Markers of cholesterol metabolism as biomarkers in predicting diabetes in the Finnish Diabetes Prevention Study.

BACKGROUND AND AIMS: We examined the effect of serum markers of cholesterol synthesis and absorption on the incidence of type 2 diabetes (T2D) in the randomized Finnish Diabetes Prevention Study (DPS). We also explored a possible interaction of ABCG8 rs4299376 on sterol levels and lifestyle intervention. METHODS AND RESULTS: We conducted a prospective cohort study including overweight, middle-aged people with impaired glucose tolerance at baseline who participated in the randomized DPS. The primary outcome of the DPS was the diagnosis of T2D based on repeated oral glucose tolerance tests (OGTTs). After active intervention (median of four years, 1994-2001), non-T2D participants were further followed until T2D diagnosis, dropout or the end of 2009. Of these, 340 participants who had ß-sitosterol, campesterol, lathosterol and desmosterol measured by gas chromatography-mass spectrometry during the active four-year follow-up and who were not using cholesterol lowering medications were analysed. Surrogate indexes of insulin sensitivity (IS) and secretion were calculated from an OGTT. In adjusted models, plant sterols during the four-year follow-up were associated with lower T2D incidence during the extended eight-year follow-up (HR for 1-SD change in ß-sitosterol and campesterol: 0.76 [0.63-0.92], and 0.81 [0.67-0.99], respectively). Lathosterol levels were associated with higher T2D incidence (HR: 1.35 [1.13-1.62]). These associations, though, were not independent of IS. There was an interaction between rs4299376 and study group on ß-sitosterol (p = 0.001) and campesterol (p = 0.004) levels during the follow-up. CONCLUSIONS: Markers of low absorption and high synthesis of cholesterol were associated with the risk of developing T2D, mostly ascribed to IS.

Associations of erythrocyte membrane fatty acids with the concentrations of C-reactive protein, interleukin 1 receptor antagonist and adiponectin in 1373 men.

Dietary and endogenous fatty acids could play a role in low-grade inflammation. In this cross-sectional study the proportions of erythrocyte membrane fatty acids (EMFA) and the concentrations of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra) and adiponectin were measured and their confounder-adjusted associations examined in 1373 randomly selected Finnish men aged 45-70 years participating in the population based Metsim study in Eastern Finland. The sum of n-6 EMFAs, without linoleic acid (LA), was positively associated with concentrations of CRP and IL-1Ra (r partial=0.139 and r partial=0.115, P<0.001). These associations were especially strong among lean men (waist circumference <94 cm; r partial=0.156 and r partial=0.189, P<0.001). Total n-3 EMFAs correlated inversely with concentrations of CRP (r partial=-0.098, P<0.001). Palmitoleic acid (16:1n-7) correlated positively with CRP (r partial=0.096, P<0.001). Cis-vaccenic acid (18:1n-7) was associated with high concentrations of adiponectin (r partial=0.139, P<0.001). In conclusion, n-6 EMFAs, except for LA, correlated positively with the inflammatory markers. Palmitoleic acid was associated with CRP, whereas, interestingly, its elongation product, cis-vaccenic acid, associated with anti-inflammatory adiponectin.

A diet high in fatty fish, bilberries and wholegrain products improves markers of endothelial function and inflammation in individuals with impaired glucose metabolism in a randomised controlled trial: the Sysdimet study.

AIMS/HYPOTHESIS: Low-grade inflammation and endothelial dysfunction may play a role in the pathogenesis of type 2 diabetes and cardiovascular disease. We evaluated whether a diet high in fatty fish, bilberries and wholegrain products (Healthy Diet) improves biomarkers reflecting inflammation and endothelial dysfunction in individuals with impaired glucose metabolism. METHODS: We recruited individuals with impaired glucose metabolism and features of the metabolic syndrome into a 12 week, parallel design, dietary intervention trial conducted at the Department of Clinical Nutrition, University of Eastern Finland (Kuopio, Finland). Randomisation was performed by matching according to sex and medians of age, BMI and fasting plasma glucose of the study population at screening. The primary endpoint in the present study was the change in plasma inflammatory markers and the measurements were performed blinded to group assignment. High-sensitivity (hs) C-reactive protein (CRP) and E-selectin responses were also analysed separately in participants not using statins (n = 76). RESULTS: Altogether, 131 individuals were assigned to either the Healthy Diet (n = 44), a whole-grain-enriched diet (WGED) (n = 42) or a control (n = 45) diet, and 104 participants (mean ± SD: age 59 ± 7 years; BMI 31.1 ± 3.5 kg/m(2)) who had completed the study, were analysed (Healthy Diet n = 36, WGED n = 34 and control diet n = 34). Plasma E-selectin decreased only in the Healthy Diet group. This occurred in all group participants (p < 0.05) and also after excluding participants using statins (p < 0.05). Plasma hsCRP levels decreased in the Healthy Diet (median -17%, p < 0.05) and WGED (median -27%, p < 0.01) groups in participants not using statins. Controlling for confounding factors, including BMI or insulin sensitivity, did not alter the results. A greater increase in plasma concentration of very-long-chain n-3 fatty acids and in the intake of fibre during the study was associated with a greater decrease in plasma E-selectin (p < 0.05). The intake of test breads consumed during the Healthy Diet and WGED interventions was inversely associated with the change in hsCRP levels (p < 0.001). CONCLUSIONS/INTERPRETATION: Our results suggest that the combined effect of fatty fish, bilberries and wholegrain products may improve endothelial dysfunction and inflammation in overweight and obese individuals at high risk of developing diabetes.

Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease.

AIMS/HYPOTHESIS: Ceramides and IL-6 have a role in immune-inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-alpha and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD. METHODS: Cross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index). RESULTS: Serum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-alpha or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-alpha or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-alpha had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001). CONCLUSIONS/INTERPRETATION: Our results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.

Downregulation of genes involved in NFkappaB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study.

AIMS/HYPOTHESIS: The transcription factor nuclear factor-kappa-B (NFkappaB) is implicated in inflammatory responses, obesity and the metabolic syndrome, while immune cells appear to play a central role in mediating insulin resistance and can be used as a model to study inflammation and its relationship with insulin resistance. In peripheral blood mononuclear cells of overweight participants with the metabolic syndrome, we evaluated (1) the effect of diet-induced weight loss on the expression of genes involved in NFkappaB activation and (2) their association with insulin sensitivity. The genes studied were: TNF receptors TNFRSF1A and TNFRSF1B, and IL1R1, TLR4, TLR2, ICAM1, CCL5 and IKBKB. METHODS: We analysed data from 34 overweight participants with abnormal glucose metabolism and the metabolic syndrome, who were randomised to a weight-reduction (n = 24) or control group (n = 10) for 33 weeks. The mRNA expression was measured using real-time PCR. Measures of insulin and glucose homeostasis were assessed by IVGTT and OGTT. RESULTS: In general, the genes studied were downregulated after weight loss intervention. The changes in TLR4, TLR2, CCL5 and TNFRSF1A mRNA expression were associated with an increase in insulin sensitivity index independently of the change in waist circumference (p < 0.05). The change in IKBKB expression correlated with most of the changes in gene expression in the weight-reduction group. CONCLUSIONS/INTERPRETATION: These results suggest that proteins encoded by CCL5, TLR2 and TLR4, and TNFRSF1A might contribute to insulin-resistant states that characterise obesity and the metabolic syndrome. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00621205.