Disagreement in normative IGF-I levels may lead to different clinical interpretations and GH dose adjustments in GH deficiency.

INTRODUCTION AND BACKGROUND: Normative data for the iSYS IGF-I assay have been published both in the VARIETE cohort and by Bidlingmaier et al. OBJECTIVE: To investigate whether normative data of the VARIETE cohort lead to differences in Z-scores for total IGF-I and clinical interpretation compared to normative data of Bidlingmaier et al. DESIGN: We used total IGF-I values previously measured by the IDS-iSYS assay in 102 GH-deficient subjects before starting GH treatment and after 12 months of GH treatment. Z-scores were calculated for all samples by using the normative data of the VARIETE cohort and by the normative data reported by Bidlingmaier et al. RESULT: Before GH treatment, Z-scores calculated by using the normative data of the VARIETE cohort were significantly lower than those calculated by the normative data of Bidlingmaier et al: -2.40 (-4.52 to +1.31) (mean [range]) vs. -1.41 (-3.14 to +1.76); P < .001). After 12 months of GH treatment, again the Z-scores based on the normative data of the VARIETE cohort were significantly lower than those based on the normative data of Bidlingmaier et al: -0.65 (-4.32 to +2.79) vs 0.21 (-3.00 to +3.28); P < .001). CONCLUSION: IGF-I Z-scores in 102 GH-deficient subjects differed significantly when normative data from two different sources were used. In daily clinical practice, this would most likely have led to different clinical interpretations and GH dose adjustments.

Efficacy and safety of bariatric surgery for craniopharyngioma-related hypothalamic obesity: a matched case-control study with 2 years of follow-up.

BACKGROUND: Hypothalamic obesity is a devastating consequence of craniopharyngioma. Bariatric surgery could be a promising therapeutic option. However, its efficacy and safety in patients with craniopharyngioma-related hypothalamic obesity remain largely unknown. OBJECTIVES: We investigated the efficacy of bariatric surgery for inducing weight loss in patients with craniopharyngioma-related hypothalamic obesity. In addition, we studied the safety of bariatric surgery regarding its effects on hormone replacement therapy for pituitary insufficiency. METHODS: In this retrospective matched case-control study, we compared weight loss after bariatric surgery (that is, Roux-en-Y gastric bypass and sleeve gastrectomy) between eight patients with craniopharyngioma-related hypothalamic obesity and 75 controls with 'common' obesity during 2 years of follow-up. We validated our results at 1 year of follow-up in a meta-analysis. In addition, we studied alterations in hormone replacement therapy after bariatric surgery in patients with craniopharyngioma. RESULTS: Mean weight loss after bariatric surgery was 19% vs 25% (difference -6%, 95% confidence of interval (CI) -14.1 to 4.6; P=0.091) at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity compared with control subjects with 'common' obesity. Mean weight loss was 25% vs 29% (difference -4%, 95% CI -11.6 to 8.1; P=0.419) after Roux-en-Y gastric bypass and 10% vs 20% (difference -10%, 95% CI -14.1 to -6.2; P=0.003) after sleeve gastrectomy at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity vs control subjects with 'common' obesity. Our meta-analysis demonstrated significant weight loss 1 year after Roux-en-Y gastric bypass, but not after sleeve gastrectomy. Seven patients with craniopharyngioma suffered from pituitary insufficiency; three of them required minor adjustments in hormone replacement therapy after bariatric surgery. CONCLUSIONS: Weight loss after Roux-en-Y gastric bypass, but not sleeve gastrectomy, was comparable between patients with craniopharyngioma-related hypothalamic obesity and control subjects with 'common' obesity at 2 years of follow-up. Bariatric surgery seems safe regarding its effects on hormone replacement therapy.

Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases IGF-I bioactivity similarly.

AIMS/HYPOTHESIS: The aim of this study was to compare IGF-I bioactivity 36 weeks after the addition of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) or NPH insulin to metformin therapy in type 2 diabetic patients who had poor glucose control under metformin monotherapy. METHODS: In the Lantus plus Metformin (LANMET) study, 110 poorly controlled insulin-naive type 2 diabetic patients were randomised to receive metformin with either insulin glargine (G+MET) or NPH insulin (NPH+MET). In the present study, IGF-I bioactivity was measured, retrospectively, in 104 out of the 110 initially included LANMET participants before and after 36 weeks of insulin therapy. IGF-I bioactivity was measured using an IGF-I kinase receptor activation assay. RESULTS: After 36 weeks of insulin therapy, insulin doses were comparable between the G+MET (68 ± 5.7 U/day) and NPH+MET (71 ± 6.2 U/day) groups (p = 0.68). Before insulin therapy, circulating IGF-I bioactivity was similar between the G+MET (134 ± 9 pmol/l) and NPH+MET (135 ± 10 pmol/l) groups (p = 0.83). After 36 weeks, IGF-I bioactivity had decreased significantly (p = 0.001) and did not differ between the G+MET (116 ± 9 pmol/l) and NPH+MET (117 ± 10 pmol/l) groups (p = 0.91). At baseline and after insulin therapy, total IGF-I concentrations were comparable in both groups (baseline: G+MET 13.3 ± 1.0 vs NPH+MET 13.3 ± 1.0 nmol/l, p = 0.97; and 36 weeks: 13.4 ± 1.0 vs 13.1 ± 0.9 nmol/l, p = 0.71). Total IGF-I concentration did not change during insulin therapy (13.3 ± 0.7 vs 13.3 ± 0.7 nmol/l, baseline vs 36 weeks, p = 0.86). CONCLUSIONS/INTERPRETATION: Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases serum IGF-I bioactivity in a similar manner.

Bioactive rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients.

BACKGROUND: Inadequate food intake plays an important role in the development of malnutrition in continuous ambulatory peritoneal dialysis (CAPD) patients. Aim of the study. The aim of the study was to investigate in CAPD patients whether circulating insulin-like growth factor-I (IGF-I) bioactivity may offer a more sensitive index to acute nutritional interventions than total IGF-I. METHODS: An open-label, randomized, crossover study of 2 days-with a 1-week interval-was performed in 12 CAPD patients in the fed state to compare a mixture of amino acids (Nutrineal 1.1%) plus glucose (AA plus G) (Physioneal 1.36% to 3.86%) dialysate versus G only as control dialysate. Fed-state conditions were created by identical liquid hourly meals. IGF-I bioactivity was measured by the kinase receptor activation assay (IGF-I KIRA); total IGF-I was measured by immunoassay. RESULTS: In the fed state, both after AA plus G as well as after G dialysis IGF-I bioactivity increased compared to baseline, while no changes in circulating total IGF-I levels were observed in both treatment arms. However, the increase in IGF-I bioactivity was only significant after AA plus G dialysis (P = 0.02). CONCLUSIONS: Our results provide evidence that in CAPD patients changes in circulating IGF-I bioactivity are associated with nutrient intake and that IGF-I bioactivity rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients.

Advantages and disadvantages of GH/IGF-I combination treatment.

Growth hormone (GH) is the primary regulator of insulin-like growth factor-I (IGF-I) production in a wide variety of tissues. There is much overlap in the endocrine, metabolic and anabolic effects of GH and IGF-I but both hormones have divergent effects on glucose metabolism, insulin sensitivity and differentiation of prechondrocytes. Theoretically combined administration of GH and IGF-I may be more effective than GH alone or IGF-I alone. Arguments in favor for this are: 1] Clearance of IGF-I may be markedly altered by the co-administration of GH and this will provide sustained actions of IGF-I. 2] Higher serum IGF-I levels are achieved with a combination treatment of GH and IGF-I than with GH treatment alone or IGF-I alone. In addition, combination therapy may have additive or synergistic effects. 3] The combination GH and IGF-I counteracts disadvantageous effects on glucose metabolism of either GH alone or IGF-I alone. 4] GH may exert direct actions on tissues independently from IGF-I. 5] Combination of GH and IGF-I may be more effective in improving tissue IGF-I levels. The combination therapy of GH and IGF-I might be beneficial in growth retardation, in certain specific subgroups of critically ill or catabolic patients and in the treatment of GH-deficient subjects with the metabolic syndrome and/or manifest diabetes. It is at present unknown whether an optimal balance between safety and efficacy can be achieved with the combination therapy of GH and IGF-I, since this combination has been evaluated in only a small number of patient populations and in studies of a relatively short duration. In addition, a disadvantage may be the financial costs of combination therapy of GH and IGF-I. In conclusion, there are many reasons for believing that administration of the combination therapy of GH and IGF-I could have advantages above GH alone or IGF-I alone. However, determination of whether co-administration of GH and IGF-I indeed is superior to either agent alone awaits further study.

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

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

Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant.

OBJECTIVE: The objective of the study was to assess whether weekly administration of 40 mg pegvisomant (PEG-V) improves quality of life (QoL) and metabolic parameters in acromegalic patients with normal age-adjusted IGF-I concentrations during long-acting somatostatin analog (SSA) treatment. DESIGN: This was a prospective, investigator-initiated, double blind, placebo-controlled, crossover study. Twenty acromegalic subjects received either PEG-V or placebo for two consecutive treatment periods of 16 wk, separated by a washout period of 4 wk. Efficacy was assessed as change between baseline and end of each treatment period. QoL was assessed by the Acromegaly Quality of Life Questionnaire (AcroQoL) and the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ). RESULTS: The AcroQoL (P = 0.008) and AcroQoL physical (P = 0.002) improved significantly after PEG-V was added. The addition of PEG-V also significantly improved the PASQ (P = 0.038) and the single PASQ questions, perspiration (P = 0.024), soft tissue swelling (P = 0.036), and overall health status (P = 0.035). No significant change in Z-score of IGF-I (P = 0.34) was observed during addition of PEG-V. Transient liver enzyme elevations were observed in five subjects (25%). CONCLUSION: Improvement in quality of life was observed without significant change in IGF-I after the addition of 40 mg pegvisomant weekly to monthly SSA therapy in acromegalic patients who had normalized IGF-I on SSA monotherapy. These data question the current recommendations in how to assess disease activity in acromegaly. Moreover, the findings question the validity of the current approach of medical treatment in which pegvisomant is used only when SSA therapy has failed to normalize IGF-I.

IGF-1 CA repeat variant and breast cancer risk in postmenopausal women.

IGF-I is an important growth factor for the mammary gland. We evaluated the relationship of the IGF-I CA(n) polymorphism with breast cancer risk in Caucasian postmenopausal women and performed a meta-analysis of published data. The IGF-I CA(n) polymorphism was genotyped in 4091 from the Rotterdam Study. A disease-free survival analysis was performed along with a meta-analysis of all available data on IGF-I CA(n) polymorphism and breast cancer risk. During follow-up 159 women were diagnosed with breast cancer. The disease-free survival analysis adjusted for age at entry, age at menopause, body mass index and waist hip ratio yielded a HR=0.97 (95% CI=0.59-1.58) for CA(19) non-carriers against carriers. The meta-analysis using the random-effects model gave a pooled OR of 1.26 (95% CI=0.95-1.82) for IGF-I CA(19) non-carriers versus CA(19) homozygous carriers. According to these results, the IGF-I CA(19) promoter polymorphism is not likely to predict the risk of breast cancer.

Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly.

Pegvisomant monotherapy once daily returns concentrations of insulin-like growth factor I (IGF-I) to normal in most patients with acromegaly, but is very costly. In a 42-week dose-finding study, we assessed the efficacy of the combination of long-acting somatostatin analogues once monthly and pegvisomant once weekly in 26 patients with active acromegaly. Dose of pegvisomant was increased until IGF-I concentration became normal or until a weekly dose of 80 mg was reached. IGF-I reached normal concentrations in 18 of 19 (95%) patients who completed 42 weeks of treatment, with a median weekly dose of 60 mg pegvisomant (range 40-80). No signs of pituitary tumour growth were noted, but mild increases in liver enzymes were observed in ten patients (38%). This combined treatment is effective, might increase compliance, and could greatly reduce the costs of medical treatment for acromegaly in some patients.

An insulin-like growth factor-I gene polymorphism modifies the risk of microalbuminuria in subjects with an abnormal glucose tolerance.

OBJECTIVE: Microalbuminuria (MA) is related to cardiovascular disease both in diabetic patients and non-diabetic subjects. DESIGN: We investigated whether a polymorphism near the promoter region of the IGF-I gene was related to the development of MA. METHODS: For this study, 1069 participants of the Rotterdam study were selected (440 participants with an abnormal glucose tolerance (AGT), 220 participants with type 2 diabetes and 254 subjects with pre-diabetes, and 595 subjects with a normal glucose tolerance (NGT). RESULTS: 787 subjects were carriers of the wild type IGF-I genotype (73.6%) and 282 subjects were variant carriers (26.4%) of this IGF-I gene polymorphism. Compared to subjects with NGT the risk for microalbuminuria was higher (Odds Ratio (OR): 3.1 (95% CI: 1.2-7.7); P = 0.02) in variant carriers with AGT than in carriers of the wild type of this IGF-I gene polymorphism (OR: 2.2 (95% CI: 1.2-4.0); P = 0.009). Compared with wild type carriers with AGT, the relative risk for MA was unadjusted and non-significantly increased in variant carriers with AGT (1.6; 95% CI: 0.8-2.9). However, after adjustment for possible confounding factors (age, gender, mean blood pressure, fasting insulin, fasting glucose and smoking) this risk became significant (OR: RR 2.1; 95% CI:1.1-4.4; P = 0.04). CONCLUSIONS: In subjects with AGT, a higher risk for MA was observed in variant carriers than in carriers of the wild type genotype of this IGF-I gene polymorphism. Since MA is primarily associated with cardiovascular disease in subjects with AGT, our study suggests that variant carriers have a higher risk for cardiovascular disease than carriers of the wild type when they develop an AGT.

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas.

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.

What is the efficacy of switching to weekly pegvisomant in acromegaly patients well controlled on combination therapy?

CONTEXT: Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients' comfort, but the efficacy is unknown. OBJECTIVE: To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV. DESIGN: Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly. SUBJECTS AND METHODS: The study included 15 subjects (eight males), with a median age of 58 years (range 35-80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels. RESULTS: After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30-0.84) to 0.83 × ULN (0.30-1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30-80) mg to 80 (50-120) mg. CONCLUSION: Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.

Postoperative evaluation of patients with acromegaly: clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor I, acid-labile subunit, and growth hormone-binding protein levels.

CONTEXT: It is not exactly known when patients with acromegaly should be evaluated for cure after transsphenoidal adenomectomy (TA). OBJECTIVE: The objective of this study was to define the optimal time point of postoperative evaluation by serial measurements of glucose-suppressed GH levels [oral glucose tolerance test (OGTT)] and the GH-dependent parameters IGF-I, free IGF-I, acid labile subunit (ALS), and GH-binding protein (GHBP). DESIGN: We describe a prospective study with 1-yr follow-up. SETTING: The study was conducted at a university hospital. PATIENTS: Seventeen patients with acromegaly were included in the study. MAIN OUTCOME MEASURES: The main outcome measures were OGTT results at 1, 2, 3, 8, and 12 wk after TA; weekly measured GH, (free) IGF-I, ALS, and GHBP levels up to 12 wk; and total IGF-I levels measured at 52 wk. RESULTS: Postoperatively, nine patients were in remission with an OGTT GH nadir of less than 0.5 microg/liter and normalized IGF-I levels, whereas eight patients had persistent acromegaly. In both cured and noncured patients, OGTT results at 1 wk after TA were highly reproducible over time. In contrast, early postoperative IGF-I levels fluctuated and only stabilized at 12 wk. In all cured patients, free IGF-I levels rapidly normalized within 2 wk after TA (specificity, 100%). Preoperative ALS levels were elevated in all patients and normalized only in the cured patients after TA (specificity, 89%). Preoperative GHBP levels were low and increased from 2 wk after surgery. CONCLUSIONS: We show that in the postoperative evaluation of patients with acromegaly, already 1 wk after surgery, an OGTT using 0.5 microg as the GH nadir cutoff value has a high predictive value for cure, whereas early IGF-I levels show varying patterns toward stabilization. Therefore, IGF-I should be measured as a predictive parameter not within 3 months after surgery. Free IGF-I and ALS levels may have an additional value in the postoperative assessment of disease activity.

The introduction of the IDS-iSYS total IGF-1 assay may have far-reaching consequences for diagnosis and treatment of GH deficiency.

CONTEXT: IGF-1 measurements are used for screening and monitoring GH deficiency (GHD) and acromegaly. OBJECTIVE: Our objective was to study whether the introduction of the IDS-iSYS IGF-1 assay would lead to different clinical interpretations in GHD and acromegaly. DESIGN: In 106 GHD subjects and in 15 acromegalic subjects visiting our university hospital, total IGF-1 levels were measured before and during therapy by using the Immulite (IM) assay and IDS-iSYS (ID) assay. Z-scores were calculated by using assay-specific age-specific normative range values. All treatment decisions were based upon results obtained by the IM assay. RESULTS: In GHD subjects, absolute IGF-1 concentrations differed significantly between both IGF-1 assays before treatment (P < .001) but not during GH treatment (P = .32), and mean Z-scores for IGF-1 differed significantly before starting (IM, -2.23, vs ID, -1.43; P < .001) and during GH treatment (IM, -0.60, vs ID, +0.21; P < .001). In acromegalic subjects, absolute IGF-1 concentrations did not differ between both IGF-1 assays before treatment (P = .18) but were significantly different during treatment (P = 0.009), and mean Z-scores for IGF-1 were not different before starting (IM, 10.93, vs ID, 10.78; P = .41) or during treatment (IM, 3.60, vs ID, 3.18; P = .23). CONCLUSIONS: In GHD subjects, mean IGF-1 Z-scores significantly differed when measured by the IM assay compared with the ID assay irrespective of treatment. In contrast, in acromegaly, mean IGF-1 Z-scores did not differ significantly between both assays. Our study suggests that replacement of the IM assay by the ID assay may have far-reaching consequences for the clinical diagnosis and treatment of GHD.

Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension.

BACKGROUND AND PURPOSE: Low circulating levels of insulin-like growth factor I (IGF-I) have been associated with an increased risk for atherosclerosis. Absence of the 192-bp (wild-type) allele in the promoter region of the IGF-I gene has been associated with low circulating IGF-I levels. We examined the role of this polymorphism in relation to blood pressure and 2 early markers of atherosclerosis: carotid intima-media thickness (IMT) and aortic pulse wave velocity (PWV). METHODS: A total of 5132 subjects of the Rotterdam Study, aged 55 to 75 years, were included in this study. In 3769 subjects who did not use blood pressure-lowering medication, the association between the IGF-I polymorphism and blood pressure was examined. In the total population, and in 3484 normotensive subjects, 1648 hypertensive and 462 untreated hypertensive subjects, the association between this polymorphism and IMT and PWV was examined. RESULTS: Mean systolic and diastolic blood pressure did not differ between genotypes. In hypertensive subjects IMT was significantly increased in noncarriers of the 192-bp allele (0.83 mm) compared with heterozygous or homozygous carriers (0.80 mm) (P=0.04). PWV was also significantly higher in hypertensive subjects who were noncarriers of the 192-bp allele (14.3 m/s) compared with heterozygous (14.1 m/s) or homozygous carriers (13.7 m/s) (P=0.02). Findings were more pronounced in hypertensive subjects without medication use. In normotensive subjects, no association between this polymorphism, IMT, and PWV was observed. CONCLUSIONS: Our study suggests that hypertensive subjects who have low IGF-I levels because of a genetic polymorphism in the IGF-I gene are at increased risk of developing atherosclerosis.

Circulating free insulin-like growth factor (IGF)-I, total IGF-I, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval.

Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels. To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area. At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer. Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores. Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer.

Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity.

We investigated the metabolic actions of ghrelin in humans by examining the effects of acute administration of acylated ghrelin, unacylated ghrelin, and the combination in eight adult-onset GH-deficient patients. We followed glucose, insulin, and free fatty acid concentrations before and after lunch and with or without the presence of GH in the circulation. We found that acylated ghrelin, which is rapidly cleared from the circulation, induced a rapid rise in glucose and insulin levels. Unacylated ghrelin, however, prevented the acylated ghrelin-induced rise in insulin and glucose when it was coadministered with acylated ghrelin. Surprisingly, the injection of acylated ghrelin induced an acute increase in unacylated ghrelin and therefore total ghrelin levels. Finally, acylated ghrelin decreased insulin sensitivity up to the end of a period of 6 h after administration. This decrease in insulin sensitivity was prevented by coinjection of unacylated ghrelin. This combined administration of acylated and unacylated ghrelin even significantly improved insulin sensitivity, compared with placebo, for at least 6 h, which warrants studies to investigate the long-term efficacy of this combination in the treatment of disorders with disturbed insulin sensitivity.

Acute stress response in children with meningococcal sepsis: important differences in the growth hormone/insulin-like growth factor I axis between nonsurvivors and survivors.

Septic shock is the most severe clinical manifestation of meningococcal disease and is predominantly seen in children under 5 yr of age. Very limited research has been performed to elucidate the alterations of the GH/IGF-I axis in critically ill children. We evaluated the GH/IGF-I axis and the levels of IGF-binding proteins (IGFBPs), IGFBP-3 protease, glucose, insulin, and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 d after admission. The median age was 22 months (range, 4-185 months). Eight patients died. Nonsurvivors had extremely high GH levels that were significant different compared with mean GH levels in survivors during a 6-h GH profile (131 vs. 7 mU/liter; P < 0.01). Significant differences were found between nonsurvivors and survivors for the levels of total IGF-I (2.6 vs. 5.6 nmol/liter), free IGF-I (0.003 vs. 0.012 nmol/liter), IGFBP-1 (44.3 vs. 8.9 nmol/liter), IGFBP-3 protease activity (61 vs. 32%), IL-6 (1200 vs. 50 ng/ml), and TNFalpha (34 vs. 5.3 pg/ml; P < 0.01). The pediatric risk of mortality score correlated significantly with levels of IGFBP-1, IGFBP-3 protease activity, IL-6, and TNFalpha (r = +0.45 to +0.69) and with levels of total IGF-I and free IGF-I (r = -0.44 and -0.55, respectively). Follow-up after 48 h in survivors showed an increased number of GH peaks, increased free IGF-I and IGFBP-3 levels, and lower IGFBP-1 levels compared with admission values. GH levels and IGFBP-1 levels were extremely elevated in nonsurvivors, whereas total and free IGF-I levels were markedly decreased and were accompanied by high levels of the cytokines IL-6 and TNFalpha. These values were different from those for the survivors. Based on these findings and literature data a hypothetical model was constructed summarizing our current knowledge and understanding of the various mechanisms.

The role of IGF-I in the development of cardiovascular disease in type 2 diabetes mellitus: is prevention possible?

The incidence of peripheral, cerebro- and cardiovascular disease (CVD) in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population. Conventional cardiovascular risk factors such as plasma lipids, lipoproteins and hypertension only partially explain this excessive risk of developing atherosclerosis and CVD. Meta-analysis of studies performed in non-diabetic populations indicates that the risk of CVD increases continuously with glucose levels above 4.2 mmol/l. The glucose hypothesis suggests that treatment which normalizes glucose levels prevents or delays the long-term complications of diabetes mellitus. However, the outcome of the UK Prospective Diabetes Study demonstrates that glucose control does not completely prevent CVD.In healthy subjects, serum IGF-I levels peak in early adulthood, after which they gradually decrease with increasing age. Several observations suggest that there is a premature and progressive age-related decline in serum IGF-I bioactivity in type 2 diabetics, which eventually results in a (relative) IGF-I deficiency. In type 2 diabetics, close relationships have been demonstrated between glycaemic control and serum IGF-I levels, with worse control being associated with lower IGF-I levels. Several studies (in non-diabetics) suggest that lowered circulating IGF-I levels account for a poor outcome of CVD. We previously observed in a population-based study that a genetically determined lowered IGF-I expression increases the risk of myocardial infarction with type 2 diabetes. This genetic approach overcomes the problem that cross-sectional studies cannot distinguish whether changes in IGF-I levels are a cause or a consequence of a disease. IGF-I is an important metabolic regulatory hormone. In addition, IGF-I suppresses myocardial apoptosis and improves myocardial function in various models of experimental cardiomyopathy. Compared with other growth factors, the 'survival' effect of IGF-I on myocardium seems rather unique.Therefore, we hypothesize that the premature and progressive decline in serum IGF-I bioactivity in ageing patients with type 2 diabetics is an important pathophysiological abnormality. It contributes not only to elevated glucose and lipid levels, but also to the progression and the poor outcome of CVD. If this hypothesis is proven to be right, treatment with IGF-I as an adjunct to insulin offers great potential and might not only improve metabolic control but also reduce the incidence and prevalence of CVD in type 2 diabetes patients. However, there is as yet no experimental evidence that long-term (replacement) treatment with IGF-I prevents, delays or reduces CVD in type 2 diabetes patients. Clinical trials are necessary to prove that long-term IGF-I treatment, preferably in the form of a better-tolerated IGF-I/IGF-binding protein-3 complex, improves the overall cardiovascular risk in type 2 diabetes.

[Still no indications that the treatment of growth hormone deficient adults with growth hormones is unsafe]. / Vooralsnog geen aanwijzingen voor onveiligheid van de behandeling met groeihormoon van volwassen patiënten met groeihormoondeficiëntie.

Although more than 100,000 patients worldwide are estimated to have received growth-hormone treatment, there are still widespread doubts about the safety aspects of growth-hormone treatment of adults with growth-hormone deficiency (GHD). The available data are scarce and the follow-up time is short. The data do not suggest that growth-hormone treatment increases the incidence or regrowth of pituitary adenomas in adults with GHD. Equally there are no data which suggest that growth-hormone treatment of adults with GHD increases the incidence of cancer, provided that concentrations of the insulin-like growth factor I (IGF-I) achieved in the blood remain within the normal range for the age of that patient. No increase in diabetes mellitus has been reported following the introduction of growth-hormone treatment in adult GHD patients. Insulin sensitivity does not appear to change in GHD patients on growth-hormone treatment as long as relatively low physiological doses of growth hormone are used. Whether growth-hormone therapy in adult patients with GHD will prove safe in the long term remains to be established.