exhibited markedly accentuated postnadir escape (4.6-fold steeper slope) of suppressed GH concentrations (P < 0.001 vs. PP or YM). Linear regression analysis of data from all 18 subjects revealed that the fasting IGF-I concentration negatively predicted fold-autoinhibition of GHRH-stimulated peak GH release (r = −0.847, P = 0.006) and positively forecast fold-autoinhibition of basal GH release (r = +0.869, P < 0.001). In contrast, the kinetics of rhGH did not differ among the three study cohorts. In summary, boys in midpuberty manifest equivalent responsiveness to exogenous GHRH-stimulated GH secretion; heightened susceptibility to rhGH-induced fractional inhibition of endogenous secretagogue-driven GH release, compared with the prepubertal or adult male; and accelerated recovery of GH output after acute autonegative feedback. This novel tripartite mechanism could engender recurrent high-amplitude GH secretory bursts that mark sex hormone-dependent activation of the human somatotropic axis.

Gender and age influence the relationship between serum GH and IGF‐I in patients with acromegaly

In patients with acromegaly serum IGF-I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF-I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and women with GH deficiency require 30-50% more exogenous GH to maintain the same serum IGF-I as GH-deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF-I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF-I. To evaluate the influence of age and gender on the relationship between serum GH and IGF-I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy. Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24-81 years) attending a colonoscopy screening programme were studied. Forty-five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight-point day profile (n = 45) and values obtained during a 75-g oral glucose tolerance test (n = 15). Serum IGF-I, IGFBP-3 and acid-labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques. The median calculated GH value was 4.7 mU/l (range 1-104). A significant linear association was observed between serum IGF-I and log10 mean serum GH for the cohort (R = 0.5, P < 0.0001). After simultaneous adjustment of the above covariates a significant difference in the relationship between mean serum GH and IGF-I was observed for males and females. On average, women had serum IGF-I levels 11.44 nmol/l lower than men with the same mean serum GH (P = 0.03, 95% CI 1.33-21.4 nmol/l). Age significantly influenced the relationship and for a given serum GH, IGF-I was estimated to fall by 0.37 nmol/l per year (P = 0.04, 95% CI 0.015-0.72). In keeping with previous observations of relative GH resistance in normal and GH-deficient females we have observed lower serum IGF-I levels for equivalent mean serum GH levels in females patients with acromegaly. This gender-dependent difference is independent of disease activity and the use of concomitant medical therapy. Additionally, we have demonstrated that for a given serum GH level, age significantly influences IGF-I concentrations in patients with acromegaly. These data have important implications for the use of serum IGF-I and GH as markers of disease activity in acromegaly.

Effect of a six-month treatment with lanreotide on cardiovascular risk factors and arterial intima-media thickness in patients with acromegaly

To evaluate the effect of a 6-month treatment with slow-release lanreotide (LAN) on cardiovascular risk and atherosclerosis in 24 normotensive patients with active acromegaly (GH=67.4 +/- 12.6 mU/l, IGF--I=866.0 +/- 55.8 microg/l) and 24 healthy subjects sex-, age- and body mass index-matched with the patients (as controls). Open, prospective, multicenter. The following were measured before and after 6 months of LAN treatment (dose 60-90 mg/month): fasting GH, IGF-I, LDL, HDL and total cholesterol, triglyceride, glucose, glycosylated hemoglobin, insulin and fibrinogen levels, intima-media thickness (IMT) and blood systolic and diastolic peak velocity (SPV and DPV respectively) in both common carotids. At study entry, insulin, total and LDL cholesterol, triglyceride and fibrinogen levels were higher while HDL cholesterol levels were lower in patients than in controls. At the right (0.88 +/- 0.04 vs 0.77 +/- 0.03 mm, P=0.05) and left (0.93 +/- 0.03 vs 0.78 +/- 0.02 mm, P=0.01) common carotid IMT was significantly higher in patients than in controls; 12 patients and two controls showed an IMT of > or = 1 mm (chi(2)=8.2, P=0.004). After 6 months of LAN treatment, disease control was achieved in 15 patients (62.5%). Insulin, triglyceride and fibrinogen levels were significantly decreased, and a trend toward a decrease of IMT in the right (from 0.90 +/- 0.05 to 0.78 +/- 0.04 mm, P=0.06) and left (from 0.95 +/- 0.04 to 0.84 +/- 0.04 mm, P=0.06) common carotid arteries was observed only in patients with disease control, while SPV and DPV did not change. LAN treatment for 6 months significantly lowered GH, IGF-I, insulin and fibrinogen levels and reduced IMT of both common carotid arteries in normotensive patients with acromegaly.

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

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

The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency.

Controversy persists with regard to the atherogenic risk associated with adult growth hormone deficiency (GHD). Endothelial dysfunction and enhanced oxidative stress are early features of atherogenesis. Therefore, we have studied the effect of three months of low dose GH replacement therapy (0.03IU/kg/day) on these parameters in GHD adults. Eight hypopituitary GHD adults (4 male, 4 female), who were receiving conventional hormone replacement therapy, were studied before and after 3 months of GH replacement (0.03IU/kg/day). All observations obtained were compared with similar measurements made in 8 matched control subjects. All study subjects were non-smokers, normotensive and gave no personal or family history of premature vascular disease. Endothelial function was assessed using a specialised vessel wall tracking system to measure endothelium-dependent, flow-mediated, brachial artery dilatation (FMD). Measurements were repeated following glyceryl-trinitrate (GTN) (endothelium-independent dilatation). Oxidative stress was assessed by directly measuring lipid-derived free radicals in venous blood by electron paramagnetic resonance spectroscopy. Fasting lipids, insulin, plasma glucose and IGF-I were also measured at baseline and following GH replacement. FMD, expressed as a percentage change from resting base-line diameter, was significantly impaired in the pre-treatment GHD patients compared with controls (3.1+/-2.1% vs 6.1+/-0.9%, P<0. 001; means+/-s.d.) indicating endothelial dysfunction. Significant increase in FMD was noted following GH therapy (3.1+/-2.1% vs 6. 5+/-1.9%, P<0.001). Free radicals (arbitrary units) were elevated in the pre-treatment GHD patients compared with controls (0.36+/-0.09 vs 0.11+/-0.12, P<0.05) and fell significantly following GH therapy (0.23+/-0.03 vs 0.36+/-0.09, P<0.05), although they remained elevated compared with controls. Fasting insulin was significantly higher (25.9+/-18.8 vs 13.9+/-6.7mu/l, P<0.05) and IGF-I concentrations lower (10.8+/-4.7 vs 20.2+/-6.3nmol/l, P<0.05) in the pre-treatment GHD subjects. After treatment there were no changes in insulin concentration, although IGF-I levels were normalised (10. 8+/-2.3 vs 23.6+/-11.4nmol/l, P<0.05). Endothelial dysfunction and enhanced oxidative stress are features of adult GHD. This study suggests plausible mechanisms underlying any proatherogenic tendency in adult GHD and demonstrates improvement of these factors following GH replacement.

The study of spontaneous GH secretion after 36-h fasting distinguishes between GH-deficient and normal adults.

Within an appropriate clinical context, GH deficiency (GHD) in adults can only be diagnosed biochemically by provocative testing. The evaluation of IGF-I, IGFBP-3 and even of spontaneous GH secretion do not establish the diagnosis of adult GHD. In fact, remarkable overlaps between normal and GHD adults have been reported for all these parameters. On the other hand, it is well known that even short-term fasting stimulates GH secretion in normal subjects. The aim of our study was to determine the effects of 36 h fasting on 8-h diurnal GH, insulin and glucose levels as well as on basal IGF-I, IGFBP-3, acid-labile subunit (ALS), IGFBP-1, GHBP and free fatty acid (FFA) levels. We studied 9 GHD adults (GHD, 8 males, 1 female; age, mean +/- SEM: 37.6 +/- 2.3 years, body mass index (BMI): 24.5 +/- 1.0 kg/m2) and 20 age-matched normal subjects (NS) as controls (13 males, 7 females; age: 28.9 +/- 0.6 years, BMI: 21.6 +/- 0.4 kg/m2). In all subjects we studied the effects of 36 h fasting on 8-h daytime GH, insulin and glucose levels (assay every 30 min from 0800 h to 1600 h) as well as on basal IGF-I, IGFBP-3, ALS, IGFBP-1, GHBP and FFA levels. Before fasting, basal mean IGF-I, IGFBP-3 and ALS levels in GHD were lower (P < 0. 0001) than in NS. IGFBP-1, GHBP and FFA levels were similar in both groups. Before fasting mean GH concentration (mGHc) in GHD was lower (P < 0.05) than in NS (0.4 +/- 0.2 vs. 2.2 +/- 0.6 mu/l) but with a clear overlap between the 2 groups (range 0.4-0.8 vs. 0.4-6.8 mu/l). After fasting, both in GHD and NS basal IGF-I, IGFBP-3, ALS and GHBP levels did not change significantly. On the other hand, in both GHD and in NS IGFBP-1 was increased (P < 0.0001) to a similar extent, while FFA increased in NS more (P < 0.01) than in GHD. Fasting significantly increased mGHc in NS (12.0 +/- 1.2 mu/l, P < 0.0001) but not in GHD (0.6 +/- 0.2 mu/l). After fasting, no overlap was present between GHD and NS (0.4-1.6 vs. 2.4-20.8 mu/l, respectively). Mean glucose and insulin concentrations over 8 h in GHD and NS in basal conditions were similar and were reduced to the same extent in both groups. Our findings demonstrate that after short-term fasting, the study of spontaneous GH secretion distinguishes between GH-deficient adults and normal subjects; this phenomenon occurs before significant changes in IGF-I and IGFBP-3 levels. These results suggest that the assessment of spontaneous GH secretion could be useful for the diagnosis of adult GH deficiency only after short-term fasting.

Elevated leptin concentrations in growth hormone-deficient hypopituitary adults.

Hypopituitarism with growth hormone (GH) deficiency is associated with obesity characterized by central (abdominal) distribution of fat. Recent work has demonstrated that leptin, a product of obese gene, is raised in obesity. To study circulating leptin levels in GH-deficient hypopituitary adults and to investigate its anthropometric, gender and metabolic relations. After an overnight fast of 10-12 hours, anthropometric parameters and body composition were measured and blood was collected for the measurement of circulating leptin, glucose, intact insulin, proinsulin, IGF-I, total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol. Fifteen (7 men) GH-deficient hypopituitary adults (maximum stimulated serum GH to provocative testing < 6 mU/l) and 21 (10 men) normal control subjects matched for age, gender and body mass index (BMI). Fasting serum leptin was significantly higher in hypopituitary patients than controls (12.0 +/- 1.8 vs 8.0 +/- 1.5 micrograms/l, P = 0.04). The increase was more marked in obese (BMI > 26.0 kg/m2) patients compared with obese controls (15.3 +/- 2.0 vs 8.8 +/- 2.3 micrograms/l, P = 0.03) than in lean patients and controls. Obese control women and men had higher leptin levels than non-obese (women, 16.6 +/- 2.7 vs 8.6 +/- 0.6 micrograms/l, P = 0.03; men, 4.9 +/- 0.5 vs 2.9 +/- 0.6 micrograms/l, P = 0.035). Similar changes were observed for obese versus non-obese patients, although the changes did not reach statistical significance. Women in each group had significantly higher leptin concentrations than men (patients: 15.5 +/- 2.3 vs 7.3 +/- 1.4 micrograms/l, P = 0.009; controls: 12.6 +/- 2.4 vs 4.3 +/- 0.5 micrograms/l, P = 0.0001). These gender differences remained significant even when expressed in relation to BMI (patients: 0.57 +/- 0.09 vs 0.26 +/- 0.05 ng.m2/ml.kg, P = 0.009; controls: 0.43 +/- 0.05 vs 0.16 +/- 0.02 ng.m2/ml.kg, P = 0.0001). Serum leptin was positively associated with body mass index (P = 0.003), percentage body fat mass (P = 0.0001) and inversely related with age (P = 0.043). It demonstrated no relation with body weight, waist circumference, waist to hip ratio, fasting IGF-I, glucose, insulin, proinsulin, total cholesterol, triglycerides, HDL and LDL cholesterol in patients nor controls; 85% of variance in leptin was explained by a model including body mass index, gender, age and hypopituitarism. Leptin concentrations are raised in GH-deficient hypopituitary adults to a greater extent than would be expected from the degree of obesity.

Body composition in growth hormone deficient adults over the age of 60 years.

Elderly patients with hypothalamic-pituitary disease exhibit a reduction in GH secretion distinct from the decline in GH secretion related to age. GH deficiency in young adults causes a change in body composition, with increased fat mass (FM) and reduced fat free mass (FFM), similar to that seen as a result of the normal ageing process. The aim of this study was to determine whether organic GH deficiency in elderly patients may cause changes in body composition beyond those due to ageing. Twenty-one patients (15 male) with documented pituitary disease and 24 controls (17 male) matched for age, height, weight and BMI, all over the age of 60, in whom GH status had been defined by a 24-hour GH profile and an arginine stimulation test. Serum was taken for fasting IGF-l and IGFBP-1 estimations. Total and regional FM and FFM were determined using dual-energy X-ray absorptiometry. FM (median (range)) was increased in the patients, 27.76 (19.25-50.24) vs 21.23 (8.81-49.15) kg in the controls (P < 0.005). FM was significantly increased in the arms, legs and trunk in the patients compared with the controls. The proportion of fat deposited centrally did not differ significantly between the two groups (57.0% (47.6-65.1) in the patients vs 55.3% (44.1-63.8) in the controls, P = 0.25). There was an inverse relation between total FM and serum IGFBP-1 present in the patients, p = -0.632, P < 0.005, and in the controls p = -0.467, P < 0.05, but the relation between total FM and area under the GH profile was significant only in the controls (p = -0.651, P < 0.001) and not in the patients. FFM (51.19 (26.96-69.18) kg in the patients vs 51.55 (32.35-60.53) kg in the controls, P = 0.99) and serum IGFBP-1 levels did not differ significantly between the two groups. Organic growth hormone deficiency causes changes in body composition beyond the changes associated with the ageing process. These changes differ from those seen in younger GH deficient adults in that they are limited to an increase in FM with no change in FFM. These findings indicate that even in the elderly, in whom GH secretion is normally very low, the additional imposition of GH deficiency due to organic disease has significant biological impact.

Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes.

Insulin-like growth factors (IGFs) circulate attached to binding proteins (IGFBPs). Only the unbound form of IGF is suggested to be biological active. The main source of circulating IGF-I and IGFBP-1 is considered to be the liver, but that of circulating IGFBP-3 is not known. IGF-I and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. The aim of the present study was to examine the effect of insulin on the hepatic secretion of IGFBP-1, IGFBP-3, and IGF-I. Seven insulin-dependent diabetic patients in whom insulin was withheld for 12 h were studied in the overnight fasted state. Blood was sampled simultaneously from the hepatic vein, a peripheral vein, and an artery before and during insulin infusion for 3 h. The basal IGFBP-1 levels in the peripheral vein were several-fold elevated (249 +/- 44 micrograms/L) compared to those in healthy subjects (37 +/- 2 micrograms/L). Fasting IGFBP-1 concentrations were inversely correlated to the insulin levels (r = -0.918; P < 0.001). The mean IGF-I concentration (175 +/- 17 micrograms/L; -1.62 +/- 0.38 SD score) was decreased compared with that in age-matched healthy subjects. The basal IGFBP-3 levels in the peripheral vein (4.50 +/- 0.33 mg/L) were within the normal range. There was a significant correlation in the hepatic vein between fasting IGF-I and IGFBP-3 levels (r = 0.928; P < 0.001). Basal splanchnic IGFBP-1 production was 18 +/- 7 micrograms/min, whereas no basal net exchanges of IGF-I or IGFBP-3 were observed across the splanchnic area. Insulin inhibited splanchnic IGFBP-1 production within 120 min and glucose output within 20 min. Serum IGF-I, but not IGFBP-3, concentrations increased significantly during the insulin infusion. In summary, this study demonstrates the existence of considerable IGFBP-1 production from the liver during insulinopenia and the complete blocking of splanchnic IGFBP-1 production and increases in serum levels of IGF-I by insulin despite no effect on IGFBP-3 levels. Thus, insulin may play a role in determining the bioavailability of IGF-I.

Changes in growth hormone concentrations during puberty in adolescents with insulin dependent diabetes.

To document the changes in pulsatile growth hormone secretion in diabetic adolescents during puberty, and to investigate their relationship to both metabolic control and stature. Auxological parameters, overnight growth hormone secretion, fasting IGF-I, hourly glucose and metabolic control were assessed in a group of adolescents with diabetes. Fifty-two diabetic adolescents (28 males and 24 females) at different pubertal stages and with varying degrees of metabolic control were studied. Ten of those with poor diabetic control were studied on two occasions. Height and weight measurements, pubertal staging, growth velocity data and bone age estimation were obtained on all the patients. Overnight growth hormone profiles (Pulsar program analysis), glycosylated haemoglobin and fasting IGF-I were performed on all the subjects. Hourly overnight glucose measurements were also obtained on the ten subjects who had two overnight growth hormone studies. For the whole diabetic growth, GH area under curve (AUC) was maximal in late puberty (pubertal stage 4), and was paralleled by maximal GH peak amplitude. No relationship between GH-AUC and metabolic control was demonstrated. No difference in GH parameters was demonstrated between the male and female subgroups. The relationship between growth hormone secretory parameters and stature was not significant. However, GH-AUC was significantly correlated with growth velocity in the males but not the females. The pattern of GH secretion in adolescents with diabetes parallels that seen in normal adolescents during puberty, with increases in GH concentration associated with increased GH pulse amplitude. The degree of metabolic control had no effect on this pattern and there was no relationship between GH secretory parameters and stature.