Seppo M. Pöykkö

Ghrelin Arg51Gln mutation is a risk factor for Type 2 diabetes and hypertension in a random sample of middle-aged subjects

Aims/hypothesisExperimental studies have suggested that ghrelin, a novel gastrointestinal peptide hormone, could play a role in glucose homeostasis. In addition, ghrelin has been associated with beneficial haemodynamic effects in experimental settings. Since the Arg51Gln mutation changes the carboxyterminal amino acid of the mature hormone and is associated with low ghrelin concentrations, we assessed the hypothesis that Arg51Gln mutation is a risk factor for Type 2 diabetes, impaired glucose tolerance, and hypertension.MethodsBlood pressure recordings and oral glucose tolerance test were carried out in the hypertensive (n=519) and control cohorts (n=526) of our well-defined OPERA study. The genotypes and plasma IGF-I and IGFBP-1 concentrations of 1031 subjects were analysed.ResultsThe ghrelin 51Gln allele was a risk factor for Type 2 diabetes, and the effect remained significant after adjustment for age, BMI, and study group (OR=2.53, CI: 1.11–5.75, p=0.027). In addition, the 51Gln allele was a risk factor for hypertension (OR=2.63, CI: 1.37–5.08, p=0.003). 51Gln carriers had lower concentrations of IGF-I and higher concentrations of IGFBP-1 compared to non-carriers.Conclusion/interpretationThe ghrelin 51Gln allele could increase the risk for Type 2 diabetes and hypertension. The low IGF-I concentrations in 51Gln carriers suggest that the mechanism might be associated with low GH concentrations.

Low plasma ghrelin concentration is an indicator of the metabolic syndrome

BACKGROUND. Low ghrelin concentration has been associated with several features of metabolic syndrome (MS), but the relationship between ghrelin concentration and MS as a cluster of metabolic aberrations has not yet been studied. AIMS OF THE STUDY. To analyse whether ghrelin concentration is associated with MS. RESEARCH DESIGN AND METHODS. Fasting plasma ghrelin concentrations of the population‐based cohort of 1037 middle‐aged men and women were analysed using a commercial radioimmunoassay kit (Phoenix Peptide). MS was determined using the new International Diabetes Federation criteria. RESULTS. The prevalence of MS was 37.2%. The ghrelin concentrations were decreased in subjects with MS (635 pg/mL) compared to those without MS (687 pg/mL) (P = 0.001). Ghrelin levels decreased with an increase in the number of metabolic abnormalities. Low ghrelin was a statistically significant predictor of MS in logistic regression analysis (P = 0.005) so that the subjects in the 1st ghrelin quartile were at higher risk of having MS compared to the subjects in the 4th quartile (OR = 1.82, 95% CI: 1.27–2.60, P = 0.001). This association remained statistically significant after adjustment for age and sex (OR = 1.76, 95% CI: 1.24–2.55, P = 0.002). CONCLUSIONS. Metabolic syndrome is associated with low ghrelin levels suggesting a relationship of ghrelin in the metabolic disturbances of MS.

Plasma ghrelin concentrations are positively associated with carotid artery atherosclerosis in males

Background.  Ghrelin, a peptide hormone from stomach, stimulates food intake and decreases fat utilization. Ghrelin binds to growth hormone secretagogue receptor (GHSR). GHSR density has been shown to be upregulated in atherosclerotic lesions, but the relationship between ghrelin concentration and atherosclerosis has not yet been studied. We, therefore, characterized the association between ghrelin concentration and carotid artery intima‐media thickness (IMT) in a population‐based cohort of 1024 middle‐aged (40–60 years) men and women.

Ghrelin, growth and obesity

The objective of this paper is to review the current evidence of a novel gastric hormone ghrelin. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) that potently stimulates growth hormone (GH) release. The discovery of ghrelin opens up a new regulatory system for the GH secretion. Surprisingly, recent studies in rodents suggest that peripherally or centrally administrated ghrelin, independent of GH, decreases fat oxidation and increases food intake and adiposity. In addition, plasma ghrelin levels are lower in obese human subjects. Ghrelin might participate in meal initiation and may signal to the hypothalamus when an increase in the metabolic efficiency is needed. However, the role of ghrelin in the regulation of body weight in humans is unknown. Whether ghrelins somatotrophic effect surpasses its adipogenic effect in the prolonged administration determines its effect on energy balance. New interesting implications for ghrelin have recently been suggested. For instance, ghrelins cardiovascular effects might have clinical relevance. Furthermore, ghrelin might be involved in the growth of some neoplasms. In conclusion, ghrelin, a new somatotrophic, orexigenic and adipogenic peptide hormone, links the regulatory systems for growth and energy balance.

The negative association between plasma ghrelin and IGF-I is modified by obesity, insulin resistance and type 2 diabetes

Aims/hypothesisGhrelin is a natural growth hormone-releasing peptide thought to be involved in the regulation of energy metabolism. The recent studies concerning the association between ghrelin and insulin-like growth factor-I (IGF-I) concentrations have shown either negative correlation or no correlation at all. The aims of this study were to clarify the association between ghrelin and IGF-I concentrations in a large cohort and to characterize whether obesity, insulin resistance and type 2 diabetes affect this association.MethodsWe analysed fasting plasma ghrelin and IGF-I concentrations of 1,004 middle-aged subjects of the population-based OPERA study. Insulin resistance was estimated using QUICKI.ResultsIGF-I concentrations were negatively associated with ghrelin concentrations in the analysis of all subjects before (β=−0.32, p<0.001) and after adjustments for BMI, insulin levels, sex and age (β=−0.40, p<0.001). The association was particularly strong in males and in the higher BMI tertiles. The degree of association varied in relation to the glycaemic status: no insulin resistance: r2=6.5% (p<0.001), insulin resistance without type 2 diabetes: r2=21.0% (p<0.001), type 2 diabetes: r2=25.4 (p<0.001). IGF-I levels explained larger proportion (r2=9.8%) of the variation in ghrelin concentrations compared to fasting insulin concentration (r2=3.0%) and BMI (r2=1.5%).Conclusions/interpretationThere is a negative and independent association between ghrelin and IGF-I concentrations in middle-aged subjects. The interaction between IGF-I and ghrelin is modified by obesity, IR and type 2 diabetes. Further studies are warranted to elucidate the role of ghrelin in the development of these states.

Interactions between ghrelin, leptin and IGF-I affect metabolic syndrome and early atherosclerosis

Background. High leptin and low ghrelin are associated with the metabolic syndrome (MS). Aims and methods. Ghrelin, leptin (RIA kits), and insulin-like growth factor I (IGF-I) (ELISA kit) concentrations of the population-based cohort of 1045 subjects and their interactions with metabolic parameters were analysed. Intima-media thickness (IMT) was measured with carotid ultrasound. Results. The interaction between leptin and ghrelin on the MS was significant (P=0.011). An additive effect of high leptin and low ghrelin on metabolic disturbances was observed: low ghrelin concentration (adjusted for age and sex) (P<0.001) was associated with the MS and type 2 diabetes in the highest but not in the lower leptin quartiles. In the highest leptin quartile, ghrelin concentrations decreased linearly when the number of International Diabetes Federation MS criteria met (P<0.01) increased. Ghrelin-leptin relation was independently associated with carotid IMT (P<0.005). The independent positive association (P<0.01) between the plasma ghrelin quartile and the carotid IMT was evident in the lowest IGF-I quartile. Conclusions. Low ghrelin is associated with MS and type 2 diabetes in the presence of insulin and leptin resistance. Ghrelin-leptin relation is associated with early atherosclerosis. The interaction between IGF-I and ghrelin modifies the association of ghrelin with early atherosclerosis.

IGF-I concentrations are positively associated with carotid artery atherosclerosis in women.

BACKGROUND. Alterations in the growth hormone (GH)/insulin‐like growth factor I (IGF‐I) axis are associated with increased cardiovascular morbidity and mortality, but previous studies have yielded conflicting results. In addition, the T1169A polymorphism in the GH1 gene has been associated with IGF‐I levels. AIMS. To investigate whether IGF‐I concentrations and the T1169A polymorphism of the GH1 gene are associated with cardiovascular risk factors and the intima media thickness (IMT) of the carotid artery. METHODS. Fasting plasma IGF‐I concentrations (n = 1008) were measured in a large population‐based OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort. Genotype variants were determined by the restriction fragment length polymorphism method. RESULTS. Low IGF‐I concentrations associated with several cardiovascular risk factors including age, adiposity, and high triglyceride, fasting insulin and C‐reactive protein concentrations in the analysis of all subjects. In the multivariate models, however, IGF‐I concentrations were positively associated with the mean IMT of women (ß = 0.127, P = 0.009) whereas the association in men was weaker and negative (ß = −0.088, P = 0.034). The 1169A allele was associated with low low‐density lipoprotein cholesterol in both sexes and with low systolic blood pressure levels in women. CONCLUSIONS. IGF‐I concentrations were associated with several traditional cardiovascular risk factors. The observed gender difference in the association between IGF‐I concentrations and carotid artery atherosclerosis warrants further study. The GH1 1169A allele may be associated with a favourable metabolic profile.