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  • Author: O Ukkola x
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O Ukkola

The objective of this review is to summarize the current evidence of a novel adipocytokine, resistin. Resistin is a novel peptide hormone that belongs to a family of tIssue-specific resistin-like molecules originally named for its resistance to insulin. Although a seminal proposal by Steppan et al. suggested resistin to be a hormone that links obesity to diabetes, several studies have subsequently been published supporting the concept that insulin resistance and obesity are actually associated with a decreased resistin expression. Resistin expression is regulated by a variety of agents and hormones, including thiazolidinediones, insulin, tumor necrosis factor alpha and growth hormone. Studies about their role in the regulation of resistin expression are, however, inconsistent in many cases. Experiments in humans have shown no differences in resistin expression between normal, insulin-resistant or type 2 diabetic samples. However, some recent genetic studies have demonstrated an association between resistin and insulin resistance and obesity. In addition, regional variation in the expression of resistin mRNA and protein levels in humans is an interesting finding with the highest levels found in the abdominal depot. In conclusion, resistin is a fascinating new hormone for which a definite role in metabolism will be revealed in the near future.

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J Vartiainen, SM Poykko, T Raisanen, YA Kesaniemi and O Ukkola

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.

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O Ukkola, J Gagnon, T Rankinen, PA Thompson, Y Hong, AS Leon, DC Rao, JS Skinner, JH Wilmore and C Bouchard

OBJECTIVE AND METHODS: To investigate from the HERITAGE Family Study database, 13 steroid hormones (androstane-3alpha, 17beta-diol glucuronide, androsterone glucuronide, cortisol, dehydroepiandrosterone (DHEA), DHEA ester (DHEAE), DHEA sulfate (DHEAS), dihydrotestosterone (DHT), estradiol, 17-hydroxyprogesterone, progesterone, pregnenolone ester, sex hormone binding globulin (SHBG) and testosterone in each sex for their relationships with age, body mass index (BMI), race and key lifestyle variables. Sample sizes varied from 676 to 750 per hormone. Incremental regression methods were used to examine the contributions of the variables to steroid hormone variability. RESULTS: Age was a major predictor for most steroid hormones. The greatest contribution of age was a negative relationship with DHEAS (R(2)=0.39). BMI was also associated with the variability of several steroid hormones, being the most important predictor of SHBG (R(2)=0.20) and of testosterone (R(2)=0.12) concentrations. When age and BMI were included, race still contributed significantly to the variations in cortisol (R(2)=0.02 for men and 0.04 for women), DHT (R(2)=0.02 for men and 0.03 for women), and progesterone (R(2)=0.03 for women). Nevertheless, race appeared to be less important than age and BMI. In addition, lifestyle indicators (food and nutrient intakes, smoking and physical activity) influenced steroid hormone variability. Their contributions, however, were minor in most cases once age, BMI and race had been taken into account. CONCLUSIONS: We conclude that age was the most important factor, followed by BMI, race and lifestyle factors in explaining steroid hormone variability.

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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.