No abstract

Objective: Ghrelin stimulates growth hormone (GH) secretion both in vivo and in vitro. Ghrelin is mainly produced in and released from the stomach but it is probably also produced in the hypothalamic arcuate nucleus. Whether pituitary GH release is under the control of ghrelin from the stomach and/or from the arcuate nucleus is not known. Moreover, no data on the feedback of GH on systemic ghrelin concentrations are available. It has recently been suggested that ghrelin may induce obesity. Design: In this study, we addressed the following two questions: a) are circulating ghrelin levels increased in human GH deficiency (GHD), and b) does GH treatment modify ghrelin levels in human GHD? Methods: The study group consisted of 23 patients with GHD. Eighteen had developed adult-onset GHD and five had developed GHD in their childhood (childhood-onset GHD). Ghrelin was measured with a commercially available radioimmunoassay. All measurements were performed twice, first at baseline, before the start of GH replacement therapy, and then again after one year of therapy. GH doses were adjusted every 3 months, targeting serum total IGF-I levels within the normal gender-and age-related reference values for the healthy population. Maintenance doses were continued once the target serum total IGF-I levels were reached. Results: The sum of skinfolds and body water increased significantly, body fat mass and percentage body fat decreased significantly and body mass index and waist-hip ratio were not significantly changed by one year of GH replacement therapy.Before the start of GH replacement therapy, mean value and range for fasting ghrelin in the studied GHD subjects tended to be lower in comparison with healthy subjects in the control group although the difference did not reach significance (GHD ghrelin mean 67.8 pmol/l, range 37.6-116.3 pmol/l; control mean 83.8 pmol/l, range 35.4 -132 pmol/l; P ¼ 0:11).One year of GH replacement therapy did not modify circulating ghrelin levels (ghrelin before GH therapy: 67.8 pmol/l, range after GH therapy: 65.3 pmol/l,; P ¼ 0:56). Conclusions: We did not observe elevated ghrelin levels in adult GHD subjects and GH replacement therapy did not modify circulating ghrelin levels, despite significant decreases in body fat mass and percentage body fat. It is conceivable that the lack of ghrelin modifications after long-term GH therapy was due to the reduction of adiposity and insulin on one hand, and increased GH secretion on the other. However, it is still possible that systemic ghrelin is involved in the development of obesity, both in normal and GHD subjects.

Objective: Recent studies have demonstrated an association between a 192 bp polymorphism of the IGF-I gene and total IGF-I serum levels, birth weight, body height and the risk of developing diabetes and cardiovascular diseases later on in life. This IGF-I gene polymorphism in the promoter region of the IGF-I gene may directly influence the expression of IGF-I. In the present study we evaluated the role of this polymorphism in the age-related decline in serum IGF-I levels. Subjects and methods: All subjects were participants of the Rotterdam Study, a population-based cohort study of diseases in the elderly. We studied a total group of 346 subjects, who comprised two subgroups: a randomly selected population-based sample of 196 subjects, and a group of 150 subjects selected on IGF-I genotype. In the total group of 346 individuals the relationship between this 192 bp polymorphism and the age-related decline in circulating total IGF-I levels was studied. Results: Homozygous carriers of the 192 bp allele demonstrated significant decline in serum IGF-I with age ðr ¼ 20:29; P ¼ 0:002Þ: This decline is similar to that seen in the general population. An agerelated decline in serum total IGF-I was not observed in heterozygotes ðr ¼ 20:06; P ¼ 0:48Þ and non-carriers (r = 20.12, P ¼ 0:32Þ: Interestingly, the relationship between age and serum IGF-binding protein-3 levels showed the same pattern. Conclusion: We observed only in homozygous carriers of the 192 bp alleles of the IGF-I gene an agerelated decline in circulating total IGF-I levels, but not in heterozygotes and non-carriers of the 192 bp allele. We hypothesize that this IGF-I gene polymorphism directly or indirectly influences GHmediated regulation of IGF-I secretion.

To estimate the prevalence of glucose intolerance in the elderly, oral glucose tolerance tests were performed as part of the Rotterdam Study, a population-based study in subjects aged 55 years and over. The study population consisted of 2,668 men and 3,950 women. Diabetes mellitus was defined as the use of antidiabetes medication, or a random or post-load serum glucose level of > or = 11.1 mmol/liter. Impaired glucose tolerance was defined as a post-load serum glucose between 7.8 and 11.1 mmol/liter. In men, the frequency of diabetes mellitus ranged from 5.9% in ages < 60 years to 19.8% in ages > 85 years, and in women from 3.8% in ages < 60 years to 18.9% in ages > 85 years; more than half of the subjects with diabetes were newly diagnosed. The prevalence of impaired glucose tolerance ranged from 8.8% and 11.0% in men and women aged < 60 years to 24.3% and 34.7% in men and women aged > 85 years. The prevalence of diabetes mellitus in the total Rotterdam Study population of 7,439 elderly men and women was estimated to be 11.3% (95% confidence interval (CI) 10.5-12.0). Waist/hip ratio, systolic blood pressure, hypertension, and number of cigarettes smoked increased with a worsening of the glucose tolerance from normal, hyperinsulinemia, impaired glucose tolerance to diabetes in both men and women (p < 0.01, adjusted for age). Body mass index was higher in subjects with glucose intolerance, but the frequency of obesity showed a relative decrease with worsening of glucose tolerance. These results show that glucose intolerance, especially impaired glucose tolerance and undetected diabetes mellitus, is common in the elderly. Moreover, not only subjects with diabetes mellitus but also subjects with hyperinsulinemia and impaired glucose tolerance have an increase of cardiovascular risk factors.

Normal as well as activated lymphocytes and macrophages have previously been shown by radioreceptor analysis to express somatostatin receptors (SS-R). The somatostatin (SS) analogue [111In-DTPA-D-Phe1]octreotide (111In-octreotide) is already used successfully in the visualization of a variety of neuro-endocrine tumours and malignant lymphomas. In the present study 20 consecutive patients were investigated, 12 with sarcoidosis, one with both sarcoidosis and aspergillosis, four with tuberculosis and three with Wegener's granulomatosis. For in vivo SS-R imaging, total-body scintigraphy was performed 24 and 48 h after the administration of 111In-octreotide. Granuloma localizations could be visualized in all patients studied; additional sites were found in nine patients with sarcoidosis and in two patients with tuberculosis. In vitro autoradiography of fresh tissue biopsies, using the SS analogue [125I-Tyr3]octreotide, showed binding at sites that were microscopically identified as granulomatous inflammation. These observations demonstrate the expression of SS-R by human granulomas. This scintigraphy procedure may contribute to a more precise staging and evaluation of granulomatous diseases, but more importantly it may be a sensitive indicator of the efficacy of glucocorticoid and/or immunosuppressive therapy.