Joseph A M J L Janssen

Serum total IGF-I, free IGF-I, and IGFBP-1 levels in an elderly population - Relation to cardiovascular risk factors and disease

Recently, a method to measure free insulin-like growth factor-I (IGF-I) levels has been developed. Free IGF-I levels may have greater physiological and clinical relevance than total (bound and free) IGF-I. The associations between the circulating IGF-I/IGF binding protein (IGFBP) system and cardiovascular disorders was studied. In a cross-sectional study of 218 healthy persons (103 men, 115 women) aged 55 to 80 years, fasting serum (total and free) IGF-I and IGFBP-1 levels, lipid profile, insulin, and glucose were measured. In addition, blood pressure, body mass index (BMI), and waist-hip ratio (WHR) were measured. Ultrasonography of both carotid arteries was performed to investigate the presence of atherosclerotic lesions. A history of angina pectoris, the presence of a possible or definite myocardial infarction on the ECG, and plaques in the carotid arteries were used as indicators of presence of cardiovascular signs and symptoms. Free IGF-I was inversely related to serum triglycerides (P=.04, adjusted for age and sex). Mean free IGF-I levels in subjects without signs or symptoms of cardiovascular diseases were significantly higher than in those with at least one cardiovascular symptom or sign (P=.002, adjusted for age and sex). Free IGF-I levels were also higher in subjects who had no atherosclerotic plaques in the carotid arteries (P=.02, adjusted for age and sex) and who had never smoked (P=.02, adjusted for age and sex). IGFBP-1 showed an inverse relation with insulin, BMI, and WHR and a positive relation with HDL cholesterol. The associations between IGFBP-1 levels and HDL cholesterol, WHR, and BMI remained significant after adjustment for fasting insulin levels. High fasting serum free IGF-I levels are associated with a decreased presence of atherosclerotic plaques and coronary artery disease and lower serum triglycerides, whereas high fasting IGFBP-1 levels are associated with a more favorable cardiovascular risk profile. The findings suggest that the IGF-I/IGFBP system is related to cardiovascular risk factors and atherosclerosis.

High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control: The Rotterdam Study

OBJECTIVE Individuals with type 2 diabetes have increased fracture risk despite higher bone mineral density (BMD). Our aim was to examine the influence of glucose control on skeletal complications. RESEARCH DESIGN AND METHODS Data of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA1c <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA1c ≥7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]). RESULTS The ICD group had 1.1–5.6% higher BMD, 4.6–5.6% thicker cortices, and −1.2 to −1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47–62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12–1.92]) and ACD (1.62 [1.09–2.40]), whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67–1.23]). CONCLUSIONS Poor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently “strong” bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.

A polymorphic CA repeat in the IGF-I gene is associated with gender-specific differences in body height, but has no effect on the secular trend in body height.

objective  A polymorphism near the promoter region of the IGF‐I gene has been associated with serum IGF‐I levels, age‐related decline of serum IGF‐I levels, body height, birth weight and intima media thickness in hypertensive subjects.

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.

Normal Values of Circulating Insulin-Like Growth Factor-I Bioactivity in the Healthy Population: Comparison with Five Widely Used IGF-I Immunoassays

BACKGROUND IGF-I immunoassays are primarily used to estimate IGF-I bioactivity. Recently an IGF-I-specific kinase receptor activation assay (KIRA) has been developed as an alternative method. However, no normative values have been established for the IGF-I KIRA. OBJECTIVE The objective of the study was to establish normative values for the IGF-I KIRA in healthy adults. DESIGN This was a cross-sectional study in healthy nonfasting blood donors. STUDY PARTICIPANTS Participants included 426 healthy individuals (310 males, 116 females; age range 18-79 yr). MAIN OUTCOME MEASURES IGF-I bioactivity determined by the KIRA was measured. Results were compared with total IGF-I, measured by five different IGF-I immunoassays. RESULTS Mean (+/- sd) IGF-I bioactivity was 423 (+/- 131) pmol/liter and decreased with age (beta = -3.4 pmol/liter.yr, P < 0.001). In subjects younger than 55 yr, mean IGF-I bioactivity was significantly higher in women than men. Above this age this relationship was inverse, suggesting a drop in IGF-I bioactivity after menopause. This drop was not reflected in total IGF-I levels. IGF-I bioactivity was significantly related to total IGF-I (r(s) varied between 0.46 and 0.52; P < 0.001). CONCLUSIONS We established age-specific normative values for the IGF-I KIRA. We observed a significant drop in IGF-I bioactivity in women between 50 and 60 yr, which was not perceived by IGF-I immunoassays. The IGF-I KIRA, when compared with IGF-I immunoassays, theoretically has the advantage that it measures net effects of IGF-binding proteins on IGF-I receptor activation. However, it has to be proven whether information obtained by the IGF-I KIRA is clinically more relevant than measurements obtained by IGF-I immunoassays.

Insulin and its analogues and their affinities for the IGF1 receptor

Insulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control. However, structural modification of the insulin molecule may result in altered binding affinities and activities to the IGF1 receptor (IGF1R). As a consequence, insulin analogues may theoretically have an increased mitogenic action compared to human insulin. In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. This hypothesis has been evaluated extensively in vitro and also in vivo by using animal models. In vitro, all at present commercially available insulin analogues have lower affinities for the insulin receptor (IR). Although it has been suggested that especially insulin analogues with an increased affinity for the IGF1R (such as insulin glargine) are more mitogenic when tested in vitro in cells expressing a high proportion of IGF1R, the question remains whether this has any clinical consequences. At present, there are several uncertainties which make it very difficult to answer this question decisively. In addition, recent data suggest that insulin (or insulin analogues)-mediated stimulation of IRs may play a key role in the progression of human cancer. More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis.

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.

The IGSF1 Deficiency Syndrome: Characteristics of Male and Female Patients

CONTEXT Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. OBJECTIVE Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes. METHODS All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. RESULTS Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. CONCLUSION In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

IGFBP‐3 is a poor parameter for assessment of clinical activity in acromegaly

OBJECTIVE Elevated serum IGF‐I and IGF binding protein‐3 (IGFBP‐3) levels have been found in patients with active acromegaly. We have studied the relative diagnostic merits of measurements of IGFBP‐3 compared with IGF‐I as a parameter of disease activity in these patients.

IGF-I Bioactivity in an Elderly Population: Relation to Insulin Sensitivity, Insulin Levels, and the Metabolic Syndrome

OBJECTIVE There is a complex relationship between IGF-I, IGF binding proteins, growth hormone, and insulin. The IGF-I kinase receptor activation assay (KIRA) is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of IGF-I bioactivity might broaden our understanding of the IGF-I system in subjects with the metabolic syndrome. The purpose of our study was to investigate whether IGF-I bioactivity was related to insulin sensitivity and the metabolic syndrome. RESEARCH DESIGN AND METHODS We conducted a cross-sectional study embedded in a random sample (1,036 elderly subjects) of a prospective population-based cohort study. IGF-I bioactivity was determined by the IGF-I KIRA. Categories of glucose (in)tolerance were defined by the 2003 American Diabetes Association criteria. Insulin sensitivity was assessed by homeostasis model assessment. The Adult Treatment Panel III definition of the metabolic syndrome was used. RESULTS In subjects with normal fasting glucose and impaired fasting glucose, IGF-I bioactivity progressively increased with increasing insulin resistance, peaked at fasting glucose levels just below 7.0 mmol/l, and dropped at higher glucose levels. Mean IGF-I bioactivity peaked when three criteria of the metabolic syndrome were present and then declined significantly when five criteria of the metabolic syndrome were present. CONCLUSIONS We observed that IGF-I bioactivity was related to insulin sensitivity, insulin levels, and the metabolic syndrome. Our study suggests that there exists an inverse U-shaped relationship between IGF-I bioactivity and number of components of the metabolic syndrome. This observation contrasts with previous results reporting an inverse relationship between total IGF-I and components of the metabolic syndrome.