Liang（孙亮） Sun

A Marker of Endotoxemia Is Associated With Obesity and Related Metabolic Disorders in Apparently Healthy Chinese

OBJECTIVE Elevated lipopolysaccharide-binding protein (LBP), a marker of subclinical endotoxemia, may be involved in the pathogenesis of obesity and metabolic risk. We aimed to investigate the association between plasma LBP and metabolic disorders in apparently healthy Chinese. RESEARCH DESIGN AND METHODS A population-based study including 559 overweight/obese (BMI ≥24.0 kg/m2) and 500 normal-weight (18.0 ≤ BMI <24.0 kg/m2) subjects aged 35–54 years was conducted in Shanghai, China. Fasting plasma glucose, lipid profile, LBP, high-sensitivity C-reactive protein, interleukin-6, high-molecular-weight (HMW) adiponectin, leptin, hepatic enzymes, and body composition were measured. Metabolic syndrome was defined by the updated National Cholesterol Education Program Adult Treatment Panel III criterion for Asian Americans. RESULTS LBP levels were significantly higher in overweight/obese individuals than in normal-weight individuals (geometric mean 27.6 [95% CI 25.2–30.3] vs. 10.0 [9.1–11.1] μg/ml; P < 0.001). After multiple adjustments including BMI, the odds ratios were 3.54 (95% CI 2.05–6.09) and 5.53 (95% CI 2.64–11.59) for metabolic syndrome and type 2 diabetes, respectively, comparing the highest with the lowest LBP quartile. Further adjustments for inflammatory markers almost abolished the significant association of LBP with metabolic syndrome but not that with type 2 diabetes, and controlling for adipokines and hepatic enzymes did not substantially alter the results. CONCLUSIONS Elevated circulating LBP was associated with obesity, metabolic syndrome, and type 2 diabetes in apparently healthy Chinese. These findings suggested a role of lipopolysaccharide via initiation of innate immune mechanism(s) in metabolic disorders. Prospective studies are needed to confirm these results.

Ferritin Concentrations, Metabolic Syndrome, and Type 2 Diabetes in Middle-Aged and Elderly Chinese

CONTEXT Elevated ferritin concentrations frequently cluster with well-established risk factors of diabetes including obesity, metabolic syndrome, chronic inflammation, and altered circulating adipokines. Few studies, however, have systematically evaluated the effect of these risk factors on ferritin-diabetes association, particularly in Chinese populations. OBJECTIVE We aimed to investigate, in a middle-aged and elderly Chinese population, whether elevated ferritin concentrations are associated with higher risk of metabolic syndrome and type 2 diabetes and to what extent the associations were influenced by obesity, inflammation, and adipokines. DESIGN AND METHODS We conducted a population-based, cross-sectional survey of 3,289 participants aged 50-70 yr in Beijing and Shanghai in 2005. Fasting plasma ferritin, glucose, insulin, lipid profile, glycohemoglobin, inflammatory markers, adipokines, and dietary profile were measured. RESULTS Median ferritin concentrations were 155.7 ng/ml for men and 111.9 ng/ml for women. After multiple adjustment, the odds ratios (ORs) were substantially higher for type 2 diabetes (OR 3.26, 95% confidence interval 2.36-4.51) and metabolic syndrome [OR 2.80 (95% confidence interval 2.24-3.49)] in the highest ferritin quartile compared with those in the lowest quartile. These associations remained significant after further adjustment for dietary factors, body mass index, inflammatory markers, and adipokines. CONCLUSIONS Elevated circulating ferritin concentrations were associated with higher risk of type 2 diabetes and metabolic syndrome in middle-aged and elderly Chinese independent of obesity, inflammation, adipokines, and other risk factors. Our data support the crucial role of iron overload for metabolic diseases, even in a country with relatively high prevalence of iron deficiency.

Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population

Aims/hypothesisThe GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms underlying these associations.MethodsThe single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals (n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes.ResultsThe GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73–1.00, p value under an additive model [p(add)] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95% CI 0.77–0.96, p[add] = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B) and fasting triacylglycerol levels (p[add] = 0.0169–5.3 × 10−6), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p[add] = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had significantly lower HOMA-B (p[add] = 5.8 × 10−5) in the combined analysis.Conclusions/interpretationConsistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition, we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through obesity.

Associations of erythrocyte palmitoleic acid with adipokines, inflammatory markers, and the metabolic syndrome in middle-aged and older Chinese

BACKGROUND Palmitoleic acid has been shown to regulate adipokine expression and systemic metabolic homeostasis in animal studies. However, its association with human metabolic diseases remains controversial. OBJECTIVE We aimed to investigate associations of erythrocyte palmitoleic acid with adipokines, inflammatory markers, and metabolic syndrome (MetS) in a Chinese population. DESIGN Erythrocyte fatty acids were measured in a population-based sample of 3107 men and women aged 50-70 y, for whom plasma glucose, insulin, lipid profile, adiponectin, retinol binding protein 4 (RBP-4), plasminogen activator inhibitor type 1, and high-sensitivity C-reactive protein (hsCRP) were measured. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. RESULTS The mean (±SD) erythrocyte palmitoleic acid value was 0.41 ± 0.20% of total fatty acids. Palmitoleic acid was positively correlated with RBP-4 (r = 0.14, P < 0.001) and inversely correlated with adiponectin (r = -0.15, P < 0.001). After multivariable adjustment, palmitoleic acid was strongly associated with MetS and its components. ORs (95% CIs) for comparisons of extreme quartiles of palmitoleic acid were 3.50 (2.66, 4.59) for MetS, 7.88 (5.90, 10.52) for hypertriglyceridemia, 2.13 (1.66, 2.72) for reduced HDL cholesterol, 1.99 (1.60, 2.48) for central obesity, and 1.86 (1.41, 2.44) for elevated blood pressure (all P < 0.001). Further control for adipokines and hsCRP abolished the association of palmitoleic acid with central obesity but not with other MetS components. CONCLUSION Erythrocyte palmitoleic acid is associated with an adverse profile of adipokines and inflammatory markers and an increased risk of MetS in this Chinese population.

Associations of erythrocyte fatty acids in the de novo lipogenesis pathway with risk of metabolic syndrome in a cohort study of middle-aged and older Chinese

BACKGROUND Experimental studies suggest that elevated de novo lipogenesis (DNL) might be involved in the pathogenesis of metabolic disorders. Few prospective studies have been conducted, especially among populations with a high carbohydrate intake, to determine whether DNL fatty acids are associated with the risk of the metabolic syndrome (MetS). OBJECTIVE We aimed to investigate associations of erythrocyte fatty acids in the DNL pathway-including myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1n-7), hexadecenoic acid (16:1n-9), stearic acid (18:0), vaccenic acid (18:1n-7), and oleic acid (18:1n-9)-with the risk of MetS in a Chinese population with an average carbohydrate intake of >60% of energy. DESIGN A total of 1176 free-living Chinese men and women aged 50-70 y from Beijing and Shanghai were included in our analysis, giving rise to 412 incident MetS cases during 6 y of follow-up. Erythrocyte fatty acids and metabolic traits were measured in these participants. RESULTS Erythrocyte fatty acids in the DNL pathway were correlated with a high ratio of carbohydrate-to-fat intake, less favorable lipid profiles, and elevated liver enzymes at baseline. In comparison with the lowest quartile, RRs (95% CIs) of MetS in the highest quartile were 1.30 (1.04, 1.62; P-trend = 0.007) for 16:1n-7, 1.48 (1.17, 1.86; P-trend < 0.001) for 16:1n-9, 1.26 (1.01, 1.56; P-trend = 0.06) for 18:1n-7, and 1.51 (1.19, 1.92; P-trend < 0.001) for 18:1n-9 after multivariate adjustment for lifestyle factors and body mass index. Moreover, 16:0 and 16:1n-7 were associated with an elevated risk of diabetes. CONCLUSION Our findings suggest that fatty acids in the DNL pathway are independently associated with an elevated risk of metabolic disorders.

Associations between Ionomic Profile and Metabolic Abnormalities in Human Population

Background Few studies assessed effects of individual and multiple ions simultaneously on metabolic outcomes, due to methodological limitation. Methodology/Principal Findings By combining advanced ionomics and mutual information, a quantifying measurement for mutual dependence between two random variables, we investigated associations of ion modules/networks with overweight/obesity, metabolic syndrome (MetS) and type 2 diabetes (T2DM) in 976 middle-aged Chinese men and women. Fasting plasma ions were measured by inductively coupled plasma mass spectroscopy. Significant ion modules were selected by mutual information to construct disease related ion networks. Plasma copper and phosphorus always ranked the first two among three specific ion networks associated with overweight/obesity, MetS and T2DM. Comparing the ranking of ion individually and in networks, three patterns were observed (1) “Individual ion,” such as potassium and chrome, which tends to work alone; (2) “Module ion,” such as iron in T2DM, which tends to act in modules/network; and (3) “Module-individual ion,” such as copper in overweight/obesity, which seems to work equivalently in either way. Conclusions In conclusion, by using the novel approach of the ionomics strategy and the information theory, we observed potential associations of ions individually or as modules/networks with metabolic disorders. Certainly, these findings need to be confirmed in future biological studies.

Independent and Opposite Associations of Trunk and Leg Fat Depots with Adipokines, Inflammatory Markers, and Metabolic Syndrome in Middle-Aged and Older Chinese Men and Women

OBJECTIVE The objective was to investigate associations of regional fat depots with adipokines, inflammatory markers, and risk of metabolic syndrome (MetS) in a Chinese population. DESIGN AND METHODS Trunk and leg fat mass were determined in a population-based sample of 1150 Chinese (479 men and 671 women) aged 50-70 yr by using whole-body dual-energy x-ray absorptiometry scan. Plasma adiponectin, plasminogen activator inhibitor-1 (PAI-1), retinol-binding protein 4 (RBP4), resistin, C-reactive protein, and IL-6 were measured. The updated National Cholesterol Education Program Adult Treatment Panel III criterion for Asian Americans was used to define MetS. RESULTS Larger body-size adjusted trunk fat mass was significantly associated with lower adiponectin and higher PAI-1, RBP4, C-reactive protein, and IL-6 levels in both genders (P < 0.05). Larger body-size adjusted leg fat mass was significantly associated with higher adiponectin levels in both genders but lower RBP4 and PAI-1 concentrations in men (P < 0.05). Comparing with the lowest body-size adjusted leg fat mass tertile, the odds ratio (95% confidence interval) of MetS in the highest tertile was 0.33 (0.18-0.62; P for trend <0.001) for men and 0.43 (0.28-0.65; P for trend <0.001) for women. The association was attenuated with further controlling adipokines and inflammatory markers (P = 0.09 for men and P = 0.004 for women). CONCLUSION In contrast to trunk fat, large leg fat appears to have favorable effects on adipokines, inflammatory markers, and MetS risk among Chinese. The opposite associations between regional fat depots and MetS risk may partially mediated by adipokines and inflammatory status.

Dairy Consumption, Type 2 Diabetes, and Changes in Cardiometabolic Traits: A Prospective Cohort Study of Middle-Aged and Older Chinese in Beijing and Shanghai

OBJECTIVE To prospectively investigate associations of dairy consumption with risk of type 2 diabetes and changes of cardiometabolic traits. RESEARCH DESIGN AND METHODS In 2005, 2,091 middle-aged and older Chinese men and women were recruited and followed for 6 years. Baseline dairy consumption was assessed by a 74-item food frequency questionnaire. Erythrocyte fatty acids were analyzed by gas chromatography coupled with flame ion detector. Cardiometabolic traits were measured at both baseline and follow-up visits. RESULTS Only 1,202 (57.5%) participants reported any dairy consumption, with a median intake of 0.89 (interquartile range 0.19–1.03) serving/day. Compared with nonconsumers, the relative risks (RRs) of type 2 diabetes among those having 0.5–1 serving/day and >1 serving/day were 0.70 (95% CI 0.55–0.88) and 0.65 (0.49–0.85), respectively, after multivariate adjustment (Ptrend < 0.001), which were attenuated by further adjusting for changes in glucose during follow-up (Ptrend = 0.07). Total dairy consumption was associated with favorable changes in glucose, waist circumference, BMI, diastolic blood pressure (all Ptrend < 0.05), and systolic blood pressure (Ptrend = 0.05) after multivariate adjustment, including baseline values of dependent variables. Erythrocyte trans-18:1 isomers were significantly correlated with total dairy consumption (rs = 0.37, Ptrend < 0.001), and these dairy food biomarkers were associated with a lower risk of type 2 diabetes. The RR of type 2 diabetes comparing extreme quartiles of trans-18:1 isomers was 0.82 (0.65–1.04, Ptrend = 0.02), which was attenuated after adjustment for dairy consumption (Ptrend = 0.15). CONCLUSIONS Dairy consumption was associated with a significantly lower risk of type 2 diabetes and favorable changes of cardiometabolic traits in Chinese.

Elevated Plasma Ferritin Is Associated with Increased Incidence of Type 2 Diabetes in Middle-Aged and Elderly Chinese Adults

Epidemiological studies suggest that elevated circulating ferritin is associated with heightened incident diabetes in mainly Western populations, although the results were not entirely consistent. We aimed to prospectively investigate the ferritin-diabetes association in an Asian population for the first time, to our knowledge, and also to examine this association with an updated meta-analysis. Our prospective study included 2198 community-living Chinese between 50 and 70 y of age in 2005. All individuals participated in a 6-y follow-up survey in 2011. Fasting plasma ferritin, high-sensitivity C-reactive protein (hsCRP), adiponectin, and γ-glutamyltransferase (GGT) were measured at baseline. A total of 538 incident diabetes cases were documented by self-reports and/or fasting glucose ≥7.0 mmol/L at the follow-up survey. After multiple adjustments, the RR of type 2 diabetes was 1.90 (95% CI: 1.37, 2.65) when comparing the highest with the lowest sex-specific ferritin quintile. The association remained significant after further controlling for BMI, hsCRP, adiponectin, and GGT. To update the evidence reported in previous meta-analyses, we searched all prospective studies evaluating the association between blood ferritin and incident diabetes on PubMed prior to October 24, 2012. Besides our prospective study, 9 additional studies were also included. The pooled RR was 1.60 (95% CI: 1.25, 2.04) when comparing the highest with the lowest category of ferritin with a moderate heterogeneity (I(2) = 49.0%; P = 0.03). A significant linear dose-response relationship was detected in this meta-analysis. Overall, our results indicate an independent and significant positive association between higher plasma ferritin, a marker of elevated body iron stores, and increased risk of developing type 2 diabetes in middle-aged and elderly Chinese adults, which is similar to Western populations.

Quantitative detection of single amino acid polymorphisms by targeted proteomics

Single-nucleotide polymorphisms (SNPs) are recognized as one kind of major genetic variants in population scale. However, polymorphisms at the proteome level in population scale remain elusive. In the present study, we named amino acid variances derived from SNPs within coding regions as single amino acid polymorphisms (SAPs) at the proteome level, and developed a pipeline of non-targeted and targeted proteomics to identify and quantify SAP peptides in human plasma. The absolute concentrations of three selected SAP-peptide pairs among 290 Asian individuals were measured by selected reaction monitoring (SRM) approach, and their associations with both obesity and diabetes were further analyzed. This work revealed that heterozygotes and homozygotes with various SAPs in a population could have different associations with particular traits. In addition, the SRM approach allows us for the first time to separately measure the absolute concentration of each SAP peptide in the heterozygotes, which also shows different associations with particular traits.