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Harald Jörn Schneider, Bernhard Saller, Jens Klotsche, Winfried März, Wolfgang Erwa, Hans-Ullrich Wittchen and Günter Karl Stalla

Objective: Insulin-like growth factor-I (IGF-I) has been suggested to be a prognostic marker for the development of cancer and, more recently, cardiovascular disease. These diseases are closely linked to obesity, but reports of the association of IGF-I with measures of obesity are divergent. In this study, we assessed the association of age-dependent IGF-I standard deviation scores with body mass index (BMI) and intra-abdominal fat accumulation in a large population.

Design: A cross-sectional, epidemiological study.

Methods: IGF-I levels were measured with an automated chemiluminescence assay system in 6282 patients from the DETECT study. Weight, height, and waist and hip circumference were measured according to the written instructions. Standard deviation scores (SDS), correcting IGF-I levels for age, were calculated and were used for further analyses.

Results: An inverse U-shaped association of IGF-I SDS with BMI, waist circumference, and the ratio of waist circumference to height was found. BMI was positively associated with IGF-I SDS in normal weight subjects, and negatively associated in obese subjects. The highest mean IGF-I SDS were seen at a BMI of 22.5–25 kg/m2 in men (+0.08), and at a BMI of 27.5–30 kg/m2 in women (+0.21). Multiple linear regression models, controlling for different diseases, medications and risk conditions, revealed a significant negative association of BMI with IGF-I SDS. BMI contributed most to the additional explained variance to the other health conditions.

Conclusions: IGF-I standard deviation scores are decreased in obesity and underweight subjects. These interactions should be taken into account when analyzing the association of IGF-I with diseases and risk conditions.

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Harald Jörn Schneider, Nele Friedrich, Jens Klotsche, Sabine Schipf, Matthias Nauck, Henry Völzke, Caroline Sievers, Lars Pieper, Winfried März, Hans-Ulrich Wittchen, Günter Karl Stalla and Henri Wallaschofski

Objective

IGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low- or high-IGF1 are at risk of diabetes. We hypothesized that both low- and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study.

Design

An analysis of two prospective cohort studies, the DETECT study and SHIP.

Methods

We measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up.

Results

There were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (P>0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age- and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07–1.94) and 1.55 (95% CI 1.06–2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline.

Conclusions

Subjects with low- or high-IGF1 level are at increased risk of developing diabetes.

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Ginevra Corneli, Carolina Di Somma, Flavia Prodam, Jaele Bellone, Simonetta Bellone, Valentina Gasco, Roberto Baldelli, Silvia Rovere, Harald Jörn Schneider, Luigi Gargantini, Roberto Gastaldi, Lucia Ghizzoni, Domenico Valle, Mariacarolina Salerno, Annamaria Colao, Gianni Bona, Ezio Ghigo, Mohamad Maghnie and Gianluca Aimaretti

Objective

To define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults.

Design and methods

We studied 152 patients with childhood-onset organic hypothalamic–pituitary disease (85 males, age (mean±s.e.m.): 19.2±0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7±0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2±0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2±0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2±0.2 years). Both patients and controls were lean (body mass index, BMI<25 kg/m2). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified.

Results

For the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 μg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 μg/l (SDS: −1.3). Assuming 19.0 μg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response <19 μg/l to the test, IGF-I levels were lower than 160 μg/l (or less than 1.3 SDS) in 68.7 and 41.6% of patients respectively predicting severe GHD in 85.7% of panhypopituitary patients (subgroup A).

Conclusions

In late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 μg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

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Harald Jörn Schneider, Jens Klotsche, Bernhard Saller, Steffen Böhler, Caroline Sievers, David Pittrow, Günther Ruf, Winfried März, Wolfang Erwa, Andreas M Zeiher, Sigmund Silber, Hendrik Lehnert, Hans-Ullrich Wittchen and Günter Karl Stalla

Objective

We aimed at investigating the association of age-dependent IGF-I SDS with diabetes, dyslipidemia, hypertension, and heart diseases, in a large patient sample.

Background

IGF-I has been suggested to be associated with several diseases and a prognostic marker for the development of cardiovascular diseases and risk factors. The findings, though, have been inconsistent possibly due to the methodological factors.

Methods

We studied 6773 consecutive primary care patients, aged 18+ years, in a cross-sectional, epidemiological study in primary care, Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment study. All patients underwent a standardized clinical diagnostic and laboratory assessment. IGF-I levels were measured with an automated chemiluminescence assay system. We calculated the odds ratios (OR) for diseases in quintiles of IGF-I, and additionally analyzed the association of age-dependent IGF-I SDS with these conditions.

Results

After multiple adjustments for confounders, we found increased ORs for coronary artery disease in patients with high IGF-I. Women, but not men, with low IGF-I also showed increased ORs for coronary artery disease. Dyslipidemia was positively associated with IGF-I. Type 2 diabetes showed a curvilinear association with IGF-I SDS.

Conclusions

The findings suggest the existence of multiple and complex interactions between IGF-I and several health conditions. The complex nature of disease- and subgroup-specific associations along with the methodological factors can be held responsible for divergent findings in previous studies.