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1.  Circulating concentrations of GLP-1 are associated with coronary atherosclerosis in humans 
Background
GLP-1 is an incretine hormone which gets secreted from intestinal L-cells in response to nutritional stimuli leading to pancreatic insulin secretion and suppression of glucagon release. GLP-1 further inhibits gastric motility and reduces appetite which in conjunction improves postprandial glucose metabolism. Additional vasoprotective effects have been described for GLP-1 in experimental models. Despite these vasoprotective actions, associations between endogenous levels of GLP-1 and cardiovascular disease have yet not been investigated in humans which was the aim of the present study.
Methods
GLP-1 serum levels were assessed in a cohort of 303 patients receiving coronary CT-angiography due to typical or atypical chest pain.
Results
GLP-1 was found to be positively associated with total coronary plaque burden in a fully adjusted model containing age, sex, BMI, hypertension, diabetes mellitus, smoking, triglycerides, LDL-C (low density lipoprotein cholesterol), hsCRP (high-sensitive C-reactive protein), and eGFR (estimated glomerular filtration rate) (OR: 2.53 (95% CI: 1.12 – 6.08; p = 0.03).
Conclusion
Circulating GLP-1 was found to be positivity associated with coronary atherosclerosis in humans. The clinical relevance of this observation needs further investigations.
doi:10.1186/1475-2840-12-117
PMCID: PMC3765863  PMID: 23953602
GLP-1; Atherosclerosis; Coronary CT angiography
2.  Expression of Human Chemerin Induces Insulin Resistance in the Skeletal Muscle but Does Not Affect Weight, Lipid Levels, and Atherosclerosis in LDL Receptor Knockout Mice on High-Fat Diet 
Diabetes  2010;59(11):2898-2903.
OBJECTIVE
Chemerin is a recently discovered hepatoadipokine that regulates adipocyte differentiation as well as chemotaxis and activation of dendritic cells and macrophages. Chemerin was reported to modulate insulin sensitivity in adipocytes and skeletal muscle cells in vitro and to exacerbate glucose intolerance in several mouse models in vivo. In humans, chemerin was shown to be associated with multiple components of the metabolic syndrome including BMI, triglycerides, HDL cholesterol, and hypertension. This study aimed to examine the effect of chemerin on weight, glucose and lipid metabolism, as well as atherosclerosis in vivo.
RESEARCH DESIGN AND METHODS
We used recombinant adeno-associated virus to express human chemerin in LDL receptor knockout mice on high-fat diet.
RESULTS
Expression of chemerin did not significantly alter weight, lipid levels, and extent of atherosclerosis. Chemerin, however, significantly increased glucose levels during the intraperitoneal glucose tolerance test without affecting endogenous insulin levels and the insulin tolerance test. Chemerin reduced insulin-stimulated Akt1 phosphorylation and activation of 5′AMP-activated protein kinase (AMPK) in the skeletal muscle, but had no effect on Akt phosphorylation and insulin-stimulated AMPK activation in the liver and gonadal adipose tissue.
CONCLUSIONS
Chemerin induces insulin resistance in the skeletal muscle in vivo. Chemerin is involved in the cross talk between liver, adipose tissue, and skeletal muscle.
doi:10.2337/db10-0362
PMCID: PMC2963549  PMID: 20724582
3.  Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians 
Clinical endocrinology  2008;70(5):698-705.
Summary
Objective
Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the −420C>G putative gain-of-function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans.
Design and methods
We examined the association of three resistin polymorphisms, −852A>G, −420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C-reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851).
Results
Resistin levels were higher, dose-dependently, with the −420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The −852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor-receptor 2 (sol-TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol-TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores.
Conclusions
Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.
doi:10.1111/j.1365-2265.2008.03375.x
PMCID: PMC3108432  PMID: 18710472
4.  Relation of Plasma Fatty Acid Binding Proteins 4 and 5 With the Metabolic Syndrome, Inflammation and Coronary Calcium in Patients With Type-2 Diabetes Mellitus 
The American journal of cardiology  2010;106(8):1118-1123.
Fatty acid–binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.
doi:10.1016/j.amjcard.2010.06.028
PMCID: PMC3108486  PMID: 20920650
5.  Reversal of Nonalcoholic Hepatic Steatosis, Hepatic Insulin Resistance, and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes 
Diabetes  2005;54(3):603-608.
To examine the mechanism by which moderate weight reduction improves basal and insulin-stimulated rates of glucose metabolism in patients with type 2 diabetes, we used 1H magnetic resonance spectroscopy to assess intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) content in conjunction with hyperinsulinemic-euglycemic clamps using [6,6-2H2]glucose to assess rates of glucose production and insulin-stimulated peripheral glucose uptake. Eight obese patients with type 2 diabetes were studied before and after weight stabilization on a moderately hypocaloric very-low-fat diet (3%). The diabetic patients were markedly insulin resistant in both liver and muscle compared with the lean control subjects. These changes were associated with marked increases in IHL (12.2 ± 3.4 vs. 0.6 ± 0.1%; P = 0.02) and IMCL (2.0 ± 0.3 vs. 1.2 ± 0.1%; P = 0.02) compared with the control subjects. A weight loss of only ~8 kg resulted in normalization of fasting plasma glucose concentrations (8.8 ± 0.5 vs. 6.4 ± 0.3 mmol/l; P < 0.0005), rates of basal glucose production (193 ± 7 vs. 153 ± 10 mg/min; P < 0.0005), and the percentage suppression of hepatic glucose production during the clamp (29 ± 22 vs. 99 ± 3%; P = 0.003). These improvements in basal and insulin-stimulated hepatic glucose metabolism were associated with an 81 ± 4% reduction in IHL (P = 0.0009) but no significant change in insulin-stimulated peripheral glucose uptake or IMCL (2.0 ± 0.3 vs. 1.9 ± 0.3%; P = 0.21). In conclusion, these data support the hypothesis that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled type 2 diabetes by mobilizing a relatively small pool of IHL, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism.
PMCID: PMC2995496  PMID: 15734833
6.  MMP-1 serum levels predict coronary atherosclerosis in humans 
Background
Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease.
Methods
260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time) to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified.
Results
In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85); p < 0.05) in a model adjusted for age, sex, BMI, classical cardiovascular risk factors, hsCRP, adiponectin, pericardial fat volume and medication. Specification of plaque morphology revealed significant association of MMP-1 serum levels with non-calcified plaques (OR: 1.16 (CI: 1.0-1.34); p = 0.05) and calcified plaques (OR: 1.22 (CI: 1,03-1.45); p < 0.05) while association with mixed plaques was lost in the fully adjusted model. No associations were found between MMP9 serum levels and total plaque burden or plaque morphology.
Conclusion
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
doi:10.1186/1475-2840-8-50
PMCID: PMC2754422  PMID: 19751510
7.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques 
PLoS ONE  2009;4(3):e4733.
Background
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
Methodology/Principal Findings
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Conclusions/Significance
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
doi:10.1371/journal.pone.0004733
PMCID: PMC2649379  PMID: 19266101
8.  Serum concentrations of cortisol, interleukin 6, leptin and adiponectin predict stress induced insulin resistance in acute inflammatory reactions 
Critical Care  2008;12(6):R157.
Introduction
Inflammatory stimuli are causative for insulin resistance in obesity as well as in acute inflammatory reactions. Ongoing research has identified a variety of secreted proteins that are released from immune cells and adipocytes as mediators of insulin resistance; however, knowledge about their relevance for acute inflammatory insulin resistance remains limited. In this study we aimed for a clarification of the relevance of different insulin resistance mediating factors in an acute inflammatory situation.
Methods
Insulin resistance was measured in a cohort of 37 non-diabetic patients undergoing cardiac surgery by assessment of insulin requirement to maintain euglycaemia and repeated measurements of an insulin glycaemic index. The kinetics of cortisol, interleukin 6 (IL6), tumour necrosis factor α (TNFα), resistin, leptin and adiponectin were assessed by repeated measurements in a period of 48 h.
Results
Insulin resistance increased during the observation period and peaked 22 h after the beginning of the operation. IL6 and TNFα displayed an early increase with peak concentrations at the 4-h time point. Serum levels of cortisol, resistin and leptin increased more slowly and peaked at the 22-h time point, while adiponectin declined, reaching a base at the 22-h time point. Model assessment identified cortisol as the best predictor of insulin resistance, followed by IL6, leptin and adiponectin. No additional information was gained by modelling for TNFα, resistin, catecholamine infusion rate, sex, age, body mass index (BMI), operation time or medication.
Conclusions
Serum cortisol levels are the best predictor for inflammatory insulin resistance followed by IL6, leptin and adiponectin. TNFα, and resistin have minor relevance as predictors of stress dependent insulin resistance.
doi:10.1186/cc7152
PMCID: PMC2646322  PMID: 19087258
9.  Adipokines and Insulin Resistance 
Molecular Medicine  2008;14(11-12):741-751.
Obesity is associated with an array of health problems in adult and pediatric populations. Understanding the pathogenesis of obesity and its metabolic sequelae has advanced rapidly over the past decades. Adipose tissue represents an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive mediators (adipokines) that signal to organs of metabolic importance including brain, liver, skeletal muscle, and the immune system—thereby modulating hemostasis, blood pressure, lipid and glucose metabolism, inflammation, and atherosclerosis. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones adiponectin, chemerin, leptin, omentin, resistin, retinol binding protein 4, tumor necrosis factor-α and interleukin-6, vaspin, and visfatin on insulin resistance.
doi:10.2119/2008-00058.Rabe
PMCID: PMC2582855  PMID: 19009016
10.  Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis 
Journal of Clinical Investigation  2006;116(11):2914-2923.
Although inflammatory bowel disease (IBD) is the result of a dysregulated immune response to commensal gut bacteria in genetically predisposed individuals, the mechanism(s) by which bacteria lead to the development of IBD are unknown. Interestingly, deletion of intestinal goblet cells protects against intestinal injury, suggesting that this epithelial cell lineage may produce molecules that exacerbate IBD. We previously reported that resistin-like molecule β (RELMβ; also known as FIZZ2) is an intestinal goblet cell–specific protein that is induced upon bacterial colonization whereupon it is expressed in the ileum and colon, regions of the gut most often involved in IBD. Herein, we show that disruption of this gene reduces the severity of colitis in the dextran sodium sulfate (DSS) model of murine colonic injury. Although RELMβ does not alter colonic epithelial proliferation or barrier function, we show that recombinant protein activates macrophages to produce TNF-α both in vitro and in vivo. RELMβ expression is also strongly induced in the terminal ileum of the SAMP1/Fc model of IBD. These results suggest a model whereby the loss of epithelial barrier function by DSS results in the activation of the innate mucosal response by RELMβ located in the lumen, supporting the hypothesis that this protein is a link among goblet cells, commensal bacteria, and the pathogenesis of IBD.
doi:10.1172/JCI28121
PMCID: PMC1590268  PMID: 17024245
11.  Genetic variants of adiponectin receptor 2 are associated with increased adiponectin levels and decreased triglyceride/VLDL levels in patients with metabolic syndrome 
Background
Adiponectin acts as an antidiabetic, antiinflammatory and antiatherogenic adipokine. These effects are assumed to be mediated by the recently discovered adiponectin receptors AdipoR1 and AdipoR2.
Aim
The purpose of this study was to determine whether variations in the AdipoR1 and AdipoR2 genes may contribute to insulin resistance, dyslipidemia and inflammation.
Methods
We sequenced all seven coding exons of both genes in 20 unrelated German subjects with metabolic syndrome and tested genetic variants for association with glucose, lipid and inflammatory parameters.
Results
We identified three AdipoR2 variants (+795G/A, +870C/A and +963C/T) in perfect linkage disequilibrium (r2 = 1) with a minor allele frequency of 0.125. This haplotype was associated with higher plasma adiponectin levels and decreased fasting triglyceride, VLDL-triglyceride and VLDL-cholesterol levels. No association, however, was observed between the AdipoR2 SNP cluster and glucose metabolism.
Conclusion
To our knowledge, this is the first study to identify an association between genetic variants of the adiponectin receptor genes and plasma adiponectin levels. Furthermore, our data suggest that AdipoR2 may play an important role in triglyceride/VLDL metabolism.
doi:10.1186/1475-2840-5-11
PMCID: PMC1482678  PMID: 16700915
12.  PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1 
Journal of Clinical Investigation  2005;115(8):2244-2256.
In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARγ dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARγ ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARγ target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARγ ligands regulate lipid metabolism and insulin sensitivity in adipocytes.
doi:10.1172/JCI24130
PMCID: PMC1172230  PMID: 16007265
13.  An Inflammatory Cascade Leading to Hyperresistinemia in Humans 
PLoS Medicine  2004;1(2):e45.
Background
Obesity, the most common cause of insulin resistance, is increasingly recognized as a low-grade inflammatory state. Adipocyte-derived resistin is a circulating protein implicated in insulin resistance in rodents, but the role of human resistin is uncertain because it is produced largely by macrophages.
Methods and Findings
The effect of endotoxin and cytokines on resistin gene and protein expression was studied in human primary blood monocytes differentiated into macrophages and in healthy human participants.
Inflammatory endotoxin induced resistin in primary human macrophages via a cascade involving the secretion of inflammatory cytokines that circulate at increased levels in individuals with obesity. Induction of resistin was attenuated by drugs with dual insulin-sensitizing and anti-inflammatory properties that converge on NF-κB. In human study participants, experimental endotoxemia, which produces an insulin-resistant state, causes a dramatic rise in circulating resistin levels. Moreover, in patients with type 2 diabetes, serum resistin levels are correlated with levels of soluble tumor necrosis factor α receptor, an inflammatory marker linked to obesity, insulin resistance, and atherosclerosis.
Conclusions
Inflammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inflammatory states.
Inflammatory stimuli affect resistin expression in human macrophages and raise serum resistin levels in healthy volunteers
doi:10.1371/journal.pmed.0010045
PMCID: PMC529430  PMID: 15578112

Results 1-13 (13)