Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. ...Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.
To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.
In 2566 individuals of the population-based Maastricht Study (age: 60 ± 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in > 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography–tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.
Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (β: 0.08; 95% CI: 0.02, 0.13) and SAF (β: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (β: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.
Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088–105234-PG).
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Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic ...diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles.
This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m
) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m
; 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation.
Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study.
In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.
BACKGROUND: Previous studies on the glycemic index (GI) and glycemic load (GL) reported inconsistent findings on their association with metabolic risk factors. This may partly have been due to ...differences in underlying dietary patterns. OBJECTIVE: We aimed to examine the association of GI and GL with food and nutrient intake and with metabolic risk factors including blood glucose, insulin, lipids, and high-sensitivity C-reactive protein (CRP). DESIGN: The study entailed cross-sectional analyses of data from 2 joint observational studies, the CoDAM Study and the Hoorn Study. RESULTS: In total, 974 subjects aged 42-87 y were included in the study. The mean (±SD) GI was 57 ± 4 and the mean GL was 130 ± 39. Dairy products, potatoes and other tubers, cereal products, and fruit were the main predictive food groups for GI. GL was closely correlated with intake of total carbohydrates (rs = 0.97), which explained >95% of the variation in GL. After adjustment for potential confounders, GI was significantly inversely associated with HDL cholesterol and positively associated with fasting insulin, the homeostasis model assessment index of insulin resistance, the ratio of total to HDL cholesterol, and CRP. No association was observed between GL and any of the metabolic risk factors, except for a borderline significant positive association with CRP. CONCLUSIONS: In this population, a low-GI diet, which is high in dairy and fruit but low in potatoes and cereals, is associated with improved insulin sensitivity and lipid metabolism and reduced chronic inflammation. GL is highly correlated with carbohydrate intake and is not clearly associated with the investigated metabolic risk factors.
Aims/hypothesis
The hyperglycaemic clamp technique and the frequently sampled IVGTT are unsuitable techniques to assess beta cell function (BCF) in large cohorts. Therefore, the aim of this study was ...to evaluate the discriminatory ability of simple OGTT-based BCF indices for prediction of prediabetes (meaning impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes.
Methods
Glucose metabolism status was assessed by 2 h 75 g OGTT at baseline (
n
= 476, mean age 59.2 years, 38.7% women) and after 7 years of follow-up (
n
= 416) in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (1999–2009). Baseline plasma glucose, insulin and C-peptide values during OGTTs were used to calculate 21 simple indices of BCF. Disposition indices (BCF index × Matsuda index), to compensate for the prevailing level of insulin resistance, were calculated for the BCF indices with the best discriminatory abilities. The discriminatory ability of the BCF indices was estimated by the area under the receiver operating characteristics curve (ROC AUC) with an outcome of incident prediabetes (
n
= 73) or type 2 diabetes (
n
= 60 and
n
= 18 cases, respectively, in individuals who were non-diabetic or had normal glucose metabolism at baseline).
Results
For incident prediabetes (
n
= 73), all ROC AUCs were less than 70%, whereas for incident type 2 diabetes, I
30
/I
0
, CP
30
/CP
0
, ΔI
30
/ΔG
30
, ΔCP
30
/ΔG
30
(where I, CP and G are the plasma concentrations of insulin, C-peptide and glucose, respectively, at the times indicated), and corrected insulin response at 30 min had ROC AUCs over 70%. In at-baseline non-diabetic individuals, disposition indices ΔI
30
/ΔG
30
, ΔCP
30
/ΔG
30
and corrected insulin response at 30 min had ROC AUCs of over 80% for incident type 2 diabetes. Moreover, these BCF disposition indices had significantly better discriminatory abilities for incident type 2 diabetes than the Matsuda index alone.
Conclusions/interpretation
BCF indices reflecting early-phase insulin secretion have the best ability to discriminate individuals who will develop prediabetes and type 2 diabetes. Of these, ΔCP
30
/ΔG
30
, often referred to as the C-peptidogenic index, performed consistently well.
Immune dysregulation can affect insulin resistance (IR) and β-cell function and hence contribute to development of type 2 diabetes mellitus (T2DM). The complement system, as a regulator of immune and ...inflammatory homeostasis, may be a relevant contributor therein. However, longitudinal studies focusing on complement as a determinant of T2DM and IR are scarce. Therefore, we prospectively investigated the association of plasma complement factor 3 (C3) with (estimates of) IR in muscle, liver, and adipocytes, as well as with glucose tolerance, including incident T2DM.
Fasting C3, nonesterified fatty acids, glucose, and insulin (the latter two during oral glucose tolerance tests) were measured at baseline (n = 545) and after 7 years of follow-up (n = 394) in a prospective cohort study.
Over the 7-year period, C3 levels (per 0.1 g/L) were longitudinally associated with higher homeostasis model assessment of IR (HOMA2-IR; β = 15.2% 95% CI 12.9-17.6), hepatic IR (β = 6.1% 95% CI 4.7-7.4), adipocyte IR (β = 16.0% 95% CI 13.0-19.1), fasting glucose (β = 1.8% 95% CI 1.2-2.4), 2-h glucose (β = 5.2% 95% CI 3.7-6.7), and area under the curve for glucose (β = 3.6% 95% CI 2.7-4.6). In addition, greater changes in C3 (per 0.1 g/L) were associated with greater changes in HOMA2-IR (β = 0.08 95% CI 0.02-0.15) and greater changes in hepatic IR (β = 0.87 95% CI 0.12-1.61) over 7 years, but not glucose tolerance. Moreover, baseline C3 was associated with the 7-year incidence of T2DM (odds ratio 1.5 95% CI 1.1-2.0).
Changes in C3 were associated with changes in several measures of IR and may reflect progression of metabolic dysregulation, which eventually leads to abnormalities in glucose tolerance and T2DM.
Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in ...DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals.
This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism.
Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.
Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore ...whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks.
We perform a functional genomics analysis on four epigenetic clocks, including Hannum's blood predictor and Horvath's multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells.
The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes.
Aims
There are sex differences in the excess risk of diabetes‐associated cardiovascular disease. However, it is not clear whether these sex differences exist with regard to other complications like ...mental health aspects. Therefore, we investigated sex differences in the association of prediabetes and type 2 diabetes (T2D) with cognitive function, depression, and quality of life (QoL).
Materials and Methods
In a population‐based cross‐sectional cohort study (n = 7639; age 40–75 years, 50% women, 25% T2D), we estimated sex‐specific associations, and differences therein, of prediabetes and T2D (reference: normal glucose metabolism) with measures of cognitive function, depression, and physical and mental QoL. Sex differences were analysed using multiple regression models with interaction terms.
Results
In general, T2D, but not prediabetes, was associated with higher odds of cognitive impairment, major depressive disorder, and poorer QoL. The odds ratio (OR) of cognitive impairment associated with T2D was 1.29 (95% CI: 0.96–1.72) for women and 1.39 (1.10–1.75) for men. The OR of major depressive disorder associated with T2D was 1.19 (0.69–2.04) for women and 1.68 (1.02–2.75) for men. The mean difference of the physical QoL score (ranging from 0 to 100, with 100 indicating the best possible QoL) associated with T2D was −2.09 (−2.92 to −1.25) for women and −1.81 (−2.48 to −1.13) for men. The mean difference of the mental QoL score associated with T2D was −0.90 (−1.79 to −0.02) for women and −0.52 (−1.23 to 0.20) for men. There was no clear pattern of sex differences in the associations of either prediabetes or T2D with measures of cognitive function, depression, or QoL.
Conclusions
In general, T2D was associated with worse cognitive function, depression, and poorer QoL. The strength of these associations was similar among women and men.
Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron ...metabolism-related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin.
Serum ferritin, transferrin, total iron, non-transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers.
Serum ferritin (β = 1.00% increase in adipocyte IR per 10 μg/L 95% CI 0.66-1.34), transferrin (4.18% per 0.1 g/L 2.88-5.50), total iron (1.36% per μmol/L 0.61-2.12), and NTBI (5.14% per μmol/L 1.88-8.52) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P < 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P < 0.01).
The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM.
Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain ...further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes. The function and cell-specific expression pattern of these genes implies that triglycerides downregulate both cellular lipid metabolism and, unexpectedly, allergic response. Indeed, a Mendelian randomization approach based on GWAS summary statistics indicates that several of these genes, including interleukin-4 (IL4) and IgE receptors (FCER1A, MS4A2), affect the incidence of allergic diseases. Our findings highlight the interplay between triglycerides and immune cells in allergic disease.
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