OBJECTIVES AND DESIGN: Ghrelin is a novel 28 amino acid peptide which is reported to have several endocrine and non-endocrine actions. It possesses strong growth hormone (GH)-releasing activity, which is mediated via the GH secretagogue receptor type 1a (GHS-R1a). We hypothesised that there might be functional sequential variations in the GHS-R1a gene affecting phenotypes linked to the GH/insulin-like growth factor-I (IGF-I)-axis. METHODS: To test our hypothesis we chose patients from our OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study with low (n=96) and high (n=96) IGF-I levels, sequenced their GHS-R1a gene exons and performed association studies. RESULTS: We found five single-nucleotide polymorphisms (SNPs) which did not change the amino acid sequence. We were unable to detect associations between the SNPs and the IGF-I plasma concentrations, but instead we showed that SNP 171C>T was associated with the values of the area under the insulin curve (AUCIN) in an oral glucose tolerance test and with IGF-binding protein-1 (IGFBP-1) concentrations (P<0.05). SNP 477G>A was associated with the low density lipoprotein and very low density lipoprotein cholesterol plasma levels and AUCIN values (P<0.05). CONCLUSIONS: This study was the first genomic screening of the GHS-R1a gene in a population. It suggests that genetic variations in the GHS-R1a gene are not the main regulators of IGF-I levels. However, the variants may be associated with IGFBP-1 concentrations and insulin metabolism.
J Vartiainen, SM Poykko, T Raisanen, YA Kesaniemi and O Ukkola
B.-A. Lamberg, V. Kivikangas, J. Vartiainen, C. Raitta and R. Pelkonen
Thirty-one patients who had been treated for acromegaly for 1–21 years with conventional pituitary irradiation were re-examined. Immunoreactive growth hormone (GH) was measured in connection with an oral glucose load. Adrenal and gonadal functions were assessed on the basis of plasma cortisol and the urinary excretion of 17-ketogenic steroids, 17-ketosteroids and gonadotrophins. In evaluating the thyroid-pituitary axis the thyrotrophin-relcasing hormone stimulation test (TRH) was used.
Initially 30 patients had experienced definite benefit from the treatment but at the time of re-examination 10 still had clinically active disease and required another type of treatment. Normal GH levels (<5 ng/ml/1) were seen in only 12 patients. Skin thickness was normal in 15 out of 30. Thus the remission rate can be evaluated as being 67 % as regards clinical activity, 50 % with regard to skin thickness and 39 % in terms of GH levels.
Hypogonadism occurred in 12 patients (39 %) and adrenal and thyroid failure in 5 patients each (16%). The response to TRH was within the normal range in 2 of the hypothyroid patients. In 22 euthyroid patients the mean increment in serum TSH in response to 200 μg of synthetic TRH was only 5.8 mU/1 which was significantly below the normal mean 12.5 mU/1. Furthermore, in 7 of these patients (32 %) the response was absent or subnormal (<3.0 mU/1). This indicated that the pituitary is
capable of secreting enough TSH for maintenance of an euthyroid state but that its capacity is limited.
Conventional pituitary irradiation is not a very effective treatment in acromegaly but may still be recommended in selected cases.
A Majuri, M Santaniemi, K Rautio, A Kunnari, J Vartiainen, A Ruokonen, Y A Kesäniemi, J S Tapanainen, O Ukkola and L Morin-Papunen
Objective: Abdominal obesity, insulin resistance and compensatory hyperinsulinaemia play a central role in the pathogenesis of the polycystic ovary syndrome (PCOS). Abdominal adipose tissue is a source of adipokines, such as adiponectin and resistin, both of which may be involved in the development of insulin resistance and chronic inflammation in PCOS. Ghrelin, an important regulatory peptide of food intake, may also play a role in metabolic disturbances related to PCOS.
The aim of this study was to examine the effects of 4 months of treatment with the insulin sensitizer rosiglitazone on plasma adiponectin, resistin and ghrelin levels in overweight women with PCOS. Design: A randomised placebo-controlled study.
Methods: Thirty overweight/obese women with PCOS (body mass index>25 kg/m2, mean age 29.1± 1.2 (s.e.m.) years) were randomly allocated to either rosiglitazone (Avandia, 4 mg twice a day) or placebo treatment. Plasma levels of adiponectin, resistin and ghrelin and their correlation to serum levels of insulin, C-peptide and steroid hormones, and insulin sensitivity (euglycaemic hyperinsulinaemic clamp) were assessed.
Results: Adiponectin and ghrelin levels correlated significantly with most metabolic markers of insulin resistance and with serum levels of DHEA and 17-hydroxyprogesterone. Plasma levels of adiponectin increased from 9.26±0.90 (s.e.m.) to 22.22±3.66 μg/ml (P<0.001) and those of resistin decreased from 12.57±1.63 to 9.21±0.53 ng/ml (P=0.009) at 4 months of treatment, but plasma ghrelin levels did not change.
Conclusions: Rosiglitazone had beneficial effects on serum levels of adiponectin and resistin, suggesting that these adipocytokines may contribute to the improvement in insulin sensitivity observed during the treatment.