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The proatherogenic cytokine interleukin-18 is secreted by human adipocytes

Thomas Skurk, Hubert Kolb, Sylvia Müller-Scholze, Karin Röhrig, Hans Hauner, and Christian Herder

Objective: Interleukin (IL)-18, an important mediator of innate immunity and strong risk factor for the development of cardiovascular disease, was shown recently to be elevated in obesity. The aim of our study was to investigate whether human adipocytes produce IL-18.

Methods: Human adipose tissue was obtained from lean women undergoing elective plastic surgery and from obese individuals undergoing laparoscopic surgery (gastric banding). Preadipocytes from mammary adipose tissue were isolated and differentiated under defined adipogenic conditions. IL-18 expression was analyzed by real-time reverse transcriptase PCR, ELISA and immunocytochemistry.

Results: Human preadipocytes of all differentiation stages spontaneously secreted IL-18. In parallel significant amounts of IL-18 mRNA were detected. Freshly isolated mature adipocytes from subcutaneous and omental depots also released IL-18. IL-18 release from adipocytes from obese donors was about 3-fold higher compared to adipocytes from non-obese donors.

Conclusions: We conclude that human adipose tissue produces IL-18 and thereby contributes to systemic IL-18 concentrations. This finding supports the concepts that adipocytes behave as primitive immune cells and that IL-18 may mediate some of the detrimental complications of obesity such as cardiovascular disease and type 2 diabetes.

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Vasoregulatory peptides pro-endothelin-1 and pro-adrenomedullin are associated with metabolic syndrome in the population-based KORA F4 study

Jochen Seissler, Nina Feghelm, Cornelia Then, Christa Meisinger, Christian Herder, Wolfgang Koenig, Annette Peters, Michael Roden, Andreas Lechner, Bernd Kowall, and Wolfgang Rathmann

Background

Metabolic alterations and endothelial dysfunction are interrelated processes in type 2 diabetes (T2D) and metabolic syndrome (MetS) that often develop in parallel. We assessed the association of vasoactive precursor peptides (VPPs) with MetS and T2D.

Design and methods

Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM) were measured by novel sensitive assays in 1590 participants of the population-based KORA F4 study. The association of the VPPs with T2D, MetS defined by IDF criteria, the components of MetS, and insulin resistance (IR) was assessed in logistic regression models.

Results

Elevated levels of CT-proET-1 and MR-proADM were associated with T2D, MetS, and IR in age- and sex-adjusted models. After adjustment for age, sex, former vascular complications, lifestyle factors, high-sensitive C-reactive protein, and serum creatinine, significant associations with MetS were found for MR-proADM (OR=5.94, 95% CI 3.78–9.33) and CT-proET-1 (OR=5.18, 95% CI 3.48–7.71) (top quartile vs bottom quartile). CT-proET-1 and MR-proADM were strongly associated with all components of MetS as defined by IDF criteria. After multivariable adjustment, association of CT-proET-1 and MR-proADM with pathological glucose tolerance and T2D disappeared and a borderline association with IR was found only for CT-proET-1 (OR=1.34, 95% CI 0.96–1.87).

Conclusions

We here demonstrate for the first time that plasma levels of both MR-proADM and CT-proET-1 levels are related to MetS and its components, thus suggesting that they possibly have a role as a surrogate biomarker for the disease and its complications.

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Adiponectin may mediate the association between omentin, circulating lipids and insulin sensitivity: results from the KORA F4 study

Christian Herder, D Margriet Ouwens, Maren Carstensen, Bernd Kowall, Cornelia Huth, Christa Meisinger, Wolfgang Rathmann, Michael Roden, and Barbara Thorand

Objective

Reduced circulating omentin levels have been reported in obesity and type 2 diabetes, but data were mostly derived from univariate analyses in small study samples. This study aimed to investigate the relationship between omentin, abnormal glucose tolerance and related metabolic factors in a large population-based cross-sectional study.

Design and methods

Serum omentin was measured by ELISA in 1092 participants of the German KORA F4 survey (2006–2008). Associations between omentin serum levels, glucose tolerance (assessed with an oral glucose tolerance test) and diabetes-related factors were estimated using logistic and linear regression models respectively.

Results

Serum levels of omentin were not related to categories of glucose tolerance. However, serum omentin was positively associated with whole-body insulin sensitivity index (ISI (composite)) and HDL cholesterol and showed inverse associations with 2-h post-load glucose, fasting insulin, homeostasis model assessment-estimated insulin resistance, BMI and triglycerides (all P≤0.03 after adjustment for age, sex and lifestyle factors). Further adjustment for BMI and/or serum lipids attenuated the associations with parameters of glucose metabolism, whereas adjustment for serum adiponectin virtually abolished all aforementioned associations. In contrast, adjustment for omentin had no effect on the positive association between adiponectin levels and ISI (composite).

Conclusions

The data from this large population-based cohort show that circulating omentin levels are associated with insulin sensitivity. Our observations further suggest that omentin acts via upregulation of adiponectin, which in turn affects lipid metabolism and thereby also indirectly enhances insulin sensitivity, but mechanistic studies are required to corroborate this hypothesis.

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Association of fetuin-A with incident type 2 diabetes: results from the MONICA/KORA Augsburg study and a systematic meta-analysis

Chaterina Sujana, Cornelia Huth, Astrid Zierer, Sophie Meesters, Julie Sudduth-Klinger, Wolfgang Koenig, Christian Herder, Annette Peters, and Barbara Thorand

Objective

We investigated the association of circulating fetuin-A with incident T2D particularly examining potential sex differences. Additionally, we determined whether putative associations were independent of subclinical inflammation, adiponectin and liver fat content.

Design

Case-cohort study plus systematic meta-analysis.

Methods

We investigated the association between baseline fetuin-A levels and incident T2D in the MONICA/KORA Augsburg study using Cox proportional hazards analyses. Furthermore, we conducted a systematic review within PubMed and EMBASE and pooled association estimates of eligible studies with the MONICA/KORA Augsburg data using a DerSimonian-Laird random effects model.

Results

Within MONICA/KORA Augsburg, 930 participants developed incident T2D (median follow-up: 14 years). We observed a significant association between fetuin-A and T2D risk after multivariable adjustment including C-reactive protein and adiponectin. The strength of the association was similar in males and females (P value for sex interaction >0.55). Seven eligible published studies were identified in addition to the MONICA/KORA Augsburg study for the meta-analysis. The pooled hazard ratio (95% CI) for incident T2D per 1 standard deviation (s.d.) increment of fetuin-A was 1.24 (1.14–1.34) for the multivariable adjusted model. Our sex-stratified meta-analysis yielded relative risk estimates per 1 s.d. of 1.19 (1.04–1.38) in males and 1.29 (1.15–1.46) in females. Further individual adjustment for subclinical inflammation, adiponectin and liver fat content had almost no impact on the strength of the association.

Conclusions

Higher fetuin-A levels are associated with incident T2D in both males and females independently of subclinical inflammation, adiponectin and liver fat content.

Free access

Gene variants of monocyte chemoattractant protein 1 and components of metabolic syndrome in KORA S4, Augsburg

Eva-Maria Sedlmeier, Harald Grallert, Cornelia Huth, Hannelore Löwel, Christian Herder, Klaus Strassburger, Guido Giani, H-Erich Wichmann, Hans Hauner, Thomas Illig, and Wolfgang Rathmann

Objective: Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the development of several components of metabolic syndrome (MetS). The present study investigated the association of nine MCP-1 single nucleotide polymorphisms (SNPs) with MetS, type 2 diabetes mellitus and metabolic risk factors.

Subjects and methods: The population-based study sample comprised 1630 subjects aged 55–74 years from KORA S4 (Cooperative Health Research in the Region of Augsburg Survey 4). Genotyping was carried out by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis of allele-dependent primer extension products.

Results: The MCP-1 SNP c.-3813C>T exhibited trends for differences between the genotype groups in triglycerides, 2-h glucose and uric acid (P = 0.0084, 0.014, 0.027). Other trends were observed for c.-928G>C associated with height and fasting glucose (P = 0.0024, 0.033), for c.105T>C with height and leukocytes (P = 0.0095, 0.047), for c.*65C>T and c.*3879C>T with MCP-1 levels (both P = 0.012) and for c.-2138A>T with interleukin-6 levels. After correction for multiple testing, none of the analysed SNPs, except c.-928G>C in men showed a significant association with MetS, T2DM or other analysed parameters. Haplotype MCP-1*1 and c.-928G>C in men (P = 0.0002, 0.0004) were significantly associated with an increase in height.

Conclusions: This is the first study to investigate the associations of MCP-1 SNPs with MetS. We found trends for several components of MetS. These parameters were hyperlipidaemia, fasting and 2-h glucose, and uric acid. A new finding is that MCP-1*1 haplotype is associated with height. Further investigation in larger populations is needed to clarify the involvement of MCP-1 in MetS.

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RANTES/CCL5 gene polymorphisms, serum concentrations, and incident type 2 diabetes: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

Christian Herder, Thomas Illig, Jens Baumert, Martina Müller, Norman Klopp, Natalie Khuseyinova, Christa Meisinger, Ulrike Poschen, Stephan Martin, Wolfgang Koenig, and Barbara Thorand

Objective

Regulated on activation, normal T-cell expressed and secreted (RANTES)/chemokine(C-C motif) ligand (CCL5) is expressed by adipocytes, and serum levels of RANTES are increased in obesity and type 2 diabetes. The aim of this study was to test the hypothesis that RANTES is involved in the pathogenesis of type 2 diabetes by analyzing the triangular association between CCL5 gene polymorphisms, systemic RANTES concentrations, and incident type 2 diabetes in a large prospective study.

Subjects and methods

The study is based on 502 individuals (293 men and 209 women) and 1632 individuals (859 men and 773 women) with and without incident type 2 diabetes from the population-based MONItoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) case–cohort study respectively (mean follow-up time±s.d. 10.1±4.9 years). CCL5 genotypes and RANTES serum concentrations were determined and associations between genotypes, haplotypes, serum levels, and incident type 2 diabetes were assessed.

Results

Minor alleles of four single nucleotide polymorphisms were associated with lower RANTES levels (P additive between 1.2×10−9 and 3.1×10−8), but neither genotypes, haplotypes, nor serum levels were associated with incident type 2 diabetes.

Conclusions

Our data suggest that RANTES/CCL5 gene variants and serum levels are not causally related with type 2 diabetes and that elevated RANTES levels in patients with type 2 diabetes may be a consequence of hyperglycemia. However, our findings cannot preclude a local role in adipose tissue where RANTES expression may contribute to leukocyte infiltration and a proinflammatory state.

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Macrophage inhibitory cytokine-1 is increased in individuals before type 2 diabetes diagnosis but is not an independent predictor of type 2 diabetes: the Whitehall II study

Maren Carstensen, Christian Herder, Eric J Brunner, Klaus Strassburger, Adam G Tabak, Michael Roden, and Daniel R Witte

Objective

Macrophage inhibitory cytokine-1 (MIC-1) belongs to the transforming growth factor (TGF)-β superfamily, and has been reported to be involved in energy homoeostasis and weight loss and to have anti-inflammatory properties. We hypothesized that decreased concentrations of MIC-1 would be associated with higher risk of developing type 2 diabetes.

Design and methods

We designed a nested case–control study within the Whitehall II cohort and measured serum concentrations of MIC-1 by ELISA in 180 individuals without type 2 diabetes at baseline who developed type 2 diabetes during the follow-up period of 11.5±3.0 years and in 372 controls frequency-matched for age, sex, and body mass index with normal glucose tolerance throughout the study.

Results

MIC-1 concentrations at baseline were higher in cases (median (25/75th percentiles) 537.1 (452.7–677.4) pg/ml) than in controls (499.7 (413.8–615.4) pg/ml; P=0.0044). In the age- and sex-adjusted model, a 1-s.d. increase in MIC-1 (206.0 pg/ml) was associated with an odds ratio (95% confidence interval) of 1.21 (0.997; 1.46; P=0.054) for type 2 diabetes. Adjustment for waist circumference, cardiovascular risk factors, socioeconomic status, proinflammatory mediators, and glycemia abolished the association.

Conclusions

Baseline MIC-1 concentrations were increased, not decreased, in individuals before type 2 diabetes manifestation, but not independently associated with incident type 2 diabetes in multivariable analyses. This upregulation of MIC-1 could be part of an anti-inflammatory response preceding the onset of type 2 diabetes, which has been described before for interleukin-1 receptor antagonist and TGF-β1.

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Systemic monocyte chemoattractant protein-1 concentrations are independent of type 2 diabetes or parameters of obesity: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4)

Christian Herder, Sylvia Müller-Scholze, Philipp Rating, Wolfgang Koenig, Barbara Thorand, Burkhard Haastert, Rolf Holle, Thomas Illig, Wolfgang Rathmann, Jochen Seissler, H-Erich Wichmann, and Hubert Kolb

Objective: Data on the relevance of monocyte chemoattractant protein (MCP)-1 in the pathophysiology of type 2 diabetes (T2D) and obesity are inconsistent. Since MCP-1 is produced by adipocytes and has been postulated to be involved in macrophage infiltration into adipose tissue, we wanted to test whether serum MCP-1 levels were correlated with T2D or obesity.

Design and methods: Out of 1653 individuals aged 55 to 74 years participating in the population-based KORA Survey S4 (KORA/Cooperative Health Research in the Region of Augsburg) in Southern Germany, 236 patients with T2D, 242 subjects with impaired glucose tolerance and 244 normoglycaemic controls matched for age and sex were analysed for circulating MCP-1 concentrations.

Results: MCP-1 serum concentrations were not associated with impaired glucose tolerance, type 2 diabetes or several parameters of obesity. Moreover, systemic MCP-1 levels were not significantly correlated with all but one (fasting triglycerides) of the biochemical markers tested.

Conclusions: Our data indicate that MCP-1 levels are not associated with T2D and that the contribution of fat mass to systemic MCP-1 protein might be low, suggesting that the possible local pathogenic role of MCP-1 may not be reflected by increased systemic levels of MCP-1.

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Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study

Christian Herder, Kristine Færch, Maren Carstensen-Kirberg, Gordon D Lowe, Rita Haapakoski, Daniel R Witte, Eric J Brunner, Michael Roden, Adam G Tabák, Mika Kivimäki, and Dorte Vistisen

Objective

Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional.

Design and methods

We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers.

Results

Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin.

Conclusions

Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

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Independent and opposite associations of serum levels of omentin-1 and adiponectin with increases of glycaemia and incident type 2 diabetes in an older population: KORA F4/FF4 study

Christian Herder, Julia M Kannenberg, Corinna Niersmann, Cornelia Huth, Maren Carstensen-Kirberg, Clemens Wittenbecher, Matthias Schulze, Matthias Blüher, Wolfgang Rathmann, Annette Peters, Michael Roden, Christa Meisinger, and Barbara Thorand

Objective

Cross-sectional studies found that higher levels of the novel adipokine omentin-1 were associated with higher adiponectin and lower levels of risk factors for type 2 diabetes, but its relevance for incident type 2 diabetes is currently not understood. Therefore this study investigated whether serum omentin-1 was associated with changes in glycaemia and incident type 2 diabetes independently of adiponectin.

Design and methods

The study was based on participants aged 62–81 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort. Associations of baseline serum levels of omentin-1 and adiponectin with changes in glycaemia were assessed in 471 non-diabetic participants, and associations between both adipokines and incident type 2 diabetes were assessed in 76 cases and 430 non-cases (follow-up time 6.5 years). Multivariable linear and logistic regression models were adjusted for multiple potential confounders.

Results

Higher serum levels of omentin-1 were associated with increases in fasting glucose, 2-h glucose and HbA1c (all P < 0.001) and with incident type 2 diabetes (adjusted odds ratio (OR) (95% CI): 1.40 (1.03; 1.90) per s.d. of log2-transformed omentin-1; P = 0.032). These associations were independent from adiponectin levels, which showed associations with changes in glycaemia and risk of type 2 diabetes in the opposite direction. We found no statistically significant interactions of omentin-1 with adiponectin or sex in the association with incident type 2 diabetes (all P > 0.1).

Conclusions

Systemic levels of omentin-1 were positively associated with increases in glycaemia and incident type 2 diabetes in this older population. These associations were independent of potential confounders including adiponectin.